4Nervous Regulation of the Circulation Adjustment of blood flow tissue by tissue is mainly the function of local tissue blood flow control mechanisms.The nervous control of the circulation has more global functions, such as redistributing blood flow to different areas of the body, increasing or decreasing pumping activity by the heart, and, especially, providing very rapid control of systemicarterial pressure.The nervous system controls the circulation almost entirely through the autonomic nervous system.
5Autonomic Nervous System By far the most important part of the autonomic nervous system for regulating the circulation is the sympathetic nervous system.The parasympathetic nervous system also contributes specifically to regulation of heart function.
7Sympathetic Nervous System Sympathetic vasomotor nerve fibers leave the spinal cord through all the thoracic spinal nerves and through the first one or two lumbar spinal nerves. They then pass immediately into a sympatheticchain, one of which lies on each side of the vertebral column. Next, they pass by two routes to the circulation:through specific sympathetic nerves that innervate mainly the vasculature of the internal viscera and the heart,almost immediately into peripheral portionsof the spinal nerves distributed to the vasculature of the peripheral areas.
8Anatomy of sympathetic nervous control of thecirculation.Also shown bythe red dashed line is avagus nerve that carriesParasympathetic signals to the heart.
10Sympathetic Innervation of the Blood Vessels In most tissues all the vessels except the precapillary sphincters, metarterioles and capillaries, areinnervated.The innervation of the small arteries and arteriolesallows sympathetic stimulation to increase resistanceto blood flow and thereby to decrease rate of bloodflow through the tissues.The innervation of the large vessels, particularly of theveins, makes it possible for sympathetic stimulation todecrease the volume of these vessels.This can pushblood into the heart and thereby play a major role inregulation of heart pumping.
12Sympathetic Nerve Fibers to the Heart. In addition to sympathetic nerve fibers supplying theblood vessels, sympathetic fibers also go directly to theheart.It should be recalled that sympathetic stimulationmarkedly increases the activity of the heart, bothincreasing the heart rate and enhancing its strengthand volume of pumping.
13Parasympathetic Control of the Heart Function Parasympathetic plays a minor role in regulating of the circulationIts most important circulatory effect is to control heart rate by way of parasymphatetic nerve fibers to the heart (N. Vagus)
16Sympathetic Vasoconstrictor System and Its Control by the CNS The sympathetic nerves carry tremendous numbers of vasoconstrictor nerve fibers and only a few vasodilatatory fibersThis sympathetic vasoconstrictor effect is especially powerful in the kidneys, intestines, spleen and skin but much less potent in skeletal muscle and the brain
17Vasomotor Center in the Brain Located in the reticular substance of the medulla and lower ponsImportant areas in this center:A vasoconstrictor areaA vasodilatator areaA sensory area, located in the nucleus tractus solitariusOutput signals from the sensory area provides a reflex control of many circulatory functions (e.g. baroreceptor reflex)
19Control of the vasomotor center by higher nervous centers Large numbers of small neurons located throughout the reticular substance of the pons, mesencephalon and diencephalon can excite or inhibit the vasomotor centerRole of hypothalamus – Limbic systemMany parts of the cerebral cortex can also excite or inhibit the vasomotor centervasovagal syncope (emotional fainting)
20Sympathetic Vasoconstrictor Transmitter Substance NoradrenalinAlpha adrenergic receptors of the vascular smooth muscle (Na+ ve Ca2+)Adrenal medullae and their relation to the sympathetic vasoconstrictor system (α receptor, adrenalin and noradrenalin)Sympathetic vasodilator system(β1; HR & kontraction, β2 ; vasodil.) and its control by the central nervous systemSkeletal muscles and vasodilator fibers…
21Role of the nervous system in rapid control of arterial pressure Rapid control of arterial pressure within 5-10 secondsStimulation of entire vasoconstrictor and cardioaccelerator functions by the sympathetic systemAlmost all arterioles of the systemic circulation are constrictedThe veins are strongly constrictedThe heart itself is directly stimulated by the ANS, further enhancing cardiac pumping
22Increase in AP During Muscle Exercise and Other Types of Stress During heavy exercise, skeletal muscle require increased blood flow – role of local vasodilationIncrease of AP (30-40%) in heavy exercise increases blood flowActivation of vasomotor centerOther types of stress and increased APAlarm reactionFight or flight
23Maintaining Blood Pressure: Short Term Mechanisms - CNS Baroreceptor initiated reflexlocated at carotid sinuses and aortic archmonitors blood pressureregulates the activity of the sympathetic nervous system (vascular tone)
24Anatomy:Baroreceptors are clusters of bare sensory nerve endings buried within the elastic layers of the aorta and the carotid sinus.Information from the former is relayed to the brain via sensory afferents traveling in the aortic nerve and the vagus nerve (cranial nerve [CN] X).Afferents from the carotid sinus travel in the sinus nerve, which joins with the glossopharyngeal nerve (CN IX) route to the brainstem.
