1. 1 Review slides Lecture Exam 3

2. 2 Overview of the Endocrine System The endocrine system consists of - collections of cells located in tissues scattered throughout the body - that produce substances released into the blood (hormones) - to ultimately affect the activity and metabolism of target cells. Secrete intoAffect activity Endocrine glandsBloodInside cells Exocrine glandsDucts or on to free surfaceOutside cells

3. 3 Classification of Hormones Hormones Eicosanoids (cell membranes) (locally acting) Steroids (cholesterol-derived) Amino Acid Derivatives Amino acids Peptides Proteins, glycoproteins Lipid Derived

4. 4 Actions of Steroid Hormones hormone crosses membranes hormone combines with receptor in nucleus or cytoplasm synthesis of mRNA activated mRNA enters cytoplasm to direct synthesis of protein, e.g., aldosterone->Na/K Pump Magnitude of cellular response proportional to the number of hormone-receptor complexes formed (Thyroid hormone has a similar mechanism of action, even though it is a tyrosine derivative)

5. 5 Actions of Amino Acid-Derived Hormones adenylate cyclase activated ATP converted to cAMP cAMP (second messenger) promotes a series of reactions leading to cellular changes Magnitude of response is not directly proportional to the number of hormone-receptor complexes – it’s amplified hormone (first messenger) binds to receptor on cell membrane

6. 6 Control of Hormonal Secretions primarily controlled by negative feedback mechanism 1) Hormonal2) Neural 3) Humoral Control mechanisms for hormone release

7. 7 Target Cell Activation By Hormones Target cells must have specific receptors to be activated by hormones Magnitude of target cell activation depends upon –Blood levels of the hormone Rate of release from producing organ Rate of degradation (target cells, kidney, liver) Half-life –Relative numbers of receptors for the hormone Cellular receptors can be up- or down-regulated –Affinity (strength) of binding of the hormone to its receptor

8. 8 Pituitary Gland Control Hypothalamic releasing hormones stimulate cells of anterior pituitary (adenohypophysis) to release their hormones Nerve impulses from hypothalamus stimulate nerve endings in the posterior pituitary (neurohypophysis) gland to release its hormones Note the hypophyseal portal system of the adenohypophysis (two capillaries in series)

9. 9 Hormones of the Anterior Pituitary (SeT GAP) Tropic hormones control the activity of other endocrine glands All anterior pituitary hormones use second messengers (an ‘axis’)

10. 10 Overview of the Pituitary Hormones Figure from: Martini, Anatomy & Physiology, Prentice Hall, 2001 All anterior and posterior pituitary hormones bind to membrane receptors and use 2 nd messengers (cAMP) SeT GAP

11. 11 Hormone Summary Table I – Pituitary Hormones Tissue NameOriginDestinationAction on Target TissueControl of Release 1 FOLLICLE STIMULATING HORMONE (FSH) anterior pituitary males: semiiferous tubules of testes; females: ovarian follicle males: sperm production females: follicle/ovum maturation Gonadotropin Releasing Hormone (GnRH) LUETINIZING HORMONE (LH) anterior pituitary In males: interstitial cells in testes; in females: mature ovarian follicle males: testosterone secretion females: ovulation Gonadotropin Releasing Hormone (GnRH) THYROID STIMULATING HORMONE (TSH) anterior pituitary thyroidsecrete hormones Thyrotropin Releasing Hormone (TRH) GROWTH HORMONE (GH) anterior pituitary bone, muscle, fatgrowth of tissues Growth Hormone Rleasing Hormone (GHRH) ADRENOCORTICO- TROPIC HORMONE (ACTH) anterior pituitary adrenal cortexsecrete adrenal hormones Corticotropin Releasing Hormone (CRH) PROLACTIN (PRL) anterior pituitary mammary glandsproduce milk Prolactin Releasing Hormone (PRH) ANTI-DIURETIC HORMONE (ADH) (VASOPRESSIN) posterior pituitary distal convoluted tubule (DCT) reabsorption of water; increases blood pressure increase in osmolarity of plasma or a decrease in blood volume OXYTOCIN (OT) posterior pituitary uterine smooth muscle; breast contraction during labor; milk letdown Stretching of uterus; infant suckling Se(x) T G A P

