MEHANIZMI REGULACIJE KRVNOG PRITISKA

MEHANIZMI REGULACIJE KRVNOG PRITISKA
When faced with a patient who appears seriously ill, clinicians focus their immediate attention on the patient’s vital signs: temperature, respiratory rate, pulse, and blood pressure. These parameters are aptly named vital because they reflect the most fundamental aspects of health and even survival; a significant abnormality in any of these components indicates that emergent care is required. Blood pressure is a critical hemodynamic factor and one that is easily measured. An adequate blood pressure is necessary for proper organ perfusion. Too low, and we say that the patient is in shock. Too high, and we say that the patient is hypertensive; an acute and profound elevation of the blood pressure can be just as dangerous as one that suddenly plummets. Here, we examine both the short- and long-term mechanisms that the body uses to regulate arterial blood pressure. Neural reflexes mediate the short-term regulation of mean arterial blood pressure. A dual system of sensors and neural reflexes controls mean arterial pressure. The primary sensors are baroreceptors, which are actually stretch receptors or mechanoreceptors that detect distention of the vascular walls. The secondary sensors are chemoreceptors that detect changes in blood PO2, PCO2 and pH. The control centers are located within the CNS, mostly in the medulla, but sites within the cerebral cortex and hypothalamus also exert control. The effectors include the pacemaker and muscle cells in the heart, the vascular smooth muscle cells (VSMCs) in arteries and veins, and the adrenal medulla. We all know from common experience that the CNS influences the circulation. Emotional stress can cause blushing of the skin or an increase in heart rate. Pain—or the stress of your first day in a gross anatomy laboratory—can elicit fainting because of a profound, generalized vasodilation and a decrease in heart rate (ibradycardia). Early physiologists, such as Claude Bernard, observed that stimulation of peripheral sympathetic nerves causes vasoconstriction and that interruption of the spinal cord in the lower cervical region drastically reduces blood pressure (produces hypotension). However, the first idea that a reflexmight be involved in regulating the cardiovascular system came from experiments in which stimulation of a particular sensory (afferent) nerve caused a change in heart rate and blood pressure. In 1866, E. de Cyon and Carl Ludwig studied the depressor nerve, a branch of the vagus nerve. After they transected this nerve, they found that stimulation of the central (icranial) end of the cut nerve slows down the heart and produces hypotension. Hering showed that stimulation of the central end of another cut nerve—the sinus nerve (nerve of Hering), which innervates the carotid sinus—also causes bradycardia and hypotension. These two experiments strongly suggested that the depressor and sinus nerves carry sensory information to the brain and that the brain in some fashion uses this information to control cardiovascular function. Corneille Heymans was the first to demonstrate that pressure receptors—called baroreceptors—are located in arteries and are part of a neural feedback mechanism that regulates mean arterial pressure. He found that injection of epineph-rine—also known as adrenalin into a dog raises blood pressure and, later, lowers heart rate. Heymans hypothesized that increased blood pressure stimulates arterial sensors, which send a neural signal to the brain, and that the brain in turn transmits a neural signal to the heart, resulting in bradycardia.

KRVNI PRITISAK Pritisak koji krv vrši na zidove krvnih sudova
kroz koje protiče (arterijski, kapilarni i venski). Arterijski krvni pritisak: sistolni (SP) i dijastolni (DP) Blood pressure (BP) is the pressure pressure of circulating blood on the walls of blood vessels. When used without further specification, "blood pressure" usually refers to the pressure in large arteries of the systemic circulation. Blood pressure is usually expressed in terms of the systolic pressure over diastolic pressure and is measured in millimeters of mercury (mmHg). The heart is a pump of the “two-stroke” variety, with a filling and an emptying phase. Because both the left and right sides of the heart perform their work in a cyclic fashion, flow is pulsatile in both the systemic and pulmonary circulations.The mean blood pressure in the large systemic arteries is ∼95 mm Hg. This is a single, time-averaged value. In reality, the blood pressure cycles between a maximal systolic arterial pressure (∼120 mm Hg) that corresponds to the contraction of the ventricle and a minimal diastolic arterial pressure (∼80 mm Hg) that corresponds to the relaxation of the ventricle. The difference between the systolic pressure and the diastolic pressure is pulse pressure. Blood pressure is always measured as a pressure difference between two points. Physicists measure pressure in the units of pascals, g/cm2, or dynes/cm2. However, physiologists most often gauge blood pressure by the height it can drive a column of liquid. Physiologists usually express this pressure in millimeters of mercury (mm Hg) or centimeters of water (cm H2O). Clinicians use the classical blood pressure gauge (sphygmomanometer) to report arterial blood pressure in millimeters of mercury.

Visina arterijskog pritiska zavisi od: 1. udarnog volumena leve komore
Poiseuille-Hagenova jednačina Visina arterijskog pritiska zavisi od: 1. udarnog volumena leve komore 2. periferne vaskularne rezistencije – otpora protoku krvi 3. osmolarnosti i zapremine vanćelijskih tečnosti 4. uzrasta - povećava se starenjem (70mmHg-95mmHg-130mmHg) 5. elastičnosti arterija 6. vazoaktivnih materija Blood pressure is influenced by cardiac output, total peripheral resistance and arterial stiffness and varies depending on situation, emotional state, activity and relative health/disease states. In the short term it is regulated by baroreceptors which act via the brain to influence nervous and endocrine systems. Total blood flow, or cardiac output, is the product (heart rate) x (stroke volume). The flow of blood delivered by the heart, or the total mean flow in the circulation, is the cardiac output (CO). The output during a single heartbeat, from either the left or the right ventricle, is the stroke volume (SV). The cardiac output is usually expressed in liters per minute; at rest, it is about 5 L/min in a 70-kg human. Cardiac output depends on body size and is best normalized to body surface area. The cardiac index (L/min/m2) is the cardiac output per square meter of body surface area. The normal adult cardiac index at rest is about 3.0 L/min/m2 According to the Poiseuille-Hagen equation, flow (Q) is directly proportional to the axial pressure difference, ΔP. The proportionality constant—(πr4)/(8ηL)—is the reciprocal of resistance (R). Flow is directly proportional to the fourth power of vessel radius, and is inversely proportional to both the length of the vessel and the viscosity of the fluid. Aging reduces the distensibility of arteries With aging, important changes occur in the elastic properties of blood vessels, primarily arteries. The compliance of the aorta first rises during growth and development to early adulthood and then falls during later life. After early adulthood, two unfavorable changes occur. First, arteriosclerotic changes reduce the vesel’s compliance per se. Thus, during ventricular ejection, a normal-sized increase in aortic volume in a young adult produces a relatively small pulse pressure in the aorta. In contrast, the same change in aortic volume in an elderly individual produces a much larger pulse pressure. Second, the elastic properties of blood vessels decrease with age, because of the progressive, diffuse fibrosis of vessel walls and because of an increase in the amount of collagen. The same degree of stretch recruits a larger number of collagen fibers. Underlying this phenomenon is an increased cross-linking among collagen fibers and thus less slack in their connections to other elements in the arterial wall. Thus, even modest elongations challenge the stiffer collagen fibers to stretch. Vascular resistance varies in time and depends critically on the action of vascular smooth muscle cells. The major site of control of vascular resistance in the systemic circulation is the terminal small arteries and arterioles.Because muscular arteries have a rather stable resistance, they are sometimes referred to as resistance vessels Blood pressure is regulated by baroreceptors The sensor component consists of a set of mechanoreceptors located at strategic high-pressure sites within the cardiovascular system. The cardiovascular system also has low-pressure sensors that detect changes in venous pressure. The two most important high-pressure loci are the carotid sinus and the aortic arch. Stretching of the vessel walls at either of these sites causes vasodilation and bradycardia. The carotid sinus is a very distensible portion of the wall of the internal carotid artery, located just above the branching of the common carotid artery into the external and internal carotid arteries. The arterial wall at the carotid sinus contains thin lamellae of elastic fibers but very little collagen or smooth muscle. The aortic arch is also a highly compliant portion of the arterial tree that distends during each left ventricular ejection. The baroreceptors in both the carotid sinus and the aortic arch are the branched and varicose (or coiled) terminals of myelinated and unmyelinated sensory nerve fibers, which are intermeshed within the elastic layers. The terminals express several nonselective cation channels in the TRP family: TRPC1, TRPC3, TRPC4, and TRPC5. TRPC channels may play a role both as primary electromechanical transducers and as modulators of transduction. An increase in the transmural pressure difference enlarges the vessel and thereby deforms the receptors. Baroreceptors are not really pressure sensitive but stretch sensitive. Indeed, TRPC1 is stretch sensitive. Direct stretching of the receptors results in increased firing of the baroreceptor’s sensory nerve. The difference between stretch sensitivity and pressure sensitivity becomes apparent when one prevents the expansion of the vessel by surrounding the arterial wall with a plaster cast. When this is done, increase of the transmural pressure fails to increase the firing rate of the baroreceptor nerve. Removal of the cast restores the response. Other tissues surrounding the receptors act as a sort of mechanical filter, although much less so than the plaster cast. USA (2011): svakih 39s smrt od KVB -Hipertenzija glavni faktor rizika- 33,5% amerikanaca (~100 miliona) starijih od 20 god su hipertoničari Još uvek nepoznat tačan razlog nastanka esencijalne hipertenzije

SA AV miokard komora 1. SNAGA I FREKVENCIJA SRČANIH KONTRAKCIJA
parasimpatička inervacija simpatička inervacija The cardiovascular system uses several effector organs to control systemic arterial pressure: the heart, arteries, veins and adrenal medulla. Sympathetic Input to the Heart (Cardiac Nerves) The sympathetic division of the autonomic nervous system influences the heart through the cardiac nerves, which form a plexus near the heart. The postganglionic fibers, which release norepinephrine, innervate the SA node, atria and ventricles. Their effect is to increase both heart rate and contractility. Because it dominates the innervation of the SA node (which is in the right atrium), sympathetic input from the right cardiac nerve has more effect on the heart rate than does input from the left cardiac nerve. On the other hand, sympathetic input from the left cardiac nerve has more effect on contractility. In general, the cardiac nerves do not exert a strong tonic cardioacceleratory activity on the heart. At rest, their firing rate is less than that of the vagus nerve. Parasympathetic Input to the Heart (Vagus Nerve) The vagus normally exerts an intense tonic, parasympathetic activity on the heart through Ach released by the postganglionic fibers. Severing of the vagus nerve or administration of atropine (which blocks the action of ACh) increases heart rate. Indeed, experiments on the effects of the vagus on the heart led to the discovery of the first neurohumoral transmitter, ACh. Vagal stimulation decrease heart rate by its effect on pacemaker activity. Just as the actions of the right and left cardiac nerves are somewhat different, the right vagus is a more effective inhibitor of the SA node than the left. The left vagus is a more effective inhibitor of conduction through the AV node. Vagal stimulation, to some extent, also reduces cardiac contractility. Adrenal Medulla Some preganglionic sympathetic fibers in the sympathetic splanchnic nerves also innervate the chromaffin cells in the adrenal medulla. Therefore, the adrenal medulla is the equivalent of a sympathetic ganglion. The synaptic terminals of the preganglionic fibers release ACh, which acts on nAChRs of the chromaffin cells of the adrenal medulla. Chromaffin cells are thus modified postganglionic neurons that release their transmitters—epinephrine and, to a far lesser degree, norepinephrine—into the bloodstream rather than onto a specific end organ. Thus, the adrenal medulla participates as a global effector that through its release of epinephrine causes generalized effects on the circulation. The epinephrine released by the adrenal medulla acts on both the heart and the blood vessels and thereby contributes to the control of the systemic arterial pressure. SA srž nadbubrežne žlezde AV miokard pretkomora svuda miokard komora

negativno hronotropni negativno inotropni negativno batmotropni
MIRAN “VAGUSNI” TONUS nc.ambiguus vagii rami cardiaci acetilholin K+ SA čvor plexus cardiaci K+ kanal muskarinski M2 receptori Cholinergic Receptors in the Heart Parasympathetic output to the heart affects heart rate and, to a much lesser extent, contractility. ACh released by postsynaptic parasympathetic neurons binds to M2 muscarinic, G protein coupled, receptors on pacemaker cells of the SA node and on ventricular myocytes. In pacemaker cells, ACh acts by three mechanisms. ACh triggers a membrane-delimited signaling pathway mediated not by the G protein α subunits but rather by the βγ heterodimers. The newly released βγ subunits directly open inward rectifier K+ channels (GIRK1 or Kir3.1) in pacemaker cells. The resulting elevation of the K+ conductance makes the maximum diastolic potential more negative during phase 4 of the action potential. (2) ACh also decreases If, thereby reducing the rate of diastolic depolarization. (3) ACh decreases ICa, thereby both reducing the rate of diastolic depolarization and making the threshold more positive. The net effect is a reduction in heart rate. In myocardial cells, ACh has a minor negative inotropic effect, which could occur by two mechanisms. Activation of the M2 receptor, through Gαi, inhibits adenylyl cyclase, reducing [cAMP]i, thereby counteracting the effects of adrenergic stimulation. (2) Activation of the M3 receptor, through Gαq, stimulates phospholipase C, raising [Ca2+]i and thus stimulating nitric oxide synthase. The newly formed NO stimulates guanylyl cyclase and increases [cGMP]i, which somehow inhibits L-type Ca2+ channels and decreases Ca2+ influx. odvajanje αGTP od βγ desni otvaranje GIRK (Kir3) kanala negativno hronotropni negativno inotropni negativno batmotropni negativno dromotropni efekat levi HIPER polarizacija ~70 otk/min