25b. Function:In the absence of stretch, the baroreceptors are inactive. When MAP increases, the walls of the aorta and carotid sinus expand, and the embedded nerve endings are stretched.The nerves respond with graded receptor potentials. If the degree of deformation is sufficiently high, the receptor potentials trigger spikes in the sensory nerve.
26Baroreceptors are especially sensitive to changes in pressure, responding to the sharp rise in pressure that occurs during rapid ejection with strong depolarization and a train of high frequency spikes. During reduced ejection and diastole, the depolarization abates and spike frequency drops to a new steady-state level that reflects diastolic pressure.
27Baroreceptor Reflexes This reflex is initiated by stretch receptors (baroreceptors or pressoreceptors) located at specific points in the walls of large systemic arteriesCarotic and Aortic baroreceptorsSignals from carotid baroreceptors – small Hering’s nerves – N. Glossopharyngeus – NTS in the medullaAortic baroreceptors – N. Vagus – NTS in the medulla
30Sensitivity of Baroreceptors: Stretch-sensitivity varies from one nerve endingto the next, thereby allowing for responsiveness over a wide pressure range.The carotid baroreceptors have a response threshold of around 50 mm Hg and saturateat 180 mm Hg.The aortic baroreceptors operate over a range of 110–200 mm Hg.
31Circulatory Reflex Initiated by the Baroreceptors After the signals from baroreceptors enter the NTS, secondary signals inhibit the vasoconstrictor center and excite vagal parasympathetic centerThe net effects are:Vasodilation of the veins and arterioles in the peripheral circulatory systemDecreased heart rate and strength of the heart contractionIncreased TPR (total peripheral resistance) and decreased cardiac output
33Baroreceptors and Changes in Body Posture AP in the head and upper parts of the body tends to fall immediately on standingThis may cause loss of consciousnessFalling pressure at the baroreceptors elicits an immediate reflex resulting in strong sympathetic dischargePressure Buffer Function of the Baroreceptor control systemReduction of minute by minute variations in arterial BPLong term regulation of arterial BP
34THE BARORECEPTOR REFLEX - AN EXAMPLE CORRECTION OF POSTURAL HYPOTENSIONOn standing up venous return fallsCardiac output diminishesArterial blood pressure is reducedBaroreceptor afferent firing reducedMedullary centres inhibition reducedEffect of gravity onvenous returnPreload diminished- Starling’s LawSubject possibly feels faintas cerebral flow is reducedDue to reduced arterial B.P.VasoconstrictionTachycardiaRaised stroke workIncreased sympathetic tone to arteriolesTend to restore arterial blood pressureReduced vagal tone to s.a. nodeIncreased myocardial sympathetic tone
37Maintaining Blood Pressure: Short Term Mechanisms - CNS Chemoreceptor initiated reflexesCarotid bodies, aortic bodiesMonitor changes in indicator chemicals (O2, CO2, H+, HCO3-) CO2, H+, O2 (stresses) result in sympathetic activity and BP
38Control of the Arterial Pressure by the Carotid and Aortic Chemoreceptors Abundant blood flow and contact with the chemoreceptorsSignals from the chemoreceptors excite the vasomotor center and this elevates the AP back to normalChemoreceptor reflex is not a powerful AP controller until the AP falls below 80 mmHgIn low pressures this reflex becomes important
39ChemoreceptorsChemoreceptors monitor local metabolite levels, which reflect adequacy of perfusion pressure and flow.Anatomy:There are two groups of chemoreceptors, one locatedin the brainstem medulla, the other peripheral.Peripheral chemoreceptors are discrete, highly vascularized glomus cell clusters lying close to the aortic arch and carotid sinus (the aortic and carotid bodies, respectively).Sensory fibers from the aortic bodies travel in the vagus nerve, whereas nerves from the carotid bodies travel with the sinus nerve and join the glossopharyngeal trunk en route to the medulla.
41Function: Peripheral chemoreceptors activate when arterial O2 levels fall (60 mm Hg) or when PCO2 or H levels rise (PCO2 40 mm Hg or pH 7.4).Medullary chemoreceptors are sensitive to the pH of brain interstitial fluid, which is dependent on arterial PCO2.The chemoreceptors seem designed to monitor lung function and are principally involved in respiratory control, but hypercapnia and acidosis can also reflect low perfusion pressures.
