BASIM ZWAIN LECTURE NOTESBASIM ZWAIN LECTURE NOTES

Renal system

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Kidney consists of 8-10 conical pyramids, bases in Kidney consists of 8-10 conical pyramids, bases in outer cortex, apices toward pelvis, medulla subdiv-outer cortex, apices toward pelvis, medulla subdiv-ided into outer & inner zones, outer zone into outer ided into outer & inner zones, outer zone into outer & inner stripes, pyramid pours urine into minor & inner stripes, pyramid pours urine into minor calyx, every 2-3 calyces unite to form major calyx calyx, every 2-3 calyces unite to form major calyx which unites with other major calyces to form which unites with other major calyces to form renal pelvis that leads urine through ureter which renal pelvis that leads urine through ureter which emerges through hilum of kidney from which renal emerges through hilum of kidney from which renal artery enters & renal vein leaves. Ureters pour into artery enters & renal vein leaves. Ureters pour into urinary bladder from which urethra emergesurinary bladder from which urethra emerges..

Renal blood supplyRenal blood supply

25%25% of cardiac output of cardiac output ﴾﴾1.25 L\min1.25 L\min ﴿ ﴿ supplies renal supplies renal tissue, greater flow to cortex tissue, greater flow to cortex ﴾﴾97%97%﴿﴿. Renal artery, . Renal artery, segmental, interlobar, arcuate arteries, segmental, interlobar, arcuate arteries, interlobular interlobular ﴾﴾radial art.s or medullary raysradial art.s or medullary rays﴿﴿, , afferent arterioles & glomerular capillaries, afferent arterioles & glomerular capillaries, efferent arterioles , peri-tubular capillaries, (vasa efferent arterioles , peri-tubular capillaries, (vasa recta,) interlobular veins, arcuate, interlobar, recta,) interlobular veins, arcuate, interlobar, segmental and renal veinssegmental and renal veins..

NephronsNephrons

Structural & functional units, more than million, in Structural & functional units, more than million, in each kidney, composed of the following structures:each kidney, composed of the following structures: GlomerulusGlomerulus: globular tuft of capillaries, : globular tuft of capillaries, afferent afferent & & efferentefferent arteriole, inside arteriole, inside Bowman's capsuleBowman's capsule, Bd , Bd is filtered & transferred to renal tubules: is filtered & transferred to renal tubules: proximal proximal tubuletubule((PCT or pars convoluta& PST or pars rectaPCT or pars convoluta& PST or pars recta) ) , , ﴾﴾tDHLtDHL﴿﴿ , , ﴾﴾tAHLtAHL﴿﴿, , ﴾﴾TAHLTAHL﴿﴿, , distal tubuledistal tubule, , JGAJGA, , DCTDCT, , collecting tubulescollecting tubules, , collecting tubescollecting tubes, , cortical & cortical &

medullary CDmedullary CD, , main ductmain duct, , minor & major calyxminor & major calyx . .

Cortical nephronsCortical nephrons: 70%-80%, outer two thirds of : 70%-80%, outer two thirds of cortex, no tAHL, efferent narrower than afferent. cortex, no tAHL, efferent narrower than afferent. Juxtamedullary nephrons:Juxtamedullary nephrons: inner third of cortex, inner third of cortex,

long tAHL, efferent wider than afferentlong tAHL, efferent wider than afferent . .

Glomerular capillary membraneGlomerular capillary membrane

Three layers: capillary endothelium, BM & Three layers: capillary endothelium, BM & visceral layer of Bowman's capsule (podocytes)visceral layer of Bowman's capsule (podocytes)..

Endothelial layer: fenestrated, even proteins Endothelial layer: fenestrated, even proteins ﴾﴾but but not cellsnot cells ﴿ ﴿ can passcan pass..

BM: high permeability, BM: high permeability, ﴾﴾>100 times other capillary >100 times other capillary membranesmembranes .﴿ .﴿

Other filtered materials & ions pass easily through Other filtered materials & ions pass easily through membrane & slit pores between feet of podocytesmembrane & slit pores between feet of podocytes . .

Functions of kidneyFunctions of kidney

Regulation of ECF vol., osmolarity & composition, Regulation of ECF vol., osmolarity & composition, regulation of BP, acid-base balance, bone metaboli-regulation of BP, acid-base balance, bone metaboli-sm (excretion of calcium & phosphate ions & sm (excretion of calcium & phosphate ions & formation 1, 25 dihydroxycholecalcipherol), produ-formation 1, 25 dihydroxycholecalcipherol), produ-ction of erythropoietin hormone, excretion of ction of erythropoietin hormone, excretion of various metabolic waste products, drugs, toxic various metabolic waste products, drugs, toxic substances & poisons.substances & poisons.