SA STIMULACIJA SIMPATIKUSA pozitivno hronotropni pozitivno inotropni
pozitivno batmotropni pozitivno dromotropni efekat /min (250/min) SA miokard komora Adrenergic Receptors in the Heart The sympathetic output to the heart affects both heart rate and contractility. Norepinephrine, released by the postganglionic sympathetic neurons, acts on postsynaptic β1-adrenergic receptors of pacemaker cells in the SA node as well as on similar receptors of myocardial cells in the atria and ventricles. The β1 adrenoceptor, through the G protein Gs, acts through the cAMP–protein kinase A pathway to phosphorylate multiple effector molecules in both pacemaker cells and cardiac myocytes. In pacemaker cells, β1 agonists stimulate: If, the diastolic Na+ current, through HCN4 channels and (2) ICa, a Ca2+ current, through T- and L-type Ca2+ channels. The net effect of these two changes is an increased rate of diastolic depolarization and a negative shift in the threshold for the action potential. Because diastole shortens, the heart rate increases. The If (funny current) is highly expressed in the sinoatrial node, the atrio-ventricular node and the Purkinje fibres of conduction tissue. Particularly unusual, the funny current is a mixed sodium-potassium current, inward and slowly activating on hyperpolarization at voltages in the diastolic range (normally from -60/-70 mV to -40 mV). When at the end of a sinoatrial action potential the membrane repolarizes below the If threshold (about -40/-50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD); by this mechanism, the If current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate. Another unusual feature of If is its dual activation by voltage and by cyclic nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind directly to HCN4 channels and increase their open probability. cAMP dependence is a particularly relevant physiological property, since it underlies the If –dependent autonomic regulation of heart rate. Sympathetic stimulation raises the level of cAMP molecules which bind to HCN channels and shift the If activation range to more positive voltages; this mechanism leads to an increase of the current at diastolic voltages and therefore to an increase of the steepness of DD and heart rate acceleration. Parasympathetic stimulation (which reduces cAMP) decreases the heart rate by the opposite action, that is by shifting the If activation curve towards more negative voltages In myocardial cells, β1 agonists exert several parallel positive inotropic effects through protein kinase A. In addition, the activated αs subunit of the G protein can directly activate L-type Ca2+ channels. The net effects of these pathways are contractions that are both stronger and briefer. NA dijastola se skraćuje, frekvencija povećava SA β1 cAMP HCN4 kanali zavisni od cikličnih nukleotida, koji se aktiviraju hiperpolarizacijom (If) T- kanali za Ca2+(ICa)

NORADRENALINA I ADRENALINA
INOTROPNI EFEKAT NORADRENALINA I ADRENALINA adrenalin noradrenalin β1 kardiomiocit AC fosforilacija L- Ca2+ kanala cAMP aktivacija PKA SARKOLEMA Positive Inotropic Agents Factors that increase myocardial contractility increase [Ca2+]i, either by opening Ca2+ channels, inhibiting Na-Ca exchange, or by inhibiting the Ca2+ pump—all at the plasma membrane. 1. Adrenergic agonists. Catecholamines (epinephrine, norepinephrine) act on β1 adrenoceptors to activate the α subunit of Gs-type heterotrimeric G proteins. The activated αs subunits produce effects by two pathways. First, αs raises intracellular levels of cyclic adenosine monophosphate (cAMP) and stimulates protein kinase A, which can then act to increase contractility and speed relaxation. Second, αs can directly open L-type Ca2+ channels in the plasma membrane, leading to an increased Ca2+ influx during action potentials, increased [Ca2+]i, and enhanced contractility In atrial and ventricular muscle, catecholamines cause an increase in the strength of contraction (positive inotropic effect) for four reasons. First, the increased Ica (Ca2+ influx) leads to a greater local increase in [Ca2+]i and also a greater Ca2+-induced Ca2+ release from the SR. Second, the catecholamines increase the sensitivity of the SR Ca2+ release channel to cytoplasmic Ca2+. Third, catecholamines also enhance Ca2+ pumping into the SR by stimulation of the SERCA Ca2+ pump, thereby increasing Ca2+ stores for later release. Fourth, the increased ICa presents more Ca2+ to SERCA, so that SR Ca2+stores increase over time. The four mechanisms make more Ca2+available to troponin C, enabling a more forceful contraction. T-tubula

Ca2+ DI/TRIADA KALSEKVESTRIN (CASQ2) sarkoplazmatski
(50 Ca2+-vezujućih mesta/proteinu) sarkoplazmatski retikulum T-tubula Ca-indukovano oslobađanje Ca2+ Ryr2 L- kanali za Ca2+ Ca2+ The L-type Ca2+ channels (Cav1.2, dihydropyridine receptors) in the T-tubule membrane activate the Ca2+ release channels made up of four RYR2 molecules in the sarcoplasmic reticulum (SR) membrane. In skeletal muscle, the linkage is mechanical and does not require Ca2+ entry per se. If you place skeletal muscle in a Ca2+ -free solution, the muscle can continue contracting until its intracellular Ca2+ stores become depleted. In contrast, cardiac muscle quickly stops beating. In cardiac muscle, Ca2+ entry through the L-type Ca2+ channel is essential for raising of [Ca2+ ]i in the vicinity of the RYR2 on the SR. A subset of Cav1.2 channels may be part of caveolae. This trigger Ca2+ activates an adjacent cluster of RYRs in concert, causing them to release Ca2+ locally into the cytoplasm (Ca2+ -induced Ca2+ release). Such single event of Ca2+-induced Ca2+ release can raise [Ca2+]i as high as 10 μM in microdomains of ∼1 μm in diameter. These localized increases in [Ca2+]i appear as calcium sparks when they are monitored with a Ca2+-sensitive dye by confocal microscopy. If many L-type Ca2+ channels open simultaneously, the spatial and temporal summation of many elementary Ca2+ sparks leads to a global increase in [Ca2+]i. sarkoplazmatski retikulum DI/TRIADA

Ca2+ Ca2+ 11nm ATPazna aktivnost afinitet za tropomiozin tropomiozin
mesto vezivanja miozinske glavice afinitet za tropomiozin tropomiozin aktin afinitet za aktin afinitet za Ca2+ kompleks troponina ADP miozin Ca2+ Ca2+ After [Ca2+]i increases, Ca2+ binds to the cardiac isoform of troponin C (TNNC1), and the Ca2+-TNNC1 complex releases the inhibition of the cardiac isoform of troponin I (TNNI3) on actin. As a result, the tropomyosin (TPM1) fiaments bound to cardiac troponin T (TNNT2) on the thin filament shift out of the way, allowing myosin to interact with active sites on the actin. ATP fuels the subsequent cross-bridge cycling. Because the heart can never rest, cardiac myocytes have a very high density of mitochondria and thus are capable of sustaining very high rates of oxidative phosphorylation (iATP synthesis) ATP ATPazna aktivnost 11nm

fosforilacije fosfolambana i I-1 ubrzavaju dijastolu
SISTOLA DIJASTOLA Ryr2 za koji veliki afinitet ima rijanodin, otrov južnoameričke biljke Ryania speciosa ADR β1 fosforilacije fosfolambana i I-1 ubrzavaju dijastolu PKA P kalstabin2 fosfolamban P I-1 P P SERCA2A Ca Ca Calcium enters the cell via activated L-type Ca2+-channels. The resulting Ca2+ influx promotes intracellular Ca2+ release from subcellular stores in the sarcoplasmic reticulum (SR) by Ca2+-induced Ca2+ release, which greatly amplifies the initial signal. Ca2+-induced Ca2+ release occurs via specialized Ca2+-release channels, also called ryanodine receptors (RyRs) because of their initial identification via high-affinity binding of the toxin ryanodine. Ca2+ release occurs via unitary events called 'sparks', reflecting activation of clusters of RyRs. The RyR (the cardiac form is RyR2) constitutes part of a large macromolecular complex of key accessory proteins including calmodulin, calstabin 2 (FKBP12.6), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase (CaMKII) and protein phosphatases 1 (PP1). Calmodulin is a key Ca2+-binding protein that regulates the action of key intracellular enzymes such as the kinase CaMKII and the protein phosphatase. PKA and CaMKII are both stimulated by adrenergic activation and phosphorylate key intracellular regulatory proteins. Calstabin 2 binds to and stabilizes the open and closed states of the RyR. Resting Ca2+ concentrations are restored mainly through re-uptake of Ca2+ into the sarcoplasmic reticulum, by the Ca2+ -uptake pump SERCA2A, which is regulated by phospholamban (PLN). Ca2+ is also removed from the cell through the sarcolemmal Na-Ca exchanger (NCX1). The binding of β -adrenergic agonists to BARs results in the activation of PKA, which leads to the phosphorylation of the L-type Ca2+ channel, RYR2, PLN and sarcomere proteins ( troponin I). This process increases both cellular contraction and relaxation, through the delivery of more Ca2+ to the myofilaments (increasing contraction) and the improved re-uptake of Ca2+ by the sarcoplasmic reticulum and desensitization of the myofilaments to Ca2+ (increasing relaxation). In addition to Ca2+ entry through L-type Ca2+ channels, Ca2+ release through RYR2 is also modulated by the interaction of RYR2 with calstabin 2. Phosphorylation of phospholamban and of troponin I speeds cardiac muscle relaxation With the waning of the phase 2 plateau of the cardiac action potential, the influx of Ca2+ through L-type Ca2+channels decreases, lessening the release of Ca2+ by the SR. By itself, halting of Ca2+ entry and release can only prevent a further increase in [Ca2+]i. The actual relaxation of the contractile proteins depends on three processes: (1) extrusion of Ca2+ into the extracellular fluid, (2) re-uptake of Ca2+ from the cytosol by the SR, and (3) dissociation of Ca2+ from troponin C. The last two of these processes are highly regulated. Extrusion of Ca2+ into the Extracellular Fluid Even during the plateau of the action potential, the myocyte extrudes some Ca2+. After the membrane potential returns to more negative values, the extrusion processes gain the upper hand and [Ca2+]i falls. In the steady state (during the course of several action potentials), the cell must extrude all the Ca2+ that enters the cytosol from the extracellular fluid through L-type Ca2+ channels. As in most other cells, this extrusion of Ca2+ into the extracellular fluid occurs by two pathways: (1) a sarcolemmal Na-Ca exchanger (NCX1), which operates at relatively high levels of [Ca2+]i; and (2) a sarcolemmal Ca2+ pump (cardiac subtype 1, 2, and 4 of PMCA), which may function at even low levels of [Ca2+] However, PMCA contributes only modestly to relaxation. Re-uptake of Ca2+ by the SR Even during the plateau of the action potential, some of the Ca2+ accumulating in the cytoplasm is sequestered into the SR by the cardiac subtype of the Ca2+ pump SERCA2a. Phospholamban (PLN), an integral SR membrane protein with a single transmembrane segment, is an important regulator of SERCA2a. In SR membranes of cardiac muscle unphosphorylated PLN can exist as a homopentamer that may function in the SR as an ion channel or as a regulator of Cl− channels. The dissociation of the pentamer allows the hydrophilic cytoplasmic domain of PLN monomers to inhibit SERCA2a. However, phosphorylation of PLN by any of several kinases relieves phospholamban’s inhibition of SERCA2a, allowing Ca2+ resequestration to accelerate. The net effect of phosphorylation is an increase in the rate of cardiac muscle relaxation. Phosphorylation of PLN by PKA explains why β1-adrenergic agonists (epinephrine), which act through the PKA pathway speed up the relaxation of cardiac muscle. Dissociation of Ca2+ from Troponin C As [Ca2+]i falls, Ca2+ dissociates from troponin C, blocking actin-myosin interactions and causing relaxation. β1-Adrenergic agonists accelerate relaxation by promoting phosphorylation of troponin I, which in turn enhances the dissociation of Ca2+ from troponin Ci L kanali za Ca2+ Ryr2 za Ca2+ PP1 fosfolamban CaMKII CaM SERCA2A Ca cTnI Ca2+ disosuje P