43Other Reflexes Regulating Blood Pressure Atrial and pulmonary artery reflexes that help regulate AP and other circulatory factors:Both atria and pulmonary arteries have in their walls stretch receptors called low-pressure receptorsAtrial reflexes that activate the kidneys (volume reflex)Stretch of the atria also causes reflex dilation of afferent arterioles in the kidney
44Cardiopulmonary receptors (Atrial and pulmonary artery reflexes) : A second set of baroreceptors is found in low-pressure regions of the cardiovascular system.They provide the CNS with information about the “fullness” of the vascular system, and their principal role is in modulating renal function.However, because fullness correlates with ventricular preload, they also have a role in maintaining MAP.
45Anatomy:The receptors are similar to those found in the arterial system: bare sensory nerve endings embedded in walls of the vena cavae, the pulmonary artery and vein, and the atria.They relay information back to the CNS via the vagal nerve trunk.
46Function: Atria contain two functionally distinct populations of baroreceptors.A receptors respond to tension that develops in the atrial wall during contraction.B receptors are sensitive to atrial wall stretching during filling. B receptors are also involved in raising HR when central venous pressure (CVP) is high, a response known as the Bainbridge reflex.
47Other Reflexes Regulating Blood Pressure Atrial reflex control of the heart rate (Bainbridge reflex)Increased atrial pressure also increases heart rateDirect effect of increased atrial volume to stretch the sinus nodeAdditional 40-60% increase in rate is caused by a nervous reflex (Bainbridge reflex) that transmits afferent signals to the medulla of the brain
49Central Nervous System Ischemic Response Most nervous control of BP is achieved by baroreceptors, chemoreceptors and low-pressure receptors: These are all located in the peripheral circulationHowever, cerebral ischemia causes strong excitation of the vasomotor centerAccumulation of carbon dioxideOther factors (build up of lactic acid)CNS ischemic response is one of the most powerful of all the activators of the sympathetic vasoconstrictor systemImportance of the CNS ischemic responseActivated only at 60 mmHg or belowEmergency pressure control system
50Special Features of Nervous Control of Arterial Pressure Abdominal compression reflexCompression of large abdominal veins and other vessels by skeletal muscles of the body, especially abdominal musclesIncreased cardiac output and arterial pressure caused by skeletal muscle contraction during exerciseCompression of blood vessels by skeletal muscles
51Respiratory Waves in the Arterial Pressure 4 to 6 mmHg fall in AP during respiratory cycleBreathing signals arise in the respiratory center of the medulla “spill over” into the vasomotor center with each respiratory cycleWith inspiration, pressure in thoracic cavity becomes negative allowing blood vessels in the chest to expand* This reduces the venous return and decreases the cardiac outputPressure changes in the thoracic vessels by respiration can excite vascular and atrial stretch receptors
52Long Term Regulation of Arterial Blood Pressure and Hypertension Balance Between Fluid Intake and Output
53LONG-TERM CONTROL PATHWAYS A drop in arterial pressure activates the baroreceptor reflex , but it also initiates pathways that require 24–48 hr to become fully effective.These pathways converge on the kidney, which is responsible for long-term control of blood pressure through regulation of vascular fullness(circulating blood volume).
54LONG-TERM CONTROL PATHWAYS Because blood is principally water, this necessarily involves regulation ofwater output andwater intake, but it also requires regulation of Na levelsbecause this is the ion that governs how water partitions between the intracellular and extracellular compartments.
55Water outputWater output is controlled by ADH, a peptide that is synthesized by the hypothalamus andthen transported to the posterior pituitary for release.It stimulates water reabsorption by the renal collecting tubule and collecting ducts.At high concentrations, ADH also increases SVR by constricting resistance vessels.
56Water outputSeveral sensors and pathways regulate ADH release includingosmoreceptors,baroreceptors, andAng-II.
571. Osmoreceptors:The brain contains a number of regions that have the potential to monitor plasma osmolality, including areas surrounding the third ventricle in close proximity to the hypothalamusTissue osmolarity is a reflection of total body water and salt concentration. When osmolarity exceeds 280 mOsm/kg, the receptors cause ADH to be released into the circulation.
582. Baroreceptors: A decrease in circulating blood volume causes CVP to fall, which is sensed by the cardiopulmonary receptors.Loss of preload also causes arterial pressure to fall and triggers a baroreceptor reflex. The CNS cardiovascular control centers respond by increasing sympathetic activity and promoting ADH release.