12. 12 Hormone Summary Table II Tissue NameOriginDestinationAction on Target TissueControl of Release TRIIODOTHYRONINE (T3) & THYROXINE (T4) Thyroid (follicular cells) all cellsincreases rate of metabolism (BMR) Thyroid Stimulating Hormone (TSH) CALCITONINThyroid (C cells) Intestine, bone, kidney Decreases plasma [Ca 2+ ] (  intestinal absorp of Ca;  action of osteoclasts;  excretion of Ca by kidney  plasma [Ca 2+ ] PARATHYROID HORMONE (PTH) Parathyroids Intestine, bone, kidney Increases plasma [Ca 2+ ] (  intestinal absorp of Ca;  action of osteoclasts;  excretion of Ca by kidney  plasma [Ca 2+ ] EPINEPHRINE/ NOREPINEPHRINE (Catecholamines) Adrenal Medulla cardiac muscle, arteriole and bronchiole smooth muscle, diaphragm, etc increases heart rate and blood pressure... (fight or flight) Sympathetic Nervous System ALDOSTERONE (Mineralocorticoids) Adrenal Cortex Kidneys; sweat glands; salivary glands; pancreas reabsorption of water and Na (increases blood pressure) and excretion of K (mineralocorticoid) Angiotensin II  plasma [Na+]  plasma [K+] CORTISOL (Glucocorticoids) Adrenal Cortexall cells Diabetogenic; anti-inflammatory (glucocorticoid) ACTH INSULIN β-cells of Pancreatic Islets all cells, liver and skeletal muscle pushes glucose into cells from blood, glycogen formation (decreases blood glucose)  plasma [glucose] SNS GLUCAGON α-cells of pancreatic Islets liver and skeletal muscle breakdown of glycogen (increase in blood glucose)  plasma [glucose] TESTOSTERONETestes secondary sex organs development and maintenanceLH ESTROGENOvaries secondary sex organs development at puberty and maintenance throughout life LH NATRIURETIC PEPTIDES atria and ventricles of heart adrenal cortex, kidneys increased excretion of sodium and water from kidneys,  blood volume,  blood pressure Stretching of atria and ventricles

13. 13 Renin-angiotensin Pathway

14. 14 Stress Types of Stress physical stress psychological (emotional) stress (Stress is any condition, physical or emotional, that threatens homeostasis) Stress Response (General Adaptation Syndrome [GAS]) hypothalamus triggers sympathetic impulses to various organs epinephrine is released cortisol is released to promote longer-term responses Three general phases of the GAS to stress ARE: Alarm phase Resistance phase Exhaustion phase

15. 15 Responses to Stress Exhaustion -  lipid reserves -  production of glucocorticoids - electrolyte imbalance - damage to vital organs

16. 16 Diabetes (= Overflow) Diabetes Mellitus (DM) –Hyposecretion or hypoactivity of insulin –Three P’s of Diabetes Mellitus (mellitum = honey) Polyuria (increased urination) Polydipsia (increased thirst) Polyphagia (increased hunger) –Hyperglycemia, ketonuria, glycosuria Renal Glycosuria –excretion of glucose in the urine in detectable amounts –normal blood glucose concentrations or absence of hyperglycemia Diabetes Insipidus (insipidus = tasteless) –Hyposecretion or hypoactivity of ADH –Polyuria –Polydipsia

17. 17 Functions of the Kidneys Make urine Regulate blood volume and blood pressure Regulate plasma concentrations of Na +, K +, Cl -, HCO 3 -, and other ions Help to stabilize blood pH Conserve valuable nutrients Assist the liver in detoxification and deamination

18. 18 Anatomical Features of Kidneys Figure from: Martini, Anatomy & Physiology, Prentice Hall, 2001 Helps maintain position of kidney Kidneys are retroperitoneal

19. 19 Location of Kidneys Figure from: Martini, Anatomy & Physiology, Prentice Hall, 2001 Located retroperitoneally from T12 to L3 Left kidney is slightly higher than right kidney Adrenal glands sit on the medial and superior part of kidneys Nephro(s) = kidney Pyel(o) = pelvis

20. 20 The Nephron Nephrons are the structural and functional units of the kidney (80%) (20%) Vasa recta are associated with juxtamedullary nephrons Sympathetic nerve fibers from the ANS innervate the kidney

21. 21 Blood Flow Through Kidney and Nephron Know this!