CaMKII CaM P P NCX Ca2+ 3Na+ PKA Ca2+ PP2A Kalstabin 2 Ser PP1 Thr
Povećana aktivnost NCX depolarizacija, aritmija DAD (engl. Delayed After Depolarisation) L kanali za Ca2+ NCX Ca2+ Smanjeno preuzimanje Ca2+ u sarkoplazmatski retikulum Srčana insuficijencija usled hiperfosforilacije RyR2 od koga se odvaja kalstabin →kroz kanal curi Ca2+ 3Na+ PKA Ca2+ PP2A Protein fosfataza Kalstabin 2 Stabilizuje otvaranje RyR2 CaMKII CaM Ser PP1 Protein fosfataza POREMEĆAJ ODRŽAVANJA Ca2+ ♥ Kongestivna srčana insuficijencija ♥ Ishemična srčana bolest ♥ Hipertrofija miokarda ♥ Atrijalna fibrilacija ♥ Kateholaminska polimorfna ventrikularna tahikardija (CPVT) Thr Rijanodinski receptori RyR2 SERCA2A 2H+ P P Fosfolamban Fosfolamban 2Ca2+ In the failing heart, there is depressed PKA activity, reduced Ca2+ re-uptake by the sarcoplasmic reticulum, increased Ca2+ extrusion through the Na+/Ca2+ exchanger (NCX), and increased RYR2 phosphorylation and calstabin-2 dissociation. In addition, there is increased activation of Gq/11-protein-coupled receptor signalling, which in turn increases PKC- activity. PKC- then blocks activity of the phosphatase inhibitor I-1, thereby increasing the activation of the serine/threonine phosphatase PP1. This further reduces PLN phosphorylation and depresses both cellular contraction and relaxation, by preventing re-uptake of Ca2+ by the sarcoplasmic reticulum. Activation of Gq/11-protein-coupled receptors also increases the amount of InsP3 generated. InsP3 interacts with receptors (InsP3R) in the sarcoplasmic-reticulum membrane to stimulate Ca2+ release. InsP3 also enters the nucleus, where it interacts with InsP3R, leading to Ca2+-mediated activation of intranuclear CAMKII. This, in turn, activates PKD, resulting in the phosphorylation of HDAC and its subsequent nuclear export and thereby altering transcriptional regulation. Pools of intracellular Ca2+ also activate cytosolic calmodulin–CAMKII, resulting in the activation of NFAT. Activated NFAT then translocates to the nucleus, where it is involved in transcriptional regulation. Therefore, in the failing heart, normal calcium cycling becomes dysregulated by multiple abnormalities. SR Ca2+ stores are determined by the rate of SR Ca2+ uptake and the rate of Ca2+ release. Ca2+ uptake occurs via the SR Ca2+-ATP'ase, SERCA (cardiac form is SERCA2A). SERCA function is negatively regulated by phospholamban (PLB), but PLB phosphorylation removes this inhibitory influence. Diastolic Ca2+ leak from dysfunctional RyRs causes a loss of SR Ca2+, reducing contractility, but might still facilitate delayed after-depolarizations (DADs) by causing excess diastolic Ca2+ concentrations. In a seminal paper, Marx et al. suggested that in the failing heart RyR 'hyperphosphorylation' causes calstabin unbinding, increases RyR Ca2+ sensitivity and makes RyRs functionally 'leaky'. RyR phosphorylation can result from PKA action at a specific serine or CaMKII-induced threonine-phosphorylation. Abnormalities in intracellular Ca2+ handling occurs in conditions such as congestive heart failure, ischaemic heart disease, myocardial hypertrophy and atrial fibrillation, as well as in inherited arrhythmogenic diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT) in which obvious structural heart disease is absent. Spontaneous diastolic Ca2+ release triggers Na+, Ca2+ exchange (NCX), which mitigates Ca2+ loading by extruding Ca2+ in exchange for extracellular Na+. NCX carries three Na+-ions in for each single Ca2+ ion extruded, and therefore causes movement of one extra positive ion into the cell for each functional cycle. This excess movement of positive ions into the cell depolarizes the cell membrane, causing arrhythmic DADs. In addition, NCX activation by abnormal cellular Ca2+ handling is believed to potentially participate in early after-depolarizations formation.

α1 2. PERIFERNA VASKULARNA REZISTENCIJA 3. VAZOAKTIVNI AGENSI
noradrenalin (opšti vazokonstriktor) adrenalin (GIT, jetra, slezina) fosfatidilinozitol bifosfat α1 q protein kinaza C fosfolipaza C G protein Ca2+ inozitol trifosfat Ca2+ IP3- aktivirajući kanal za Ca2+ (InsP3R) KALRETIKULIN KALSEKVESTRIN Adrenergic Receptors in Blood Vessels The sympathetic division of the autonomic nervous system can modulate the tone of vascular smooth muscle in arteries, arterioles and veins through two distinct routes—post-ganglionic sympathetic neurons and the adrenal medulla. Whether the net effect of sympathetic stimulation in a particular vessel is vasoconstriction (increased VSMC tone) or vasodilation (decreased VSMC tone) depends on four factors: (1) which agonist is released, (2) which adrenoceptors that agonist binds to, (3) whether receptor occupancy tends to cause vasoconstriction or vasodilation, and (4) which receptor subtypes happen to be present on a particular VSMC. Postganglionic sympathetic neurons release norepinephrine, and the adrenal medulla releases primarily epinephrine. Norepinephrine and epinephrine do not have exclusive affinity for a single type of adrenoceptor. The original α and β designations followed from the observation that norepinephrine appeared to have its greatest activity on α receptors, and epinephrine, on β receptors. However, although norepinephrine binds with a greater affinity to α than to β receptors, it also can activate β receptors. Similarly, although epinephrine binds with a greater affinity to β receptors than to α receptors, it can also activate α receptors. Of course, synthetic agonists may be more specific and potent than either norepinephrine or epinephrine (the αagonist phenylephrine and βagonist isoproterenol). A finer pharmacological and molecular dissection reveals that both α and β receptors have subgroups (β1 and β2), and even the subgroups have subgroups. Each of these many adrenoceptor types has a unique pharmacology. Thus, the β1 receptor has about the same affinity for epinephrine and norepinephrine, but the β2 receptor has a higher affinity for epinephrine than for norepinephrine. The vasoconstriction elicited by catecholamines is an α effect, in particular, an α1 effect. Thus, norepinephrine released from nerve terminals acts on the α1 adrenoceptor, which is coupled to the G protein Gq. The resulting activation of phospholipase C and formation of inositol 1,4,5-trisphosphate (IP3) lead to a rise in [Ca2+]i and smooth muscle contraction. In contrast, vasodilation, elicited by epinephrine released from the adrenal medulla, is a β2 effect. Occupancy of the β2 adrenoceptor triggers the cAMP–protein kinase A pathway, leading to phosphorylation of myosin light chain kinase (MLCK), which reduces the sensitivity of MLCK to the Ca2+-calmodulin complex, resulting by default in smooth muscle relaxation. Which receptor subtypes happen to be present on a particular VSMC is a complex issue. Many blood vessels are populated with a mixture of α-receptor or β-receptor subtypes, each stimulated to varying degrees by norepinephrine and epinephrine. Therefore, the response of the cell depends on the relative dominance of the subtype of receptor present on the cell surface. Fortunately, the only two subtypes in blood vessels that matter clinically are α1 and β2. The ultimate outcome in the target tissue (vasoconstriction versus vasodilation) depends on both the heterogeneous mixture of agonists (norepinephrine versus epinephrine) applied and the heterogeneous mixture of VSMC receptors (α1 and β2) present in tissues. As an example, consider blood vessels in the skin and heart. Because cutaneous blood vessels have only α1receptors, they can only vasoconstrict, regardless of whether the agonist is norepinephrine or epinephrine. On the other hand, epinephrine causes coronary blood vessels to dilate because they have a greater number of β2 receptors than α1 receptor INTERMEDIATE AND LONG-TERM CONTROL OF THE CIRCULATION In addition to the rapidly acting neural mechanisms that control the total peripheral resistance and cardiac output, humoral controls contribute to the homeostasis of the circulation. In most instances, these control systems operate on a time scale of hours or days, far more slowly than the neurotransmitter-mediated reflex control by the CNS. Two classes of humoral controls influence the circulation. 1. Vasoactive substances released in the blood, or in the proximity of vascular smooth muscle, modulate the vasomotor tone of arteries and veins, affecting blood pressure and the distribution of blood flow. 2. Non-vasoactive substances, which act on targets other than the cardiovascular system, control the effective circulating volume by modulating extracellular fluid volume. By determining the filling of the blood vessels, these non-vasoactive agents also modulate the mean arterial pressure and cardiac output. Endocrine and paracrine vasoactive compounds control the circulatory system on an intermediate to long-term basis Vasoactive substances, both endocrine and paracrine, cause blood vessels to contract or to relax. In many instances, paracrine control dominates over endocrine control. The chemical messengers controlling the blood vessels can be amines, peptides, or proteins; derivatives of arachidonic acid; or gases such as NO. Biogenic Amines Monoamines may be either vasoconstrictors (epinephrine, nor and serotonin) or vasodilators (histamine). 1.Epinephrine.The source of this hormone is the adrenal medulla. Epinephrine binds to α1 receptors on VSMCs, causing vasoconstriction and to β2 receptors on VSMCs, causing vasodilation. Because β2 receptors are largely confined to the blood vessels of skeletal muscle, the heart, the liver and the adrenal medulla itself, epinephrine is not a systemic vasodilator. Epinephrine also binds to β1 receptors in the heart, thereby increasing the heart rate and contractility. For the cardiovascular system, the effects of catecholamines originating from the adrenal medulla are usually minor compared with those of the norepinephrine released from the sympathetic nerve endings. Adrenergic receptor, α1 Norepinephrine released from nerve terminals acts on the α1 adrenoceptor, which is coupled to the G protein Gq. The resulting activation of phospholipase C and formation of inositol 1,4,5-trisphosphate (IP3) lead to a rise in [Ca2+]i- The Ca2+ -calmodulin complex (Ca2+-CaM) activates myosin light chain kinase (MLCK), which in turn phosphorylates the regulatory myosin light chain (MLC) on each myosin head. Phosphorylation of MLC allows the myosin to interact with actin, producing contraction. Agonist (norepinephrine, epinephrine) → adrenoreceptor α1→↑Gαq/11→↑PLC →↑[IP3]i→ IP3 receptor in SR →↑Ca2+ release →↑[Ca2+ ]→Ca2+-CaM→activation of MLCK →↑phosphorylation of MLC→↑myosin-actin interaction→VASOCONSTRICTION glatki mišići nemaju T tubule i troponin Ca2+ fosforilacija regulatornog lakog lanca glavice miozina simpatička inervacija krvnih sudova srca, mišića, mozga, je manja u poređenju sa GIT, bubrezima, kožom, slezinom...  vezivanje za aktin kinaza lakog lanca miozina MLCK KALMODULIN

ANGIOTENZIN II angiotenzin II β1 jukstaglomerulne AT1A PIP2 DAG IP3
Ca2+ PIP2 AT1A DAG PLCβ IP3 β1 jukstaglomerulne ćelije PKC Ca2+ angiotenzin II8 IP3- aktivirajući kanal za Ca2+(InsP3R) PKC Ca2+ RENIN340 ACE kalretikulin angiotenzin I10 Ca-kalmodulin These data demonstrate that activation of the reninangiotensin system during Na depletion increases renal interstitial PGE2 and cGMP. The AT1 receptor mediates renal production of PGE2. The AT2 receptor mediates cGMP. AT2 blockade potentiates angiotensin-induced PGE2 production at the AT1 receptor. ANGIOTENSIN II (ANG II). Part of the renin-angiotensin-aldosterone cascade, ANG II, as its name implies, is a powerful vasoconstrictor. The liver secretes angiotensinogen into the blood. The enzyme renin, released into the blood by the kidney, then converts angiotensinogen to the decapeptide ANG I. Finally, angiotensin-converting enzyme (ACE), which is present primarily on endothelial cells, particularly those of the lung, cleaves ANG I to the octapeptide ANG II. Aminopeptidases further cleave it to the heptapeptide ANG III, which is somewhat less vasoactive than ANG II. In VSMCs, ANG II binds to G protein–coupled AT1A receptors, activating phospholipase C, raising [Ca2+]i and leading to vasoconstriction. However, ANG II is normally not present in plasma concentrations high enough to produce systemic vasoconstriction. In contrast, ANG II plays a major role in cardiovascular control during blood loss, exercise, and similar circumstances that reduce renal blood flow. Reduced perfusion pressure in the kidney causes the release of renin. Plasma ANG II levels rise, leading to an intense vasoconstriction in the splanchnic and renal circulations. The resulting reduced renal blood flow leads to even more renin release and higher ANG II levels, a dangerous positive feedback system that can lead to acute renal failure. A widely studied model of hypertension that demonstrates the importance of this mechanism is the Goldblatt model for hypertension. ANG II has a range of other effects—besides direct vasoactive effects—that indirectly increase mean arterial pressure: ANG II increases cardiac contractility; (2) reduces renal plasma flow, thereby enhancing Na+ reabsorption in the kidney; (3) ANG II and ANG III also stimulate the adrenal cortex to release aldosterone; (4) in the CNS, ANG II stimulates thirst and leads to the release of another vasoconstrictor, AVP; (5) ANG II facilitates the release of norepinephrine by postganglionic sympathetic nerve terminals; and (6) finally, ANG II also acts as a cardiac growth factor (cardiac hypertrophy) Angiotensin receptor, AT1 ANG II → AT1A receptor →Gαq/11→↑PLC →↑[IP3]i→ IP3 receptor in SR →↑Ca2+ release →↑[Ca2+ ]→Ca2+-CaM→activation of MLCK →↑phosphorylation of the regulatory myosin light chain (MLC) on each myosin head→↑myosin-actin interaction→VASOCONSTRICTION angiotenzinogen U fiziološkim uslovima nije prisutan u dovoljnim koncentracijama u krvi, ali se sintetiše u odgovoru na fizički napor, stres, hemoragiju i smanjen protok krvi kroz bubrege (renin). α2 globulin jetre RENIN ACE 40X potentniji vazokontriktor od NA