593. Angiotensin II:Activating the renin-angiotensin-aldosterone system (RAAS) causes circulating Ang-II levels to rise. The list of target organs for Ang-II includes the hypothalamus, where it stimulates ADH release.
61B. Water intakeWater enters the body along with food, but the bulk of liquid intake occurs through drinking, driven by thirst. The sensation is triggered by decreasing blood volume and arterial pressure, suggesting a prominent role for the cardiovascular control center.C. Sodium outputOsmoreceptors control water retention and excretion, but they sense the “saltiness” of body fluids rather than water per se. Thus, if tissue osmolality remains high, they will urge retention of water regardless of total accumulated volume. The primary determinant of circulating blood volume is Na concentration, which is regulated through RAAS
621. Renin-Angiotensin-Aldosterone system: Renin is a proteolytic enzyme synthesized by granular cells in the wall of glomerular afferent arterioles. The cells form a part of the juxtaglomerular apparatus (JGA), which senses and regulates Na recovery by the renal tubule. When the JGA is stimulated appropriately, it releases renin into the bloodstream. Here, renin breaks down angiotensinogen (a circulating plasma protein formed in the liver), to release angiotensin I.
631. Renin-Angiotensin-Aldosterone system: The latter serves as a substrate for angiotensin-converting enzyme (ACE). ACE is expressed by many tissues, including the kidney, but conversion largely occurs during transit through the lungs. The product is Ang-II, which constricts resistance vessels,stimulates ADH release from the posterior pituitary, stimulates thirst, andpromotes aldosterone release from the adrenal cortex.
642. Aldosterone: Aldosterone targets principal cells in the renal collecting tubule epithelium. It has multiple actions,all of which promote recovery of Na and osmotically obligated water from the tubule.Aldosterone acts by modifying expression of genes that encode Na channels and pumps, which is why it takes up to 48 hours for this pressure control pathway to become maximally effective.
653. Renin:The afferent arteriole of the renal glomerulus is a baroreceptor that triggers renin release from the granular cells when arteriolar pressure falls. Release is potentiated by the SNS, which activates following a drop in MAP.
674. Atrial natriuretic peptide: Atrial myocytes synthesize and store atrial natriuretic peptide (ANP), releasing it when stretched by high filling volumes.ANP has multiple sites of action along the length of the kidney tubule, all of which are geared toward excretion of Na and water.The ventricles release a related compound, brain natriuretic peptide, which has similar release characteristics and actions as ANP.
68D. Sodium intakeJust as thirst stimulates water intake, salt craving triggers a need to ingest NaCl.Salt appetite is controlled through the nucleus accumbens in the forebrain and is stimulated by aldosterone and Ang-II.
69Pressure Natriuresis. Arterial pressure is a signal for regulation of NaCl excretion. arterial pressure NaCl reabsorbed in the proximal tubule more NaCl to the macula densa TGF autoregulation RBF, GFR.Pressure natriuresis can normalize BP by decreasing the effective circulating volume – this response connects BP and ECFV.
70Renal-Body Fluid System for Arterial Pressure Control When the body contains too much extracellular fluid, the blood volume and arterial pressure risePressure Diuresis and Pressure NatriuresisAt high pressure, the kidneys excretes the excess volume into urine and relieves the pressureAt low pressure, the kidney excretes far less fluid than is ingested
71Pressure Control by Renal-Body Fluid Mechanism Over the long period, water and salt output must equal intakeEqulibrium pointReturn of the arterial pressure always exactly back to the equlibrium point in the “infinite feedback gain” principle
72Failure of increased TPR to elevate the long-term level of AP if fluid intake and renal function do not changeAP = Cardiac output x Total Peripheral ResistanceSo, increase in TPR should elevate APBut this acute rise in AP is not maintained if the kidneys function properlyWhy?Pressure diuresis and pressure natriuresis
73Failure of increased TPR to elevate the long-term level of AP if fluid intake and renal function do not change
74Increased Fluid Volume Can Elevate AP by Increasing Cardiac Output or Total Peripheral Resistance
75Importance of salt (NaCl) in the renal-body fluid diagram for arterial pressure regulation An increase in salt is far more likely to elevate AP than is an increase in water intakeWater can be eliminated easily, but salt notAccummulation of salt in the bodyStimulation of thirst center in the brainIncreased osmotic pressure stimulates release of vasopressin (ADH)
76Hypertension“Hypertension is defined as sustained abnormal elevation of the arterial blood pressure”
77Hypertension STROKE HEART FAILURE ATHEROSCLEROSIS Leads to wear and tearis a major risk factor for cardiovascular diseases such as:STROKEHEART FAILUREATHEROSCLEROSIS30% of world’s deaths
78Complications Complications as a result of hypertension include: StrokeDementiaMyocardial InfarctionCongestive Heart FailureRetinal VasculopathyRenal Disease or FailureSlide #18:Untreated, resistant or uncontrolled hypertension can result in these complications. Mild hypertension left untreated can progress into severe or malignant hypertension. Hypertension is usually asymptomatic until it reaches severe stages (Brashers, 2006).