22. 22 Renal Corpuscle (Glomerulus + Capsule) Efferent arteriole is smaller than the afferent arteriole This creates a high pressure (~55-60 mm Hg) in the glomerular capillary bed Filtrate in capsular space Podocytes form the visceral layer of the glomerular capsule. Their pedicels (foot processes) form filtration slits (or slit pores) that function in forming filtrate.

23. 23 The Nephron 1. Glomerular capsule 2. PCT – simple cuboidal with a brush border 3. Thin segment of the descending nephron loop - simple squamous epithelium 4. Thick ascending nephron loop - cuboidal/low columnar 5. DCT - simple cuboidal with no microvilli (specialized for secretion, not absorption) The order of the parts of the nephron is important to know (PCT) (DCT)

24. 24 Juxtaglomerular Apparatus Juxtaglomerular cells (JG) - modified smooth muscle cells in the wall of the afferent arteriole that contract (and secrete renin) Cells of the macula densa (MD) are osmoreceptors responding to solute concentration of filtrate MD + JG cells = juxtaglomerular apparatus

25. 25 Glomerular Filtrate and Urine Composition Glomerular filtrate is about the same composition as plasma: H 2 O, glucose, amino acids, urea, uric acid, creatine, creatinine, Na, Cl, K, HCO 3 -, PO 4 3-, SO 4 2-. But notice how different the composition of urine is. Additionally, note that protein is not normally present in urine. (1.8 L/day)

26. 26 Urine Formation Glomerular Filtration (GF) *Adds to volume of urine produced substances move from blood to glomerular capsule Tubular Reabsorption (TR) *Subtracts from volume of urine produced substances move from renal tubules into blood of peritubular capillaries glucose, water, urea, proteins, creatine amino, lactic, citric, and uric acids phosphate, sulfate, calcium, potassium, and sodium ions Tubular Secretion (TS) *Adds to volume of urine produced substances move from blood of peritubular capillaries into renal tubules drugs and ions, urea, uric acid, H +  Urine formation = GF + TS - TR Fluid from plasma passes into the glomerular capsule and becomes filtrate at an average rate of 125 ml/minute. This is known as the Glomerular Filtration Rate (GFR)

27. 27 Glomerular Filtration Glomerular filtrate is plasma that passes through 1) the fenestrae of the capillary endothelium, 2) the basement membrane around the endothelium, and 3) the filtration slits (slit pores) of the pedicels This is called the ‘filtration membrane’ Glomerular filtration is a mechanical process based primarily on molecule size

28. 28 Glomerular Filtration and Urine Formation Glomerular Filtration Rate (GFR) is directly proportional to the net filtration pressure GFR  125 ml/min (180 L/day) Urine output is only 0.6 – 2.5 L per day (an average of about 1.8 L, or about 1% of glomerular filtrate) Net Filtration Pressure = force favoring filtration – forces opposing filtration (*glomerular capillary ( capsular hydrostatic pressure hydrostatic pressure) + glomerular capillary osmotic pressure ) NFP = HP g – (HP c + OP g ) 99% of filtrate is reabsorbed!! * Blood pressure is the most important factor altering the glomerular hydrostatic pressure (and NFP). A MAP fall of 10% will severely impair glomerular filtration; a fall of 15-20% will stop it.

29. 29 Summary of Factors Affecting GFR FactorEffect Vasoconstriction Afferent arteriole ( Δ radius  GFR)  GFR Efferent arteriole ( Δ radius  1/GFR) ↑ GFR Vasodilation Afferent arteriole↑ GFR Efferent arteriole  GFR Increased capillary hydrostatic pressure↑ GFR Increased colloid osmotic pressure  GFR Increased capsular hydrostatic pressure  GFR Know this table – it’s important!