2- 3% Na+ se reapsorbuje pod kontrolom aldosterona
ANGIOTENZIN II ●prebacivanje holesterola u mitohondrije, ●aktivacija P450 SCC (side chain cleavage) enzima koji prevodi holesterol u pregnenolon, ●aktivacija aldosteron sintaze, koja konvertuje kortikosteron u aldosteron aldosteron kompleks hormon-receptor u jedru vezuje se za HRE promotora gena DAG, IP3→ Ca2+ MRC AT1 RC zone glomerulose aldosteron A MRC ENaCs angiotenzin II8 RENIN ACE angiotenzin I10 (3) ANG II also stimulates the adrenal cortex to release ALDOSTERONE The liver synthesizes and secretes a very large protein called angiotensinogen, which is an α2-globulin. Renin, which is synthesized by the granular cells (or juxtaglomerular cells) of the juxtaglomerular apparatus (JGA) in the kidney, is the enzyme that cleaves this angiotensinogen to form ANG I, a decapeptide. Finally, angiotensin-converting enzyme (ACE) cleaves the ANG I to form the octapeptide ANG II. ACE is present in the vascular endothelium of the lung (~40%) and elsewhere (~60%). In addition to its role as a potent secretagogue for aldosterone, ANG II exerts powerful vasoconstrictor actions on vascular smooth muscle. ANG II has a short half-life (<1 minute) because plasma aminopeptidases further cleave it to the heptapeptide ANG III. On the plasma membrane of the glomerulosa cell, ANG II binds to the AT1 receptor (type 1 ANG II receptor), which couples through the Gαq-mediated pathway to phospholipase C (PLC). Stimulation of PLC leads to the formation of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG activates protein kinase C (PKC). IP3 triggers the release of Ca2+ from intracellular stores, thus causing a rise in [Ca2+]i, which activates Ca2+-dependent enzymes such as PKC and Ca2+–calmodulin-dependent protein kinases. These changes lead to depolarization of the glomerulosa cell’s plasma membrane, opening of voltage-activated Ca2+channels, and a sustained increase in Ca2+influx from the extracellular space. This rise in [Ca2+]I is primarily responsible for triggering the synthesis and secretion of aldosterone. Aldosterone secretion increases because the rise in [Ca2+]I facilitates the production of pregnenolone either by directly increasing the activity of SCC or by enhancing the delivery of cholesterol to the SCC enzyme in the mitochondria. In addition, increased [Ca2+]I also stimulates aldosterone synthase and in this manner enhances the conversion of corticosterone to aldosterone. The glomerulosa cells of the adrenal cortex synthesize aldosterone from cholesterol, through progesterone. The adrenal cortex synthesizes aldosterone from cholesterol by using P-450 enzymes in a series of five steps. The initial steps in the synthesis of aldosterone from cholesterol follow the same synthetic pathway that cortisol-secreting cells use to generate progesterone. Because glomerulosa cells are the only ones that contain aldosterone synthase, these cells are the exclusive site of aldosterone synthesis. 1. The cytochrome P-450 SCC enzyme (P-450 SSC) produces pregnenolone from cholesterol. This enzyme—or the supply of substrate to it—appears to be the rate-limiting step for the overall process of steroid hormone synthesis. 2. The SER enzyme 3β-HSD, which is nota P-450 enzyme, oxidizes pregnenolone to form progesterone. 3. Because glomerulosa cells have minimal 17α-hydroxylase (P-450c17), they do not convert progesterone to 17α-hydroxyprogesterone. Instead, glomerulosa cells use a 21α-hydroxylase (P-450 c21) in the SER to hydroxylate the progesterone further at position 21 and to produce 11-deoxycorticosterone (DOC). 4. In the mitochondria, 11β-hydroxylase (P-450c11) adds an —OH at position 11 to produce corticosterone. This pair of hydroxylations in steps 3 and 4 are catalyzed by the same two enzymes that produce cortisol from 17α-hydroxyprogesterone. 5. The glomerulosa cells—but not the fasciculata and reticularis cells—also have aldosterone synthase (P-450aldo), which first adds an —OH group to the methyl at position 18 and then oxidizes this hydroxyl to an aldehydegroup, hence the name aldosterone. This mitochondrial P-450 enzyme, also called 18-methyloxidase, is an isoform of the same 11β-hydroxylase (P-450c11) that catalyzes the DOC-to-corticosterone step. In fact, aldosterone synthase can catalyze all three steps between DOC and aldosterone: 11β-hydroxylation, 18-methyl hydroxylation, and 18-methyl oxidation. Aldosterone—the final element in the renin-angiotensin-aldosterone axis—stimulates Na+ reabsorption by the initial tubule and the CCT, and by medullary collecting ducts. Normally, only 2% to 3% of the filtered Na+ load is under humoral control by aldosterone. Nevertheless, the sustained loss of even such a small fraction would exceed the daily Na+ intake significantly. Accordingly, the lack of aldosterone that occurs in adrenal insufficiency (Addison disease) can lead to severe Na+ depletion, contraction of the ECF volume, and circulatory insufficiency. Aldosterone acts on the principal cells of the collecting ducts by binding to cytoplasmic mineralocorticoid receptors (MRs) that then translocate to the nucleus and upregulate transcription. Thus, the effects of aldosterone require a few hours to manifest themselves because they depend on the increased production of aldosterone-induced proteins. One of these is SGK (serum- and glucocorticoid-regulated kinase), a key player in the early phase of aldosterone action. Early cellular actions of aldosterone action include upregulation of apical ENaCs, apical K+ channels, the basolateral Na-K pump and mitochondrial metabolism. The effects on ENaC involve an increase in the product of channel number and open probability, and thus apical Na+ permeability. The simultaneous activation of apical Na+ entry and basolateral Na+ extrusion ensures that, even with very high levels of Na+ reabsorption, [Na+]i and cell volume are stable. Long-term exposure to aldosterone leads to the targeting of newly synthesized Na-K pumps to the basolateral membrane. enzima→ATP angiotenzinogen Na/K ATPaze, za nekoliko sati. 2- 3% Na+ se reapsorbuje pod kontrolom aldosterona osnovne ćelije distalnih tubula i sabirnih kanalića α2 globulin jetre RENIN 4. OSMOLARNOST I ZAPREMINA VANĆELIJSKIH TEČNOSTI ACE

ANGIOTENZIN II ADH V1 Ca2+ Ca2+ KALMODULIN
Angiotenzin II u hipotalamusu stvara osećaj žeđi i stimuliše sintezu i sekreciju ADH tj. vazopresina q AQP2 ADH V2 egzocitoza fosforilacija Ser256 postojećih AQP2 AGREGOFORE vezikula Ca2+ SNARE_ Dinamin Rho, Rab, Ran fosforilacija proteina PKA ADH endocitoza aksoplazmatski transport sinteza AQP2 fosforiliše CRE vezujući protein (CREB) AQP3 cAMP responsivni elementi (CRE) apikalna membrana osnovnih ćelija bazolateralna membrana osnovnih ćelija drugog dela distalnih tubula sabirnih cevčica (4) ANG II stimulates thirst and leads to the release of ARGININE VASOPRESSIN (AVP) In the CNS, ANG II stimulates thirst and leads to the release of another vasoconstrictor arginine vasopressin (AVP). Large-bodied neurons in the paraventricular and supraoptic nuclei of the hypothalamus synthesize AVP, a nonapeptide also known as antidiuretic hormone. These neurons package the AVP and transport it along their axons to the posterior pituitary, where they release AVP through a breech in the blood-brain barrier into the systemic circulation. AVP has synergistic effects on two target organs. First, at rather high circulating levels, such as those seen in hypovolemic or hemorrhagics hock, AVP acts on vascular smooth muscle to cause vasoconstriction and thus to increase blood pressure. AVP binds to V1a receptors on VSMCs, causing vasoconstriction, but only at concentrations higher than those that are strongly antidiuretic. Vasoconstriction contributes to a transient restoration of arterial pressure. AVP receptor, V1aR or V1R AVP → V1a receptor →↑Gαq/11→↑PLC →↑[IP3]i→ IP3 receptor in SR →↑Ca2+ release →↑[Ca2+ ]→Ca2+-CaM→activation of MLCK →↑phosphorylation of MLC→↑myosin-actin interaction →VASOCONSTRICTION Second, and more importantly, AVP acts on the kidney, where it is the major regulator of water excretion. AVP increases water reabsorption by enhancing the water permeabilities of the collecting tubules and ducts. AVP dramatically increases the water permeabilities of the collecting tubules (ICT and CCT) and ducts (OMCD and IMCD) by causing AQP2 water channels to insert into the apical membrane. AVP binds to V2 receptors in the basolateral membrane of the principal cells from the ICT to the end of the nephron. Receptor binding activates the Gs heterotrimeric G protein, thus stimulating adenylyl cyclase to generate cAMP. The latter activates protein kinase A, which phosphorylates unknown proteins that play a role in the trafficking of intracellular vesicles containing AQP2 and the fusion of these vesicles with the apical membrane. These water channels are AVP sensitive, not in the sense that AVP modulates their single-channel water conductance, but rather in the context of their density in the apical membrane. In conditions of low AVP, AQP2 water channels are mainly in the membrane of intracellular vesicles just beneath the apical membrane. In the membrane of these vesicles, the AQP2 water channels are present as aggregophores—aggregates of AQP2 proteins. Under the influence of AVP, the vesicles containing AQP2 move to the apical membrane of principal cells of the collecting tubules and ducts. By exocytosis, these vesicles fuse with the apical membrane, thus increasing the density of AQP2. When AVP levels in the blood decline, endocytosis retrieves the water channel–containing aggregates from the apical membrane and shuttles them back to the cytoplasmic vesicle pool. In addition to the short-term effects, elevation of cAMP levels can activate the AQP2 transcription via PKA. Increases in [cAMP]i stimulate PKA by causing dissociation of the PKA regulatory subunit. The catalytic subunit of PKA then translocates into the nucleus, where it phosphorylates CREB and other proteins. Activation of CREB is rapid and its phosphorylation greatly increases the affinity of CREB for the coactivator CBP. One CBPdomain binds to phosphorylated CREB and another activates components of the basal transcriptional machinery. Ca2+ kinaza lakog lanca miozina MLCK KALMODULIN

presinaptički AT1 receptor
ANGIOTENZIN II postsinaptički α1 receptor postsinaptički AT1 receptor SNS neuron angiotenzin II presinaptički AT1 receptor noradrenalin krvni sud (+) (5) ANG II facilitates the release of NOREPINEPHRINE by postganglionic sympathetic nerve terminals There is growing evidence supporting the concept that angiotensin II can regulate the amount of norepinephrine released from peripheral sympathetic neurones. Animal studies indicate that it does this by stimulating angiotensin II ‘type 1’ (AT1) receptors located on the presynaptic nerve terminal of sympathetic neurones, and this triggers enhanced release of norepinephrine into the synapse. This is in addition to its effects on AT1 receptors located postsynaptically on blood vessels, which trigger its direct vasoconstrictor effects. DODATNA DEJSTVA ANGIOTENZINA II ● pozitivno inotropno i hronotropno dejstvo ● oslobađa NA i inhibira NA preuzimanje ● stimuliše oslobađanje KTHL srži nadbubrega ● stimuliše sintezu endotelina-1

ENDOTELINI ET1, ET2, ET3 (21AK)
snažni vazokonstriktori oslobađaju se iz endotelnih ćelija oštećenih krvnih sudova Prostaciklin NO ANP EGF Endotelna ćelija NOS pro-ET-1 NO Adrenalin Angiotenzin II ADH (osmolarnost) IL-1, TGF-β… prepro-ET-1 pro-ET-1 ETB ECE-1 ECE-1 ET-1 ETB ET-1 ETB NO ETA cGMP PLC PIP2 IP3 ENDOTHELINS (Ets: ET-1, ET-2, and ET-3) Endothelin-1 (ET-1) is a 21 amino acid peptide that is produced by the vascular endothelium during many acute and chronic pathological conditions, including hypoxia. It cause an extremely potent and long-lasting vasoconstriction in most VSMCs. ET1 binds to smooth muscle endothelin receptors, of which there are two subtypes: ETA and ETB, classic heptahelical G-protein-coupled receptors. The product of ET1 transcription is prepro-ET-1, which is cleaved by a neutral endopeptidase to form the active precursor pro-ET-1 or big ET-1. Big ET-1 is converted to the mature peptide by the metalloproteinase endothelin-converting enzyme-1 (ECE-1)1. Two ET receptors have been identified in the vasculature: ET type-A receptors (ETA) reside in vascular smooth muscle cells and mediate vasoconstriction and cell proliferation, whereas ETB receptors reside on endothelial cells and are mainly vasodilatory through NO (which in turn can mediate the anti-apoptotic effects of ET-1), and regulate the synthesis of ET-1. ETB receptors on smooth muscle cells can elicit vessel contraction. ETA receptors predominate in high-pressure parts of the circulation, whereas ETB receptors predominate in low-pressure parts of the circulation. ETA receptors are coupled to a Gq-protein, which activates phospholipase C (PLC) to cause hydrolysis of phosphatidylinositol and generation of cytosolic inositol trisphosphate (IP3) and membrane-bound diacylglycerol (DAG). IP3 causes the release of calcium by the sarcoplasmic reticulum (SR) and increased smooth muscle contraction and vasoconstriction. There are also ETB receptors located on the endothelium that stimulate the formation of nitric oxide, which produces vasodilation in the absence of smooth muscle ETA and ETB receptor activation. This receptor distribution helps to explain the phenomenon that ET-1 administration causes transient vasodilation (initial endothelial ETB activation) and hypotension, followed by prolong vasoconstriction (smooth muscle ETA and ETB activation) and hypertension. Endothelin receptor, ETA ET → endothelin receptor ETA→↑Gαq/11→↑PLC →↑[IP3]i→IP3 receptor in SR →↑Ca2+ release → ↑[Ca2+)i→Ca2+-CaM→activation of MLCK →↑phosphorylation of MLC→↑myosin-actin interaction → VASOCONSTRICTION ET-1 receptors in the heart are also linked to the Gq-protein and IP3 signal transduction pathway. Therefore, ET-1 in the heart causes SR release of calcium, which increases contractility. ET-1 also increases heart rate. KONSTRIKCIJA DILATACIJA Ca2+ ETB Ćelija glatkog mišića ETA Ćelija glatkog mišića KONSTRiKCIJA ET-1 povećava kontraktilnost i frekvenciju rada srca ET-1 uzrokuje tranzitornu dilataciju i hipotenziju, praćenu produženom vazokonstrikcijom i hipertenzijom