79Chronic Hypertension is Caused by Impaired Renal Function Mean Arterial Pressure > 110 mmHg (normal is about 90 mmHg)Systolic >140, diastolic >90 mmHgHypertension can be lethalHeart failureDamage of a large vessel in the brain (cerebral infarct or stroke)Kidney failureVolume-loading hypertension means hypertension caused by excess accumulation of extracellular fluid in the body
80Volume-loading hypertension: Two separate sequential stages The first stage: increased fluid volume causing increased cardiac output hypertensionThe second stage: High blood pressure, high TPR but return of the cardiac output near the normalHypertensionMarked increase in TPRAlmost complete return of the extracellular fluid volume blood volume and cardiac output back to normalVolume-loading hypertension in patients who have no kidneys and need for dialysis
81Hypertension caused by primary Aldosteronism Another type of volume-loading hypertension is caused by excess aldosterone in the body – (other steroids)A small tumor of adrenal glands and primary aldosteronismAldesteron increases reabsorbtion of salt and water increased blood volume and reduced urine outputConsequently, hypertension develops
82The Renin-Angiotensin System Pressure control and Hypertension Renin is an enzyme released by the kidneys when the arterial pressure falls too lowIt is synthesized and stored in inactive form called prorenin in juxtaglomerular cellsJG cells are modified smooth muscle cells in the walls of afferent arteriolesRenin acts on angiotensinogen (a plasma globulin)Half life of renin is about 30 minsAngiotensin I, converting enzyme and Angiotensin II
83The Renin-Angiotensin System Pressure control and Hypertension
84Rapidity and Intensity of Vasoconstrictor Pressure Response to the Renin-Angiotensin System Renin-angiotensin vasoconstrictor system requires about 20 mins to become fully active
85Effect of Angiotensin in the Kidneys to Cause Renal Retention of Salt and Water Angiotensin acts directly on the kidneys to cause salt and water retentionMakes the kidneys retain salt and waterCauses vasoconstriction in renal arteriesAngiotensin causes the adrenal gland to secrete aldosterone- Aldosterone increases salt and water retention by the kidneys
86Role of Renin-Angiotensin System in Maintaining a Normal Arterial Pressure Despite Wide Variations in Salt IntakeWhen the renin-angiotensin system functions normally, pressure rises no more than 4 to 6 mmHg in response to as much as a 50-fold increase in salt intake
87Primary (Essential) Hypertension 90 to 95% of hypertension cases are of primaryIt is of unknown originGenetics: there is a strong hereditary tendencyEnvironment: Excess weight and sedentary life styleNeurohormonal mediators
88Some Characteristics of Primary Hypertension Cardiac output is increased due to additional blood flow required for the extra adipose tissue and increased metabolismSympathetic nerve activity (especially in kidneys) is increased in OW patients (leptin – vasomotor center ?)Angiotensin II and aldosterone are increased (sympathetic stimulation-renin-aldosterone …)Renal-pressure natriuresis mechanism is impairedIf hypertension is not treated, there may also be vascular damage in the kidney that can reduce glomerular filtration rate
89Summary for Arterial Pressure Regulation AP is regulated not by a single pressure controlling system (several inter-related systems)To achieveSurvivalReturning the blood volume and pressure back to normalMechanismsRapidly acting pressure control mechanismsIntermediate mechanisms that act after several minutes – hoursLong-term arterial pressure regulation
90Intermediate mechanisms that act after several minutes – hours Renin-Angiotensin vasoconstrictor mechanismStress-relaxation of the vasculatureShift of fluid through capillary walls in and out of circulation* These mechanisms become mostly activated within 30 mins to several hours
91Long term mechanisms for AP regulation Role of the kidneysMany factors can affect pressure-regulating level of the renal-body fluid mechanismAldosteroneRenin-Angiotensin systemNervous system (increased sympathetic activity)