30. 30 Three Major Ways of Regulating GFR 1) Autoregulation –Maintains GFR despite changes in local blood pressure and blood flow (between 90 – 180 mm Hg mean systemic pressure) –Myogenic (muscular) mechanism – contraction of afferent arteriolar vascular smooth muscle when stretched (increased BP); relaxation occurs when BP declines –Tubuloglomerular mechanism – MD cells detect  flow rate and/or  osmolarity of filtrate in DCT -> JG cells contract -> afferent arteriole constricts ->  GFR

31. 31 Three Major Ways of Regulating GFR 2) Neural (Autonomic) Regulation –Mostly sympathetic postganglionic fibers = vasoconstriction of afferent arterioles  GFR (conserves water, redirects blood to other organs) –Stimulates juxtaglomerular apparatus to secrete renin –May override autoregulatory mechanism at afferent arteriole 3) Hormonal Regulation –Renin-angiotensin system –  ECF volume and BP –Atrial Natriuretic Peptide (ANP) - ↑ GFR, ↑ fluid loss (dilates afferent arteriole, constricts efferent arteriole)

32. 32 Renin-Angiotensin System Renin is released by the juxtaglomerular apparatus due to: 1) Decline of BP (Renin  1/Pressure) 2) Juxtaglomerular stimulation by sympathethic NS 3) Decline in osmotic concentration of tubular fluid at macula densa ( Renin  1/[NaCl] ) Stabilizes systemic blood pressure and extracellular fluid volume (ACE) Actions of Angiotensin II

33. 33 Tubular Reabsorption in PCT 65% of filtrate volume is reabsorbed in the PCT 8 mm Hg  COP Tubular fluid All uric acid, about 50% of urea, and no creatinine is reabsorbed Tubular reabsorption - reclaiming of substances in filtrate by body (tubule  blood) Peritubular cap: 1) Low hydrostatic pressure 2) High COP 3) High permeability Renal threshold is the plasma level (concentration) above which a particular solute will appear in urine, e.g., 180 mg/dl

34. 34 Summary of Reabsorption and Secretion Nephron Loop (of Henle) ProcessPCTDescendingAscendingDCTCollecting duct Reabsorption Glucose, aa, protein, urea, uric acid, Na +, Cl -, HCO 3 - H 2 O Na + /Cl -, K + (NO H 2 O) Na + /Cl - H 2 O HCO 3 - H 2 O (only if ADH is present), urea Secretion Creatinine H + Some drugs Urea - H + /K + NH 4 + -

35. 35 Reabsorption in the PCT SubstanceMechanism of Reabsorption Notes Na + (Cl - )Primary Active TransportNa + reabsorption is the driving force for most other reabsorption H2OH2OOsmosisClosely associated with movement of Na + (Obligatory water reabsorption) GlucoseSecondary Active transportLimited # of molecules can be handled (T m = 375 mg/min); attracts H 2 0 Amino AcidsSecondary Active transportThree different active transport modalities; difficult to overwhelm Other electrolytesSecondary Active transport

36. 36 Secretion in the PCT and DCT In the DCT potassium ions or hydrogen ions may be secreted in exchange for reabsorbed sodium ions. Reabsorption of Na + in the DCT is increased by the hormone, aldosterone. Other compounds are actively secreted as well, e.g., histamine, ammonia, creatinine, penicillin, phenobarbital. Active Active and Passive Renal threshold is the plasma level (concentration) above which a particular solute will appear in urine, e.g., 180 mg/dl

37. 37 Summary of Events in the Nephron 1.Filtrate produced 2.Reabsorption of 65% of filtrate 3.Obligatory water reabsorption 4.Reabsorption of Na + and Cl - by active transport (NO H 2 O reabsorption) 5,6. Facultative reabsorption of water (ADH is needed) 7. Absorption of solutes and water by vasa recta to maintain osmotic gradient (Aldosterone)