smanjena fosforilacija MLC smanjena aktivnost MLCK
ADRENALIN – vazokonstriktor(1) i vazodilatator (2) NORADRENALIN – opšti vazokonstriktor (1) smanjena fosforilacija MLC smanjena aktivnost MLCK fosforilacija kinaze lakog lanca miozina adrenalin β2 ćelije glatkih mišića krvnih sudova Biogenic Amines Monoamines may be either vasoconstrictors (epinephrine and serotonin) or vasodilators (epinephrine and histamine). The source of epinephrine is the adrenal medulla. This hormone binds to α1 receptors on VSMCs, causing vasoconstriction and to β2 receptors on VSMCs, causing vasodilation. Because β2 receptors are largely confined to the blood vessels of skeletal muscle, the heart, the liver and the adrenal medulla itself, epinephrine is not a systemic vasodilator. Epinephrine also binds to β1 receptors in the heart, thereby increasing the heart rate and contractility. For the cardiovascular system, the effects of catecholamines originating from the adrenal medulla are usually minor compared with those of the norepinephrine released from the sympathetic nerve endings. The binding of epinephrine to α1 receptors on VSMCs results in an increase in [Ca2+]i. The Ca2+ -calmodulin complex (Ca2+-CaM) activates myosin light chain kinase (MLCK), which in turn phosphorylates the regulatory myosin light chain (MLC) on each myosin head. Phosphorylation of MLC allows the myosin to interact with actin, producing contraction. Relaxation occurs when myosin light chain phosphatase dephosphorylates the MLC. In addition to changes in [Ca2+]i, changes in the activity of MLCK itself can modulate the contraction of VSMCs. Phosphorylation of MLCK by cAMP-dependent protein kinase (PKA) or cGMP-dependent protein kinase (PKG) inactivates the enzyme and thus prevents contraction. Adrenergic receptor, β2 Epinephrine→adrenoreceptor β2→↑Gαs→↑AC →↑[cAMP]i→↑PKA →↑phosphorylation of MLCK →inactivation of MLCK →↓phosphorylation of MLC→VASODILATATION Adrenergic receptor, α1 Agonist (norepinephrine, epinephrine) → adrenoreceptor α1→↑Gαq/11→↑PLC →↑[IP3]i→ IP3 receptor in SR →↑Ca2+ release →↑[Ca2+ ]→Ca2+-CaM→activation of MLCK →↑phosphorylation of MLC→↑myosin-actin interaction→VASOCONSTRICTION adenil ciklaza protein kinaza A krvni sudovi skeletnih mišića i srca

VAZOAKTIVNI INTESTINALNI POLIPEPTID
● hormon prisutan u svim tkivima kičmenjaka, naročito u nervnom i digestivnom sistemu; ● antagonizuje efekat vazokonstriktora smanjena fosforilacija MLC smanjena aktivnost MLCK VIPR2 vazodilatacija uzrokovana hiperpolarizacijom fosforilacija kinaze lakog lanca miozina VIP ćelije glatkih mišića krvnih sudova VIP ↓ otvaranje BK Ca2+ - AKTIVIRAJUĆIH i VOLTAŽNO ZAVISNIH KANALA za K+ Hiperpolarizacija zatvaranje voltažno zavisnih kanala za Ca2+ ↓[Ca2+] relaksacija glatkih mišićnih ćelija Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a neuropeptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus. VIP causes vasodilation and lowers arterial blood pressure. VIP receptor, VIPR1 and VIPR2 VIP → VIPR1 and VIPR2 receptors →↑Gαs→↑AC →↑[cAMP]i→↑PKA →↑phosphorylation of MLCK →↓MLCK →↓phosphorylation of MLC→VASODILATATION → both Ca2+-dependent (BK) and voltage-gated K+ channels open → hyperpolarization → Ca2+ channels close →↓[Ca2+]i→VASODILATATION adenil ciklaza protein kinaza A

smanjena fosforilacija MLC smanjena aktivnost MLCK
HISTAMIN smanjena fosforilacija MLC smanjena aktivnost MLCK H2 fosforilacija kinaze lakog lanca miozina HISTAMIN ćelije glatkih mišića krvnih sudova Histamine. Like serotonin, histamine may also be present in nerve terminals. In addition, mast cells release histamine in response to tissue injury and inflammation. Histamine binds to H2 receptors on VSMCs, causing vasodilation. Although histamine causes vascular smooth muscle to relax, it causes visceral smooth muscle (bronchial smooth muscle in asthma) to contract. Histamine receptor, H2 Histamine → H2 receptor →↑Gαs→↑AC →↑[cAMP]i→↑PKA →↑phosphorylation of MLCK →↓MLCK →↓phosphorylation of MLC→VASODILATATION adenil ciklaza protein kinaza A

PKG ćelija glatkog mišića krvnog suda endotelna ćelija
ACETILHOLIN smanjuje sintezu endotelina M3 IP3 NO GC Gαq PLC PKG cGMP Ca2+ kalmodulin ćelija glatkog mišića krvnog suda Cholinergic Receptors in or near Blood Vessels The addition of ACh to an isolated VSMC causes contraction. Thus, in an artificial situation in which the nerve terminals release only ACh and in which no other tissues are present, ACh would lead to vasoconstriction. In real life, however, ACh dilates blood vessels by binding to muscarinic receptors on neighboring cells and generating other messengers that indirectly cause vasodilation. For example, in skeletal muscle, ACh may bind to M2 receptors on the presynaptic membranes of postganglionic sympathetic neurons and inhibit the release of norepinephrine. Thus, inhibition of vasoconstriction produces vasodilation. In erectile tissue, Ach binds to M3 receptors on vascular endothelial cells and, through the phospholipase C pathway, releases IP3 and raises [Ca2+]I. The Ca2+ stimulates NOS to produce NO, which diffuses from the endothelial cell to the VSMC. Inside the VSMC, the NO activates soluble guanylyl cyclase, resulting in the production of cGMP and activation of protein kinase G. The subsequent phosphorylation of MLCK causes relaxation. Muscarinic receptor, M3 Acetylcholine→ M3 receptor on endothelial cell→↑Gαq/11→↑PLC →↑[Ca2+ ]i→↑eNOS →↑NO release→NO receptor, sGC (a soluble guanylyl cyclase)→↑[cGMP]i→↑PKG →↑phosphorylation of MLCK →↓MLCK activity →↓phosphorylation of MLC→VASODILATATION ↑PKG →↑ phosphorylation of SERCA2 in SR →↓[Ca2+]i→VASODILATATION In salivary glands, postganglionic parasympathetic neurons release ACh, which may stimulate gland cells to secrete kallikrein, an enzyme that cleaves kininogens to vasodilating kinins. A similar paracrine sequence of events may occur in the sweat glands of nonapical skin, where postganglionic sympathetic fibers release ACh, indirectly leading to local vasodilation. Nitric Oxide (NO) Originally called endothelium-derived relaxing factor, NO is a potent vasodilator. NO also inhibits platelet aggregation, induces platelet disaggregation and inhibits platelet adhesion. Bradykinin and acetylcholine both stimulate the NOS III (or eNOS) isoform of NO synthase that is constitutively present in endothelial cells. NOS III, which depends on both Ca2+ and calmodulin for its activity, catalyzes the formation of NO from arginine. NO, a lipophilic gas with a short half-life, diffuses locally outside the endothelial cell. Inside the VSMC is the “receptor” for NO, a soluble guanylyl cyclase that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP-dependent protein kinase (PKG) then phosphorylates MLCK and SERCA. Phosphorylation inhibits the MLCK, thus leading to a net decrease in the phosphorylation of MLC and a decrease in the interaction between myosin and actin. Phosphorylation activates SERCA, thereby decreasing [Ca2+]i. The net result is that NO released by endothelial cells relaxes VSMCs, producing vasodilation. Physicians have used exogenous organic nitrates (nitroglycerin) for decades to dilate peripheral vessels for relief of the pain of angina pectoris. These powerful vasodilators exert their activity by breaking down chemically, thereby releasing NO near VSMCs. eNOS endotelna ćelija NO 1998. god., Nobelova nagrada za fiziologiju ili medicinu: Robert Furchgott, Louis Ignarro, Ferid Murad NO, signalni molekul u kardiovaskularnom sistemu

ACETILHOLIN ACETILHOLIN vazodilatacija uzrokovana hiperpolarizacijom
Ca2+ Ca2+ Ca-kalmodulin CaMKβ NOS Endotelna ćelija NO EDHF (engl. Endothelium-derived hyperpolarizing factor ) = H2O2 NO EDHF otvaranje BK Ca2+- AKTIVIRAJUĆIH KANALA za K+ Guanil ciklaza Endothelium-Derived Hyperpolarizing Factor (EDHF) In addition to releasing NO, endothelial cells release another relaxing factor in response to acetylcholine, endothelium-derived hyperpolarizing factor (EDHF). Edwards et al. propose that BK Ca2+-dependent K+ channels in vascular smooth muscle cells open, leading to their hyperpolarization Thus, EDHF causes VSMC relaxation by making the membrane potential more negative. NO may predominate in large arteries, whereas EDHF takes over in smaller blood vessels or in large arteries when the release of NO is curtailed. Prostacyclin (PGI2) activates adenylate cyclase, leading to increased production of cyclic AMP (cAMP). Nitric oxide (NO) activates soluble guanylate cyclase, yielding increased levels of cyclic GMP (cGMP).. Glatka mišićna ćelija hiperpolarizacija cGMP vazodilatacija uzrokovana hiperpolarizacijom NO širi prevashodno velike arterije, dok EDHF širi manje arterije ili velike u nedostatku NO

BRADIKININ α2 globulin cGMP-zavisna L-Arg NO NO eNOS bradikinin B2
krv i tkiva nonapeptid, kinin plazme n min L-Arg NO NO lipofilan eNOS bradikinin B2 guanil ciklaza Ca-kalmodulin Kinins. At least three different kinins exist: (1) the nona-peptide bradykinin, which is formed in plasma; (2) the decapeptide lysyl-bradykinin, which is liberated from tissues; and (3) methionyl-lysyl bradykinin, which is present in the urine. These kinins are breakdown products of kininogens, catalyzed by kallikreins—enzymes that are present in plasma and in tissues such as the salivary glands, pancreas, sweat glands, intestine and kidney. Kallikreins form in the blood from the following cascade. Plasmin acts on clotting factor XII, releasing fragments with proteolytic activity. These factor XII fragments convert an inactive precursor, prekallikrein, to kallikreins. The kinins formed by the action of these kallikreins are eliminated by the kininases (kininase I and II). Kininase II is the same as angiotensin-converting enzyme. Thus, the same enzyme (ACE) that generates a vasoconstrictor (ANG II) also disposes of vasodilators (bradykinin). Bradykinin binds to B2 receptors on endothelial cells, causing release of NO and prostaglandins and thereby vasodilation. Like histamine, the kinins relax vascular smoot muscle but contract visceral smooth muscle. Probably, bradykinin can be involved in the formation of the eicosanoids from AA, which can act as local vasodilatators. Bradykinin B2 receptor Bradykinin→ B2R receptor on endothelial cell→↑Gαq/11→↑PLC →↑[Ca2+ ]i→↑eNOS →↑NO release→NO receptor, sGC→↑[cGMP]i→↑PKG →↑phosphorylation of MLCK →↓MLCK activity →↓phosphorylation of MLC→VASODILATATION ↑PKG →↑ phosphorylation of SERCA2 in SR →↓[Ca2+]i→VASODILATATION → ↑PLA2→↑PGI2 and PGE2 release→VASODILATATION Several distinct mechanisms have been proposed for the reduction in [Ca2+ ]i caused by PKG. Increased activity of the BK channels following PKG activation has been reported to induce membrane hyperpolarization, thereby decreasing the rate of Ca2+ entry into(VSMCs through voltage-dependent Ca2+ channels. → Ca2+-dependent (BK) K+ channels open → hyperpolarization → Ca2+ channels close →↓[Ca2+]i→VASODILATATION TRPC6 is a Ca2+-permeable channel regulated negatively by PKG-mediated phosphorylation in the NO/cGMP signaling pathway in heterologous systems and the rat vascular myocytes A7r5. Macroscopic and single-channel current recordings using patch clamp techniques have demonstrated that SNAP (100 μM)-induced inhibition of receptor-activated TRPC6 currents is abolished by pharmacological blockade of cGMP/PKG signaling with 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), 2,3,9,10,11,12-hexahydro-10R-methoxy-2,9-dimethyl-1-oxo-9S,12R-epoxy-1H-diindolo[1, 2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT5823) or membrane permeable PKG inhibitory peptide (DT3). It is also ablated by site-directed alanine mutation of a PKG phosphorylation site [threonine (Thr) 69] within the N-terminal cytoplasmic region of TRPC6. The critical involvement of Thr69 in PKG phosphorylation is confirmed by 32P-incorporation assays of wild-type and alanine-substitution mutant TRPC6 proteins. Similar NO/cGMP/PKG pathway-mediated negative regulation is also observed for TRPC6-like currents recorded in A7r5 VSMCs. Indeed, vasopressin-evoked membrane depolarization of these cells, which is expected secondarily to activate VDCCs, is significantly slowed and attenuated after application of SNAP (100 μM). The TRPC6 protein is abundantly expressed in various types of VSMCs and has been shown to be a constituent of vasoconstrictor-activated cation channels, which increase Ca2+ entry into VSMCs via direct Ca2+ permeation or secondary activation of a VDCC and/or Na+-Ca2+ exchanger. Thus, it is highly possible that, in a direct or indirect manner (i.e., via changes in membrane potential or an increase in intracellular Na+ concentration), PKG-mediated mechanisms may work as a universal negative feedback to regulate neurohormonal Ca2+ mobilization across the VSMC membrane. This mechanism may be physiologically important in vascular tissues where NO is constantly released from vascular endothelial cells or nitrergic nerves. GTP cGMP Ca2+  cGMP-zavisna protein kinaza kalmodulin  fosforiliše MLCK, SERCA