Renal clearance (Cx) = GFR – TR + TSRenal clearance (Cx) = GFR – TR + TS

GFR = glomerular filtration rate of x GFR = glomerular filtration rate of x

TR = tubular reabsorption of x TR = tubular reabsorption of x

TS = tubular secretion of xTS = tubular secretion of x

Glomerular filtration rate Glomerular filtration rate ﴾﴾GFRGFR﴿﴿

GFR = RPF * FFGFR = RPF * FF

FF = filtration fraction, RPF = renal plasma flow FF = filtration fraction, RPF = renal plasma flow

GFR = 625 ml\min * 20%GFR = 625 ml\min * 20%

GFR = 125 ml\minGFR = 125 ml\min

RPF = renal blood flow RPF = renal blood flow ﴾ ﴾ RBF RBF ﴿﴿* (1-hematocrit)* (1-hematocrit)

= 1250 ml\min * 0.5= 1250 ml\min * 0.5

= 625 ml\min = 625 ml\min

Measurements of GFR and RBFMeasurements of GFR and RBF

Substance used to measure GFR & RBF must: Substance used to measure GFR & RBF must: 1. Not be toxic.1. Not be toxic.2. Not be stored, or metabolized by kidney.2. Not be stored, or metabolized by kidney.3. Not be produced, secreted or reabsorbed by 3. Not be produced, secreted or reabsorbed by renal tubules.renal tubules.4. Not affect GFR or RBF by itself.4. Not affect GFR or RBF by itself.

Measurement of GFRMeasurement of GFREndogenous (creatinine) or exogenous (inulin) Endogenous (creatinine) or exogenous (inulin) substance used to measure GFR.substance used to measure GFR. GFR = CGFR = Cinin = U = Uinin * V \ P * V \ Pinin

Where CWhere Cinin = Clearance of inulin = Clearance of inulin

UUinin = Urinary concentration of inulin = Urinary concentration of inulin

V = Urine flowV = Urine flow PPinin = Plasma concentration of inulin = Plasma concentration of inulin

Measurement of RBFMeasurement of RBFRBF = RPF \ (1-hematocrit)RBF = RPF \ (1-hematocrit)When When xx is 100% extracted from plasma& excreted; is 100% extracted from plasma& excreted; its extraction ratio Eits extraction ratio Exx= 1.0 & its clearance= C= 1.0 & its clearance= Cxx

RPF = CRPF = Cxx \ E \ Ex x = C= Cxx \ 1.0 \ 1.0 == CCxx

Substance (x) is not found yet. Instead, substance Substance (x) is not found yet. Instead, substance called paraaminohippuric acid (PAH) its extraction called paraaminohippuric acid (PAH) its extraction ratio is 0.9 (Eratio is 0.9 (EPAHPAH = 0.9) = 0.9)

RPF = CRPF = CPAHPAH \ E \ EPAHPAH = C = CPAHPAH \ 0.9 \ 0.9

Factors affecting GFRFactors affecting GFR

GFR = Kf * (net ultrafiltration pressure) GFR = Kf * (net ultrafiltration pressure) = Kf * (PG + ΠB – PB - ΠG)= Kf * (PG + ΠB – PB - ΠG) = Kf * (60 + 0 – 18 - 32) respectively= Kf * (60 + 0 – 18 - 32) respectively = Kf * (+10 mmHg)= Kf * (+10 mmHg)KfKf=ultrafiltration coefficient (=surface area*capill-=ultrafiltration coefficient (=surface area*capill-ary permeability), ary permeability), PP=hydrostatic pr., =hydrostatic pr., ΠΠ=smotic pr. =smotic pr. of colloids, of colloids, BB=inside Bowman's capsule, =inside Bowman's capsule, GG=inside =inside glomerular capillaries. These are Starling forcesglomerular capillaries. These are Starling forces

RBFRBF: increases GFR: increases GFRFFFF: increases GFR: increases GFRVasoconstriction of afferent arteriolesVasoconstriction of afferent arterioles decreases decreases GFR (decreased PG) GFR (decreased PG) Slight vasoconstriction of efferent arteriolesSlight vasoconstriction of efferent arterioles increases GFR (increased PG) increases GFR (increased PG) Severe vasoconstriction of efferent arteriolesSevere vasoconstriction of efferent arterioles decreases GFR (increased ΠG)decreases GFR (increased ΠG)