38. 38 The Countercurrent Multiplier Figure from: Martini, Anatomy & Physiology, Prentice Hall, 2001 The mechanism shown is called the “countercurrent multiplier” Countercurrent multiplier allows the kidneys to vary the concentration of urine Vasa recta maintains the osmotic gradient of the renal medulla so the countercurrent multiplier can work Approximate normal osmolarity of body fluids Reduced osmolarity of tubular fluid due to action of counter- current multiplier

39. 39 Urea,Uric Acid, and Diuretics Urea product of amino acid catabolism plasma concentration reflects the amount or protein in diet enters renal tubules through glomerular filtration 50% reabsorbed rest is excreted Uric Acid product of nucleic acid metabolism enters renal tubules through glomerular filtration 100% of filtered uric acid is reabsorbed 10% secreted and excreted A diuretic promotes the loss of water in the urine. Anything that adds more solute to tubular fluid will attract H 2 O and can function as a diuretic to increase the volume of urine, e.g., glucose (osmotic diuretic)

40. 40 Urine Urine composition varies depending upon –Diet –Level of activity Major constituents of urine –H 2 O (95%) –Creatinine (remember, NONE of this is reabsorbed) –Urea (most abundant solute), uric acid –Trace amounts of amino acids –Electrolytes –Urochrome (yellow color), urobilin, trace of bilirubin Normal urine output is 0.6-2.5 L/day (25-100 ml/hr) Output below about 25 ml/hour = kidney failure (oliguria -> anuria)

41. 41 Terms to know… Anuria – absence of urine Diuresis – increased production of urine Dysuria – difficult or painful urination Enuresis – uncontrolled (involuntary) urination Glycosuria (glucosuria) – glucose in the urine Hematuria – blood in the urine Oliguria – scanty output of urine Polyuria – excessive urine output

42. 42 Elimination of Urine nephrons collecting ducts renal papillae minor and major calyces renal pelvis ureters urinary bladder urethra outside world Flow of Urine Know this…

43. 43 Ureters and Urinary Bladder Ureters - retroperitoneal tubes about 25 cm long - carry urine from kidneys to bladder by peristaltic contractions Urinary bladder (cyst[o]) - temporary storage reservoir for urine Smooth muscular layer runs in all directions (detrusor muscle) under parasympathetic control. Contraction compresses the bladder and causes urine to flow into urethra Internal sphincter is thickening of detrusor muscle at neck of bladder – closed when detrusor is relaxed; open when detrusor contracts Urinary elimination system is lined mostly by transitional epithelium

44. 44 Urethra Note the long male urethra (about 18-20 cm). There are three sections to the male urethra: - Prostatic urethra - Membranous urethra - Penile urethra Figure from: Saladin, Anatomy & Physiology, McGraw Hill, 2007 Note the short urethra in females (about 4 cm)

45. 45 Micturition (Urination) Reflex Figure from: Saladin, Anatomy & Physiology, McGraw Hill, 2007

46. 46 Fluid and Body Compartments ‘Compartments’ commonly behave as distinct entities in terms of ion distribution, but ICF and ECF osmotic concentrations (about 290-300 mOsm/L) are identical. This is because H 2 O is free to flow between compartments and any disturbance in osmolarity is quickly corrected by H 2 O movement. About 40 L of fluid (avg. adult male; less in females due to greater proportion of body fat)  25L  15L Major forces affecting movement of fluid between compartments: 1) Hydrostatic pressure 2) Osmotic pressure (ICF) (ECF)

47. 47 Body Fluid Ionic Composition ECF major ions: - sodium, chloride, and bicarbonate ICF major ions: - potassium, magnesium, and phosphate (plus negatively charged proteins) You should know these chemical symbols and charges of ions

48. 48 Fluid (Water) Balance * urine production is the most important regulator of water balance (water in = water out) Balance; =

49. 49 Major Regulators of H 2 O Intake and Output Regulation of water intake increase in osmotic pressure of ECF → osmoreceptors in hypothalamic thirst center → stimulates thirst and drinking Regulation of water output Obligatory water losses (must happen) insensible water losses (lungs, skin) water loss in feces water loss in urine (min about 500 ml/day) increase in osmotic pressure of ECF → ADH is released concentrated urine is excreted more water is retained LARGE changes in blood vol/pressure → Renin and ADH release