Inhibicija sekrecije renina
NATRIURETSKI PEPTIDI ATRIJUMSKI NATRIURETSKI PEPTID (ANP) NATRIURETSKI PEPTID MOZGA (BNP) NATRIURETSKI PEPTID ENDOTELNIH ĆELIJA (CNP) ANP ANP VĆD VĆD dimerizacija Inhibicija sekrecije renina SRCE povećanje zapremine кrvi DIUREZA NATRIUREZA NEUROHIPOFIZA guanil ciklazna aktivnost GTP Atrial natriuretic peptide (ANP) Atrial myocytes release ANP in response to stretch, caused by increased atrial pressure and thus effective circulating volume. This 28–amino acid peptide binds to ANP receptor A (NPR1) on VSMCs, which is membrane-bound guanylyl cyclase, causing vasodilation. The major effect of ANP is hemodynamic: it markedly vasodilates nephron arterioles, thereby increasing blood flow and lowers the sensitivity of the TGF mechanism. The net effect is an increase in glomerular filtration rate. ANP also affects renal hemodynamics indirectly, by inhibiting secretion of renin (thus lowering ANG II levels) and AVP. Because ANP also has powerful diuretic and natriuretic actions, it ultimately reduces plasma volume and therefore blood pressure. At higher levels, ANP decreases systemic arterial pressure and increases capillary permeability. ANP plays a role in the diuretic response to the redistribution of extracellular fluid and plasma volume into the thorax that occurs during space flight and water immersion. Natriuretic peptide receptor A, NPR1 ANP → NPR1 receptor →↑GC →↑[cGMP]I→↑PKG → ↑phosphorylation of MLCK →↓MLCK →↓phosphorylation of MLC↑→VASODILATATION → ↑phosphorylation of SERCA2 in SR →↓[Ca2+]i→VASODILATATION BUBREG cGMP ANP28 + BNP32 inhibicija sekrecije VAZOPRESINA CNP22 vazodilatacija Hiperpolarizacija KORA NADBUBREGA EDHF? inhibicija sinteze i sekrecije ALDOSTERONA parakrini inhibitor renin-angiotenzin s.

hidroliza fosfolipida
EIKOZANOIDI – vazodilatatori i vazokonstriktori serotonin, glutamat, IFNα,γ dopamin, adenozin, noradrenalin, serotonin HT2 GLUR1 hidroliza fosfolipida membrane D2 A1 α2 HT1 MAG DAG PIP2 βγ PLA2 DAG lipaza PLCβ α α EICOSANOIDI (grk.eicosi-20) ARAHIDONSKA KISELINA CIKLOOKSIGENAZE PGH2 As previously discussed phospholipaseA2 (PLA2) release arachidonic acid (AA) from glycerol-based phospholipids. A series of enzymes subsequently convert AA into a family of biologically active metabolites that are collectively called eicosanoids (from the Greek eikosi for 20) because, like AA, they all have 20 carbon atoms. In the first pathway, cyclooxygenase (COX) enzymes produce thromboxanes, prostaglandins and prostacyclins. The eicosanoids formed from AA can act as second messengers as well as act as local mediators and have profound paracrine effects on neighboring cells. The metabolism of PGH2 to generate selected prostanoid derivates is cell-specific. Many cells produce prostaglandins. Prostaglandins are vasoactive and are important in the regulation of renal blood flow. Platelets convert PGH2 to thromboxane A2 (TXA2), a short-lived compound that can aggregate platelets, bring about the platelet release reaction and constrict small blood vessels. In contrast, endothelial cells convert PGH2 to prostacyclin I2 (also known as PGI2), which inhibits platelet aggregation and dilates blood vessels. Prostaglandin synthesis has also been implicated in the pathophysiology of cardiovascular disease.. The diverse cellular responses to prostanoids are mediated by a family of G protein–coupled prostanoid receptors. This family currently has nine proposed members, including receptors for thromboxane/prostaglandin H2 (TP), PGI2 (IP), PGE2 (EP1-4), PGD2 (DP and CRTH2), and PGF2 (FP). These prostanoid receptors signal through Gq, Gi or Gs, depending on cell type. These in turn regulate intracellular adenylyl cyclase and phospholipases. Thromboxane A2 (TXA2) TXA2 activates TXA2/prostaglandin H2 (TP) receptors, leading to opening of L-type Ca channels, thereby increasing [Ca2+]i. In addition, TP activation increases the levels of superoxide anion radical O2− in VSMCs. In turn, O2− reacts with NO, thereby reducing the vasodilating effect of NO. Thromboxane receptor, TP TXA2→ TP receptor:• → Ca2+ channels open → Ca2+ entry →↑[Ca2+ ]I • →↑ O2–→↓NO→VASOCONSTRICTION Prostacyclin (PGI2) receptor (IP) and prostaglandin E2 (PGE2) receptor (EP2 and EP4) PGI2→ IP and PGE2→ EP2 and EP4→↑Gαs→↑AC →↑[cAMP]i→↑PKA →↑phosphorylation of MLCK →↓MLCK →↓phosphorylation of MLC→VASODILATATION krvne pločice TROMBOKSANI VD VK endotel PROSTACIKLINI VK VD TXA2 VK VD ↓ TP PGI2 većina ćelija PGD2 ↓ IP PGE2 PGF2α VK VD PROSTAGLANDINI ↓ DP ↓ EP ↓ FP

corpus cavernosum penisa
Heptahelični receptori spregnuti sa proteinom G E-prostanoidski receptori (EP1, EP2, EP3, EP4) konstrikcija bubrežnih arterija i arteriola Thromboxane A2 (TXA2) TXA2 activates TXA2/prostaglandin H2 (TP) receptors, leading to opening of L-type Ca channels, thereby increasing [Ca2+]i. In addition, TP activation increases the levels of superoxide anion radical O2− in VSMCs. In turn, O2− reacts with NO, thereby reducing the vasodilating effect of NO. Thromboxane receptor, TP TXA2→ TP receptor:• → Ca2+ channels open → Ca2+ entry →↑[Ca2+ ]I • →↑ O2–→↓NO→VASOCONSTRICTION Prostacyclin (PGI2) receptor (IP) and prostaglandin E2 (PGE2) receptor (EP2 and EP4) PGI2→ IP and PGE2→ EP2 and EP4→↑Gαs→↑AC →↑[cAMP]i→↑PKA →↑phosphorylation of MLCK →↓MLCK →↓phosphorylation of MLC→VASODILATATION The level of intracellular cyclic adenosine 3’,5’-monophosphate (cAMP) within vascular cells is a principal determinant of arterial tone. Elevated intracellular cAMP can induce vasodilatation via the prototypic cAMP effector protein kinase A (PKA). However, new data suggest the role of the exchange proteins directly-activated by cAMP (Epacs) in mediating vasorelaxation. These data suggest a novel mechanism of vasorelaxation whereby Epac increases the activity of Ca2+ sparks in arterial myocytes, which activates BK Ca channels and hyperpolarizes the cell membrane. This limits Ca2+ entry via voltage-sensitive Ca2+ channels, leading to a decrease in [Ca2+]i and myocyte relaxation. In addition, these data suggest that Epac-mediated vasodilatation is partly mediated via an endothelial-dependent mechanism, involving the activation of SKCa/IKCa channels and and nitric oxide synthase (NOS). VAZOKONSTRIKCIJA Epac (GEF) Koeksprimirani u corpus cavernosum penisa bubrezima, mozgu SK/IK NOS VAZODILATACIJA

AV- zatvaranje kanala za Ca2+
ADENOZIN EDHF (engl. Endothelium-derived hyperpolarizing factor ) = H2O2 koronarni krvni sudovi KATP kanali P PKA Hiperpolarizacija Glatki mišić krvnog suda ↑cAMP A2 AC Gs purinski adenozin 5´nukleotidaza adenozin AMP AMP ADP A1 ATP Gi AC Pojačana hidroliza ATP hipoksija ↓cAMP ADENOSINE Adenosine is a naturally occurring purine nucleoside that forms from the breakdown of adenosine triphosphate (ATP). ATP is the primary energy source in cells for transport systems and many enzymes. Most ATP is hydrolyzed to ADP, which can be further dephosphorylated to AMP. Most ADP and AMP that form in the cell is rephosphorylated in the mitochondria by enzymatic reactions requiring oxygen. If there are large amounts of ATP hydrolyzed, and especially if there is insufficient oxygen available (hypoxia), then some of the AMP can be further dephosphorylated to adenosine by the cell membrane associated enzyme, 5'-nucleotidase. Adenosine can bind to purinergic receptors in different cell types where it can produce a number of different physiological actions. One important action is vascular smooth muscle relaxation, which leads to vasodilation. This is a particularly important mechanism for matching coronary blood flow to the metabolic needs of the heart. In coronary vascular smooth muscle, adenosine binds to adenosine type 2A (A2A) receptors, which are coupled to the Gs-protein. Activation of this G-protein stimulates adenylyl cyclase (AC), increases cAMP and causes protein kinase activation. This stimulates KATP channels, which hyperpolarizes the smooth muscle, causing relaxation. Increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase (MLCK), which leads to decreased myosin phosphorylation and a decrease in contractile force. Purinergic receptor (adenosine/P1 type), A1, A2A, A2B ↑[Adenosine]o→ A1, A2A, and A2B receptor on VSMC→↑Gαs→↑AC →↑[cAMP]i→↑PKA → KATP channels open →hyperpolarization → voltage-gated Ca2+ channels close →↓[Ca2+]i ↑Phosphorylation of MLCK →↓MLCK →↓phosphorylation of MLC→VASODILATATION [Adenosine]o→ A1 on endothelial cell→↑NOS →NO release→VASODILATATION There is also evidence that adenosine inhibits calcium entry into the cell through L-type calcium channels. Since calcium regulates smooth muscle contraction reduced intracellular calcium causes relaxation. In some types of blood vessels, there is evidence that adenosine produces vasodilation through increases in cGMP, which leads to inhibition of calcium entry into the cells as well as opening of potassium channels. In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins. Activation of this pathway opens potassium channels, which hyperpolarizes the cell. Activation of the Gi-protein also decreases cAMP, which inhibits L-type calcium channels and therefore calcium entry into the cell. In cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits the pacemaker current (If), which decreases the slope of phase 4 of the pacemaker action potential thereby decreasing its spontaneous firing rate (negative chronotropy). Inhibition of L-type calcium channels also decreases conduction velocity (negative dromotropic effect) particularly at the atrioventricular (AV) nodes. Finally, adenosine by acting on presynaptic purinergic receptors located on sympathetic nerve terminals inhibits the release of norepinephrine. In terms of its electrical effects in the heart, adenosine decreases heart rate and reduces conduction velocity, especially at the AV node, which can produce atrioventricular block. Therapeutic Use and Rationale Although adenosine is a powerful vasodilator, especially in the coronary circulation, it is not used clinically as a vasodilator. The reason is that it is very short acting and in the heart it can produce coronary vascular steal. When administered by intravenous infusion, it can produce substantial hypotension. Adenosine is used, however, as an antiarrhythmic drug for the rapid treatment of supraventricular tachycardias. Its effects on atrioventricular conduction make it very useful in treating paroxysmal supraventricular tachycardia in which the AV node is part of the reentry pathway (as in Wolff-Parkinson-White Syndrome. Adenosine is administered either as bolus intravenous injection or as an intravenous infusion. Adenosine is not effective for atrial flutter or fibrillation. Side Effects and Contraindications Most of adenosine's side effects are related to its vasodilatory properties. Patients can experience flushing and headache, both of which are related to vasodilation. Adenosine can produce rapid arterial hypotension; however, this is reversed shortly after ceasing the infusion of adenosine. Coronary vascular steal is of theoretical concern in some patients with coronary artery disease, although there is no clinical evidence supporting this adverse effect. Methylxanthines such as caffeine and theophylline competitively antagonize the binding of adenosine at its purinergic receptor. Finally, adenosine may produce undesirable AV block; however, this is usually rapidly corrected by stopping adenosine administration. Therefore, adenosine is contraindicated in patients with second or third degree AV block. Purinergic receptor, P2y ↑[ATP]o→ P2Y metabotropic receptor →↑Gαq/11→↑PLC →↑[Ca2+]i→↑NOS →NO release→VASODILATATION Purinergic receptor (adenosine/P1 type), A1 ↑[Adenosine]o→A1 receptor on VSMC in renal afferent arterioles →↑Gαq/11→↑PLC →↑[IP3]i→ IP3 receptor in SR →↑Ca2+ release →↑[Ca2+]i→VASOCONSTRICTION Purinergic receptor, P2X ↑[ATP]o→ P2X receptor (ligand-gated Ca2+ channel = receptor-operated Ca2+ channel = ROC) → Ca2+ entry →↑[Ca2+)i→VASOCONSTRICTION SA, AV čvor SA- inhibicija If AV- zatvaranje kanala za Ca2+ Preko presinaptičkih receptora na simpatičkim nervnim završecima inhibira oslobađanje NOR

povišen arterijski pritisak koji se održava ≥140/90 mm Hg
HIPERTENZIJA povišen arterijski pritisak koji se održava ≥140/90 mm Hg normalan pritisak <120/80 mm Hg prehipertenzija / mm Hg I faza hipertenzije / mm Hg II faza hipertenzije ≥ 160/ 100 mm Hg promena načina života i ishrane!!! ANTIHIPERTENZIVI HYPERTENSION Hypertension is found in ∼20% of the adult population. It can damage endothelial cells, producing a number of proliferative responses, including arteriosclerosis. In the long term, hypertension can lead to coronary artery disease, myocardial infarction, heart failure, stroke and renal failure. In the great majority of cases, hypertension is the result of dysfunction of the mechanisms used by the circulation for the long-term rather than short-term control of arterial pressure. In fact, chronically hypertensive patients may have diminished sensitivity of their arterial baroreceptors. Most people with an elevated blood pressure have “primary hypertension or essential hypertension” in which it is not possible to identify a single, specific cause. Renal artery stenosis, which compromises renal blood flow, is the most common cause of secondary hypertension. The cumulative obstruction of smaller arteries and arterioles may also produce hypertension, as is often seen in diseases of the renal parenchyma or any end-stage renal disease. Conversely, constriction of larger vessels proximal to the kidneys can also cause hypertension, as is the case with coarctation of the aorta, a congenital malformation that constricts flow through the aorta to the lower parts of the body. Another cause of secondary hypertension is chronic volume overload. Volume overload can be acquired, such as in primary aldosteronism (caused by either a benign adenoma or bilateral hyperplasia) and pheochromocytoma (a tumor of the adrenal medulla that releases excessive amounts of catecholamines into the circulation). Volume overload can be genetic, as in rare mendelian forms of hypertension, such as Liddle disease, and pseudohypoaldosteronism type 2 Pharmacologic Treatment of Hypertension Patients with primary hypertension are generally treated with drugs that reduce blood volume (which reduces central venous pressure and cardiac output), reduce systemic vascular resistance, or reduce cardiac output by depressing heart rate and stroke volume. Patients with secondary hypertension are best treated by controlling or removing the underlying disease or pathology, although they may still require antihypertensive drugs. Reducing Arterial Pressure 1. Reduce Cardiac Output (reduce blood volume, heart rate and stroke volume) 2. Reduce Systemic Vascular Resistance (dilate systemic vasculature) Arterial pressure can be reduced by decreasing cardiac output, systemic vascular resistance or central venous pressure. An effective and inexpensive way of reducing venous pressure and cardiac output is by using drugs that reduce blood volume. These drugs (diuretics) act on the kidney to enhance sodium and water excretion. Reducing blood volume not only reduces central venous pressure, but even more importantly, reduces cardiac output by the Frank-Starling mechanism due to the reduction in ventricular preload. An added benefit of these drugs is that they reduce systemic vascular resistance with long-term use. Many antihypertensive drugs have their primary action on systemic vascular resistance. Some of these drugs produce vasodilation by interfering with sympathetic adrenergic vascular tone (sympatholytics) or by blocking the formation of angiotensin II or its vascular receptors. Other drugs are direct arterial dilators, and some are mixed arterial and venous dilators. Although less commonly used because of a high incidence of side effects, there are drugs that act on regions in the brain that control sympathetic autonomic outflow. By reducing sympathetic efferent activity, centrally acting drugs decrease arterial pressure by decreasing systemic vascular resistance and cardiac output. Some antihypertensive drugs, most notably beta-blockers, depress heart rate and contractility (this decreases stroke volume) by blocking the influence of sympathetic nerves on the heart. Calcium-channel blockers, especially those that are more cardioselective, also reduce cardiac output by decreasing heart rate and contractility. Some calcium-channel blockers (most notably the dihydropyridines) are more selective for the systemic vasculature and therefore reduce systemic vascular resistance. Classes of drugs used in the treatment of hypertension: Diuretics - thiazide diuretics - loop diuretics - potassium-sparing diuretics Vasodilators - alpha-adrenoceptor antagonists (alpha-blockers) - angiotensin converting enzyme inhibitors (ACE inhibitors) - angiotensin receptor blockers (ARBs) - calcium-channel blockers - direct acting arterial dilators - ganglionic blockers - nitrodilators - potassium-channel openers - renin inhibitors Cardioinhibitory drugs - beta-blockers 1. BLOKATORI KATEHOLAMINSKIH RECEPTORA 2. Ca2+ ANTAGONISTI, BLOKATORI KANALA za Ca2+ 3. ACE INHIBITORI (ANGIOTENZIN KONVERTUJUĆI ENZIM) 4. ANTAGONISTI RECEPTORA ZA ANGIOTENZIN II 5. DIURETICI 6. BLOKATORI RECEPTORA ZA ENDOTELIN 7. VAZODILATATORI (NO…)

↓ ↓ α BLOKATORI, ANTAGONISTI α RECEPTORA 1948, Ahlquist
neselektivni (FENTOLAMIN) 1948, Ahlquist Adrenotropni RC selektivni α1 (PRAZOSIN) selektivni α2 (YOHIMBIN) BARORECEPTORI karotidnih sinusa blokada α1 receptora inhibira vazokonstrikciju indukovanu NA n.sinus carotici (IX) nc.tractus solitarius ↓ n.aorticus (X) nc. ambiguus baroreceptorski refleks ↓ luka aorte Raymond Perry Ahlquist (1914– 1983) was an American pharmacist and pharmacologist. He published seminal work in 1948 that divided adrenoceptors into α- and β-adrenoceptor subtypes. This discovery explained the activity of several existing drugs and also laid the ground work for new drugs including the widely prescribed blockers Alpha-Adrenoceptor Antagonists (Alpha-Blockers) These drugs block the effect of sympathetic nerves on blood vessels by binding to alpha-adrenoceptors located on the vascular smooth muscle. Most of these drugs act as competitive antagonists to the binding of norepinephrine that is released by sympathetic nerves synapsing on smooth muscle. Therefore, sometimes these drugs are referred to as sympatholytics because they antagonize sympathetic activity. Some alpha-blockers are non-competitive (phenoxybenzamine), which greatly prolongs their action, whereas others are relatively selective for one type of alpha-adrenoceptor. Vascular smooth muscle has two types of alpha-adrenoceptors: alpha1 (α1) and alpha2 (α2). The α1-adrenoceptors are the predominant α-receptor located on vascular smooth muscle. These receptors are linked to Gq-proteins that activate smooth muscle contraction through the IP3 signal transduction pathway. Depending on the tissue and type of vessel, there are also α2-adrenoceptors found on the smooth muscle. These receptors are linked to Gi-proteins, and binding of an alpha-agonist to these receptors decreases intracellular cAMP, which causes smooth muscle contraction. There are also α2-adrenoceptors located on the sympathetic nerve terminals that inhibit the release of norepinephrine and therefore act as a feedback mechanism for modulating the release of norepinephrine. α1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine to the smooth muscle receptors. Non-selective α1 and α2-adrenoceptor antagonists block postjunctional α1 and α2-adrenoceptors, which causes vasodilation; however, the blocking of prejunctional α2-adrenoceptors leads to increased release of norepinephrine, which attenuates the effectiveness of the α1 and α2-postjunctional adrenoceptor blockade. Furthermore, blocking α2-prejunctional adrenoceptors in the heart can lead to increases in heart rate and contractility due to the enhanced release of norepinephrine that binds to beta1-adrenoceptors. Alpha-blockers dilate both arteries and veins because both vessel types are innervated by sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial resistance vessels. Because most blood vessels have some degree of sympathetic tone under basal conditions, these drugs are effective dilators. They are even more effective under conditions of elevated sympathetic activity (during stress) or during pathologic increases in circulating catecholamines caused by an adrenal gland tumor (pheochromocytoma). Therapeutic Uses Alpha-blockers, especially α1-adrenoceptor antagonists, are useful in the treatment of primary hypertension, although their use is not as widespread as other antihypertensive drugs. The non-selective antagonists are usually reserve for use in hypertensive emergencies caused by a pheochromocytoma. This hypertensive condition, which is most commonly caused by an adrenal gland tumor that secretes large amounts of catecholamines, can be managed by non-selective alpha-blockers (in conjunction with beta-blockade to blunt the reflex tachycardia) until the tumor can be surgically removed. Specific Drugs Newer alpha-blockers used in treating hypertension are relatively selective α1-adrenoceptor antagonists (e.g., prazosin, terazosin, doxazosin, trimazosin), whereas some older drugs are non-selective antagonists (e.g., phentolamine, phenoxybenzamine). (Go to for specific drug information) Side Effects and Contraindications The most common side effects are related directly to alpha-adrenoceptor blockade. These side effects include dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon standing), nasal congestion (due to dilation of nasal mucosal arterioles), headache, and reflex tachycardia (especially with non-selective alpha-blockers). Fluid retention is also a problem that can be rectified by use of a diuretic in conjunction with the alpha-blocker. Alpha blockers have not been shown to be beneficial in heart failure or angina, and should not be used in these conditions. kompenzacija povećanje frekvencije i udarnog volumena

β BLOKATORI, ANTAGONISTI β RECEPTORA
I generacije, neselektivni (PROPRANOLOL-Inderal) II generacije, selektivni β1 (ATENOLOL-Prinorm, METOPROLOL-Presolol) III generacije, neselektivni sa kardiovaskularnim efektom α1β (CARVEDILOL) ispoljavaju efekat kada je povećana aktivnost SNS snižavaju pritisak samo kod hipertoničara Negativno hronotropno i inotropno dejstvo Smanjuju sekreciju renina i angiotenzina II Povećavaju sintezu prostaciklina Povećavaju stvaranje NO Džep za KTHL aktivacija RC 1988. god. Sir James Black Beta-blockers In 1964, James Black synthesized the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century. Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors by competing for the binding site. This inhibits normal sympathetic effects that act through these receptors. Therefore, beta-blockers are sympatholytic drugs. Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system and contracting myocytes. The heart has both β1 and β2 adrenoceptors, although the predominant receptor type in number and function is β1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood. Because there is generally some level of sympathetic tone on the heart, beta-blockers are able to reduce sympathetic influences that normally stimulate chronotropy (heart rate), inotropy (contractility), dromotropy (electrical conduction) and lusitropy (relaxation). Therefore, beta-blockers cause decreases in heart rate, contractility, conduction velocity, and relaxation rate. These drugs have an even greater effect when there is elevated sympathetic activity. Compared to their effects in the heart, beta-blockers have relatively little vascular effect because β2-adrenoceptors have only a small modulatory role on basal vascular tone. Nevertheless, blockade of β2-adrenoceptors is associated with a small degree of vasoconstriction in many vascular beds. This occurs because beta-blockers remove a small β2-adrenoceptor vasodilator influence that is normally opposing the more dominant alpha-adrenoceptor mediated vasoconstrictor influence. The first generation of beta-blockers were non-selective, meaning that they blocked both β1 and β2 adrenoceptors. Second generation beta-blockers are more cardioselective in that they are relatively selective for β1 adrenoceptors. Finally, the third generation beta-blockers are drugs that also possess vasodilator actions through blockade of vascular alpha-adrenoceptors. Beta-blockers decrease arterial blood pressure by reducing cardiac output. Many forms of hypertension are associated with an increase in blood volume and cardiac output. Therefore, reducing cardiac output by beta-blockade can be an effective treatment for hypertension, especially when used in conjunction with a diuretic. Acute treatment with a beta-blocker is not very effective in reducing arterial pressure because of a compensatory increase in systemic vascular resistance. This may occur because of baroreceptor reflexes working in conjunction with the removal of β2 vasodilatory influences that normally offset, to a small degree, alpha-adrenergic mediated vascular tone. Chronic treatment with beta-blockers lowers arterial pressure more than acute treatment possibly because of reduced renin release and effects of beta-blockade on central and peripheral nervous systems. Beta-blockers have an additional benefit as a treatment for hypertension in that they inhibit the release of renin by the kidneys (the release of which is partly regulated by β1-adrenoceptors in the kidney). Decreasing circulating plasma renin leads to a decrease in angiotensin II and aldosterone, which enhances renal loss of sodium and water and further diminishes arterial pressure. 15 AK, interakcija sa Gs 1. Približavanje C kraja trećoj petlji