50. 50 Dehydration and Overhydration Dehydration osmotic pressure increases in extracellular fluids water moves out of cells osmoreceptors in hypothalamus stimulated hypothalamus signals posterior pituitary to release ADH urine output decreases Overhydration osmotic pressure decreases in extracellular fluids water moves into cells osmoreceptors inhibited in hypothalamus hypothalamus signals posterior pituitary to decrease ADH output urine output increases ‘Drunken’ behavior (water intoxication), confusion, hallucinations, convulsions, coma, death Severe thirst, wrinkling of skin, fall in plasma volume and decreased blood pressure, circulatory shock, death

51. 51 Osmolarity and Milliequivalents (mEq) Recall that osmolarity expresses total solute concentration of a solution (Osmolarity = Amt of solute / Vol of H 2 O) –Osmolarity (effect on H 2 O) of body solutions is determined by the total number of dissolved particles (regardless of where they came from) –The term ‘osmole’ reflects the number of particles yielded by a particular solute (milliosmole, mOsm, = osmole/1000) 1 mole of glucose (180g/mol) 1 mole of NaCl (58g/mol) An equivalent is the positive or negative charge equal to the amount of charge in one mole of H + –A milliequivalent (mEq) is one-thousandth of an Eq –Used to express the concentration of CHARGED particles in a solution -> 1 osmole of particles -> 2 osmoles of particles

52. 52 Electrolyte Balance Electrolyte balance is important because: 1.It regulates fluid (water) balance 2.Concentrations of individual electrolytes can affect cellular functions Electrolyte Normal plasma concentration (mEq/L) Major mechanism(s) regulating retention and loss Na + 1401. Renin-angiotensin pathway 2. Aldosterone (Angiontensin II, Na +, K + ) 3. Natriuretic peptides Cl - 105Follows Na + K+K+ 4.01. Secretion at DCT (aldosterone sensitive) Ca 2+ 5.01. Calcitonin (children mainly) 2. Parathyroid hormone 3. Vitamin D (dietary uptake from intestines)

53. 53 Summary Table of Fluid and Electrolyte Balance ConditionInitial ChangeInitial EffectCorrectionResult Change in OSMOLARITY (**Corrected by change in H 2 O levels)  H 2 O in the ECF  Na + concentration,  ECF osmolarity  Thirst →  H 2 O intake  ADH →  H 2 O output  H 2 O in the ECF  Na + concentration,  ECF osmolarity  Thirst →  H 2 O intake  ADH →  H 2 O output  H 2 O in the ECF Change in VOLUME (**Corrected by change in Na + levels)  H 2 O/Na + in the ECF  volume,  BP Renin-angiotensin:  Thirst  ADH  aldosterone  vasoconstriction  H 2 O intake  Na + /H 2 O reabsorption  H 2 O loss  H 2 O/Na + in the ECF  volume,  BP Natriuretic peptides:  Thirst  ADH  aldosterone  H 2 O intake  Na + /H 2 O reabsorption  H 2 O loss You should understand this table

54. 54 Acid/Base Buffers BufferTypeSpeedEliminate H+ from body? Examples ChemicalPhysical (first line of defense) SecondsNoBicarbonate, phoshate, proteins (ICF, plasma proteins, Hb) RespiratoryPhysiologicalMinutesYes (indirectly as CO 2 ) H 2 O + CO 2   H + + HCO 3 - RenalPhysiologicalHours - Days YesH + excretion HCO 3 - excretion/retention* A buffer resists changes in pH *Normal plasma [HCO 3 - ] ≈ 25 mEq/L

55. 55 Acidosis and Alkalosis If the pH of arterial blood drops to 6.8 or rises to 8.0 for more than a few hours, survival is jeopardized Classified according to: 1.Whether the cause is respiratory (CO 2 ), or metabolic (other acids, bases) 2.Whether the blood pH is acid or alkaline Respiratory system compensates for metabolic acidosis/alkalosis Renal system compensates for respiratory acidosis/alkalosis