4. karvedilol i njegov metabolit imaju antioksidativna svojstva
ATP P2Y 2. aktivira ATP efluks iz endotelnih ćelija arteriola bubrega NO GC PKG cGMP Ca2+ kalmodulin Endotelna ćelija ćelija glatkog mišića krvnog suda eNOS NO 1. Carvedilol treatment induces a conformational change resulting in the intracellular tail of the receptor being positioned more closely to the third intracellular loop; this inverse agonism of the receptor in theory would lead to decreased Gs coupling and reduced cAMP accumulation. 2. ATP released from endothelial cells by hypoxia acts on G protein– coupled P2Y-purinoceptors on endothelial cells to release NO and produce vasodilatation. vasodilator effect of carvedilol in renal glomerular microvasculature is associated with the activation of ATP efflux with consequent stimulation of P2Y-purinoceptor–mediated liberation of NO from glomerular microvascular endothelial cells. 3.Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Here we show that carvedilol is the only beta blocker tested that effectively suppresses Ca overload by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. 4. karvedilol i njegov metabolit imaju antioksidativna svojstva 3. skraćuje vreme otvaranja RyR2

neophodna za formiranje pore, kao i
Ca2+ ANTAGONISTI, BLOKATORI ULASKA Ca2+ neophodna za formiranje pore, kao i interakciju sa RyR2 kanalima DI/TRIJADE α1 α1 L voltažno zavisni kanal za Ca2+ Calcium-channel blockers Currently approved CCBs bind to L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, L-type calcium channels play an important role in pacemaker currents and in phase 0 of the action potentials. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation (negative inotropy), decreased heart rate (negative chronotropy), and decreased conduction velocity within the heart (negative dromotropy), particularly at the atrioventricular node. By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular resistance, which lowers arterial blood pressure. These drugs primarily affect arterial resistance vessels, with only minimal effects on venous capacitance vessels. There are three classes of CCBs. They differ not only in their basic chemical structure, but also in their relative selectivity toward cardiac versus vascular L-type calcium channels. The most smooth muscle selective class of CCBs are the dihydropyridines. Because of their high vascular selectivity, these drugs are primarily used to reduce systemic vascular resistance and arterial pressure, and therefore are used to treat hypertension. Extended release formulations or long-acting compounds are used to treat angina and are particularly effecting for vasospastic angina; however, their powerful systemic vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia and increased inotropy), which can offset the beneficial effects of afterload reduction on myocardial oxygen demand. Note that dihydropyridines are easy to recognize because the drug name ends in "pine.” Non-dihydropyridines, of which there are only two currently used clinically, comprise the other two classes of CCBs. Verapamil (phenylalkylamine class), is relatively selective for the myocardium, and is less effective as a systemic vasodilator drug. This drug has a very important role in treating angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and arrhythmias. Diltiazem (benzothiazepine class) is intermediate between verapamil and dihydropyridines in its selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. negativno inotropno dejstvo VERAPAMIL (Isoptin) se vezuje za S6 IV dom DILTIAZEM (Cortiazem) se vezuje za most III i IV AMPLODIPIN (Norvasc) se vezuje za III S6 i IV S6 negativno hronotropno dejstvo T voltažno zavisni kanal za Ca2+ (SA ČVOR) → MIBEFRADIL

ACE INHIBITORI (ANGIOTENZIN KONVERTUJUCIH ENZIMA)
ACE = dipeptidil karboksimetalopeptidaza sa dva katalitička mesta i dva Zn2+ vezujuća mesta. CAPTOPRIL ENALAPRIL FOSINOPRIL Inhibicija ACE ostvaruje se grupama inhibitora, koje dužinom odgovaraju dipeptidima, koje isecaju iz angiotenzina I ili bradikinina. Angiotensin converting enzyme inhibitors (ACE inhibitors) ACE inhibitors produce vasodilation by inhibiting the formation of angiotensin II. This vasoconstrictor is formed by the proteolytic action of renin (released by the kidneys) acting on circulating angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme.ACE also breaks down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors. Angiotensin II constricts arteries and veins by binding to AT1 receptors located on the smooth muscle, which are coupled to a Gq-protein and the the IP3 signal transduction pathway. Angiotensin II also facilitates the release of norepinephrine from sympathetic adrenergic nerves and inhibits norepinephrine reuptake by these nerves. This effect of angiotensin II augments sympathetic activity on the heart and blood vessels. Cardiorenal Effects of ACE Inhibitors Vasodilation (arterial & venous) - reduce arterial & venous pressure - reduce ventricular afterload & preload Decrease blood volume - natriuretic - diuretic Depress sympathetic activity Inhibit cardiac and vascular hypertrophy ACE inhibitors have the following actions: Dilate arteries and veins by blocking angiotensin II formation and inhibiting bradykinin metabolism. This vasodilation reduces arterial pressure, preload and afterload on the heart. Down regulate sympathetic adrenergic activity by blocking the facilitating effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine. Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of angiotensin II in the kidney and by blocking angiotensin II stimulation of aldosterone secretion. This reduces blood volume, venous pressure and arterial pressure. Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction. Elevated plasma renin is not required for the actions of ACE inhibitors, although ACE inhibitors are more efficacious when circulating levels of renin are elevated. We know that renin-angiotensin system is found in many tissues, including heart, brain, vascular and renal tissues. Therefore, ACE inhibitors may act at these sites in addition to blocking the conversion of angiotensin in the circulating plasma. Therapeutic Use of ACE Inhibitors Hypertension Heart failure Post-myocardial infarction ACE inhibitors are effective in the treatment of primary hypertension and hypertension caused by renal artery stenosis, which causes renin-dependent hypertension owing to the increased release of renin by the kidneys. Reducing angiotensin II formation leads to arterial and venous dilation, which reduces arterial and venous pressures. By reducing the effects of angiotensin II on the kidney, ACE inhibitors cause natriuresis and diuresis, which decreases blood volume and cardiac output, thereby lowering arterial pressure. Smanjuju stvaranje angiotenzina II,povećavaju nivo bradikinina!!! ♥snižavaju otpor perifernih krvnih sudova ne indukujući kompenzatorni baroreceptorski refleks, jer modulišu senzitivnost baroreceptora. ♥inhibiraju oslobađanje NA preko angiotenzina II, suprimirajući efekat NA na srce i krvne sudove ♥diureza i natriureza

ANTAGONISTI RECEPTORA ZA ANGIOTENZIN
većinu fizioloških efekata angiotenzin ispoljava preko AT1, receptora spregnutog sa proteinom G Prvi antagonisti sarcosine ~1970 god 1995 god. prvi nepeptidni antagonist LOSARTAN + 6 bifenil tetrazoli (VALSARTAN-Diovan) MEHANIZAM DELOVANJA: ♥ alternativna vezujuća mesta ♥ disocijacija sa AT1 receptora ♥ internalizacija receptora Angiotensin receptor blockers (ARBs) Generally, ACE inhibitors should remain the initial treatment of choice for hypertension. Angiotensin II receptor antagonists or angiotensin receptor blockers (ARBs) are used for patients who are unable to tolerate ACE inhibitors. ARBs competitively block binding of angiotensin-II to angiotensin type I (AT1) receptors, thereby reducing effects of angiotensin II–induced vasoconstriction, sodium retention, and aldosterone release; the breakdown of bradykinin should not be inhibited. If monotherapy with an ARB is not sufficient, adding a diuretic should be considered. These drugs have very similar effects to angiotensin converting enzyme (ACE) inhibitors and are used for the same indications (hypertension, heart failure, post- myocardial infarction). Their mechanism of action, however, is very different from ACE inhibitors, which inhibit the formation of angiotensin II. ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors on bloods vessels and other tissues such as the heart. These receptors are coupled to the Gq-protein and IP3 signal transduction pathway that stimulates vascular smooth muscle contraction. Because ARBs do not inhibit ACE, they do not cause an increase in bradykinin, which contributes to the vasodilation produced by ACE inhibitors and also some of the side effects of ACE inhibitors (cough and angioedema). ARBs have the following actions, which are very similar to ACE inhibitors: 1.Dilate arteries and veins and thereby reduce arterial pressure and preload and afterload on the heart. 2.Down regulate sympathetic adrenergic activity by blocking the effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine. 3.Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of angiotensin II in the kidney and by blocking angiotensin II stimulation of aldosterone secretion. 4.Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction. ARBs are used in the treatment of hypertension and heart failure in a similar manner as ACE inhibitors (see ACE inhibitors for details). They are not yet approved for post-myocardial infarction, although this is under investigation. INHIBIRAJU ♥ vazokonstrikciju ♥ oslobađanje ADH i stvaranje osećaja žeđi ♥ sekreciju aldosterona ♥ oslobađanje hormona srži ♥ oslobađanje NA

ANTAGONISTI RECEPTORA ZA ANGIOTENZIN
Blokada postsinaptičkih AT1 receptora inhibira vazokonstriktorno dejstvo angiotenzina II ACE inhibitors down regulate sympathetic adrenergic activity by blocking the effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine. Blokada presinaptičkih AT1 receptora inhibira oslobadjanje NA u sinapsu

ANTAGONISTI MRC (ALDOSTERON)
DIURETICI : povećavaju diurezu i natriurezu (Cl-), Inhibitori karboanhidraze: ACETAZOLAMID (Diamox) Inhibitori NKCC2: FUROSEMID (Lasix) ANTAGONISTI MRC (ALDOSTERON) deblji deo Henleove petlje (25%) proksimalne tubule (65%) MRC Cl- Na+ glukoza AK SGLT2 AKT K+ NKCC2 2Cl- Na+ NHE3 H+ Na+ SPIRONOLAKTON MRC ENaCs H+ CA HCO3- HCO3- Na+ Cl- Cl- Na+ H2O Inhibitori NaCl simportera: THIAZIDI K kanal Inhibitori ENaC: AMILORID Diuretics (thiazide, loop and potassium-sparing diuretics) Diuretic drugs increase urine output by the kidney (promote diuresis). This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase. Most diuretics produce diuresis by inhibiting the reabsorption of sodium at different segments of the renal tubular system. Sometimes a combination of two diuretics is given because this can be significantly more effective than either compound alone (synergistic effect). The reason for this is that one nephron segment can compensate for altered sodium reabsorption at another nephron segment; therefore, blocking multiple nephron sites significantly enhances efficacy. Loop diuretics inhibit the NKCC sodium-potassium-chloride cotransporter in the thick ascending limb. This transporter normally reabsorbs about 25% of the sodium load; therefore, inhibition of this transporter can lead to a significant increase in the distal tubular concentration of sodium, reduced hypertonicity of the surrounding interstitium, and less water reabsorption in the collecting duct. This altered handling of sodium and water leads to both diuresis (increased water loss) and natriuresis (increased sodium loss). By acting on the thick ascending limb, which handles a significant fraction of sodium reabsorption, loop diuretics are very powerful diuretics. Thiazide diuretics, which are the most commonly used diuretic, inhibit the NCC sodium-chloride transporter in the distal tubule. Because this transporter normally only reabsorbs about 5% of filtered sodium, these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis. Nevertheless, they are sufficiently powerful to satisfy most therapeutic needs requiring a diuretic. Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this increases potassium loss (potentially causing hypokalemia) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine. The increased hydrogen ion loss can lead to metabolic alkalosis. Part of the loss of potassium and hydrogen ion by loop and thiazide diuretics results from activation of the renin-angiotensin-aldosterone system that occurs because of reduced blood volume and arterial pressure. Increased aldosterone stimulates sodium reabsorption and increases potassium and hydrogen ion excretion into the urine. There is a third class of diuretic that is referred to as potassium-sparing diuretics. Unlike loop and thiazide diuretics, some of these drugs do not act directly on sodium transport. Some drugs in this class antagonize the actions of aldosterone (aldosterone receptor antagonists) at the distal segment of the distal tubule. This causes more sodium (and water) to pass into the collecting duct and be excreted in the urine. They are called K+-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics. The reason for this is that by inhibiting aldosterone-sensitive sodium reabsorption, less potassium and hydrogen ion are exchanged for sodium by this transporter and therefore less potassium and hydrogen are lost to the urine. Other potassium-sparing diuretics directly inhibit sodium channels associated with the aldosterone-sensitive sodium pump, and therefore have similar effects on potassium and hydrogen ion as the aldosterone antagonists. Their mechanism depends on renal prostaglandin production. Because this class of diuretic has relatively weak effects on overall sodium balance, they are often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia. Carbonic anhydrase inhibitors inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium, which leads to less sodium reabsorption at this site and therefore greater sodium, bicarbonate and water loss in the urine. These are the weakest of the diuretics and seldom used in cardiovascular disease. Their main use is in the treatment of glaucoma Hypertension Most patients with hypertension, of which 90-95% have hypertension of unknown origin (primary or essential hypertension), are effectively treated with diuretics. Antihypertensive therapy with diuretics is particularly effective when coupled with reduced dietary sodium intake. The efficacy of these drugs is derived from their ability to reduce blood volume, cardiac output, and with long-term therapy, systemic vascular resistance. The vast majority of hypertensive patients are treated with thiazide diuretics. Potassium-sparing, aldosterone-blocking diuretics (e.g., spironolactone) are used in secondary hypertension caused by hyperaldosteronism, and sometimes as an adjunct to thiazide treatment in primary hypertension to prevent hypokalemia. enzima→ATP prvi deo distalnih tubula (5%) drugi deo distalnih tubula (2%) Na/K ATPaze Na+ ENaC Na+ osnovne ćelije distalnih tubula i sabirnih kanalića Cl- ENCC1 K+ Na+ K+ osnovne ćelije Cl-

BLOKATORI ET RECEPTORA Endotelini- snažni vazokonstriktori
Sistemska hipertenzija Vazospazam koronarnih arterija Poremećaj rada srca, hipertrofija Plućna hipertenzija Bosentan Neselektivni ETA i ETB Koristi se u tretmanu plućne hipertenzije Therapeutic Indications Because of its powerful vasoconstrictor properties, and its effects on intracellular calcium, ET-1 has been implicated in the pathogenesis of hypertension, coronary vasospasm and heart failure. A number of studies suggest a role for ET-1 in pulmonary hypertension, as well as in systemic hypertension. ET-1 has been shown to be released by the failing myocardium where it can contribute to cardiac calcium overload and hypertrophy. Endothelin receptor antagonists, by blocking the vasoconstrictor and cardiotonic effects of ET-1, produce vasodilation and cardiac inhibition. Endothelin receptor antagonists have been shown to decrease mortality and improve hemodynamics in experimental models of heart failure. At present, the one approved indication for endothelin antagonists is pulmonary hypertension. Specific Drugs One endothelin receptor antagonist has been approved. Bosentan, a non-selective ET-1 receptor antagonist (blocks for ETA and ETB receptors) is currently used in the treatment of pulmonary hypertension. Blokiraju vazokonstiktorno i kardiotonično dejstvo ET1

MEHANIZMI REGULACIJE KRVNOG PRITISKA

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