BASIM ZWAIN LECTURE NOTESBASIM ZWAIN LECTURE NOTES

Renal system

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Control of GFRControl of GFR

1-Sympathetic nervous activity1-Sympathetic nervous activity2-Hormones and autacoids2-Hormones and autacoids3-Autoregulation3-Autoregulation4-Plasma levels of amino acids and glucose4-Plasma levels of amino acids and glucose

1-Sympathetic nervous activity1-Sympathetic nervous activity:Strong sympathetic :Strong sympathetic activity decreases GFR e.g., in severe hemorrhage activity decreases GFR e.g., in severe hemorrhage & cerebral ischemia while role of parasympathetic & cerebral ischemia while role of parasympathetic (vagal) innervations is yet unknown.(vagal) innervations is yet unknown.2-Hormones&autacoids2-Hormones&autacoids:Adrenaline, noradrenaline :Adrenaline, noradrenaline , angiotensin II, aspirin& endothelin decrease , angiotensin II, aspirin& endothelin decrease GFR. GFR. Nitric oxide, prostaglandin & bradykinin increase Nitric oxide, prostaglandin & bradykinin increase GFRGFR

3-Autoregulation3-Autoregulation::a.Juxtaglomerular feedback mechanisma.Juxtaglomerular feedback mechanism: Juxtaglo-: Juxtaglo-merular apparatus (JGA): specific distal tubular merular apparatus (JGA): specific distal tubular epithelial cells (macula densa: osmoreceptors, epithelial cells (macula densa: osmoreceptors, sensitive to changes in conc. of NaCl) in contact sensitive to changes in conc. of NaCl) in contact with specific smooth muscle cells in wall of afferent with specific smooth muscle cells in wall of afferent arterioles, juxtaglomerular cells. arterioles, juxtaglomerular cells.

When GFR is decreased; tubular flow slows down, When GFR is decreased; tubular flow slows down, increased tubular reabsorption of NaCl, decrease increased tubular reabsorption of NaCl, decrease NaCl near osmoreceptors, macula densa send NaCl near osmoreceptors, macula densa send impulses to JG cells to relax, vasodilatation of impulses to JG cells to relax, vasodilatation of afferent arterioles, increase Bd flow to glomerular afferent arterioles, increase Bd flow to glomerular capillaries, increase GFR & vice versa capillaries, increase GFR & vice versa Renin is also produced by JG cells in response to Renin is also produced by JG cells in response to increase in GFR or RBF, production of angiotensin increase in GFR or RBF, production of angiotensin I & angiotensin II to decrease GFR & RBF.I & angiotensin II to decrease GFR & RBF.

b.Myogenic mechanismb.Myogenic mechanism: Increased RBF that causes : Increased RBF that causes increase in GFR; at the same time causes distension increase in GFR; at the same time causes distension of afferent arterioles and stretch of smooth muscles of afferent arterioles and stretch of smooth muscles lining their walls. This stretch results in myogenic lining their walls. This stretch results in myogenic contraction of smooth muscles & vasoconstriction contraction of smooth muscles & vasoconstriction of afferent arterioles & decreased RBF & GFR. of afferent arterioles & decreased RBF & GFR.

4- Plasma levels of amino acids & glucose4- Plasma levels of amino acids & glucose: tubular : tubular reabsorption of amino acid and glucose is reabsorption of amino acid and glucose is unlimited , when plasma levels of amino acids and unlimited , when plasma levels of amino acids and glucose increase; tubular reabsorption increase, glucose increase; tubular reabsorption increase, decreased amounts of NaCl near osmoreceptors of decreased amounts of NaCl near osmoreceptors of macula densa, send impulses to JG cells to relax macula densa, send impulses to JG cells to relax resulting in vasodilatation of afferent arterioles, resulting in vasodilatation of afferent arterioles, increase Bd flow to glomerular capillaries, increase increase Bd flow to glomerular capillaries, increase GFR.GFR.

Tubular reabsorptionTubular reabsorption

Highly selective process, passive or active, Some Highly selective process, passive or active, Some substances completely reabsorbed: aa & glucose, substances completely reabsorbed: aa & glucose, some are mostly reabsorbed: bicarbonates & some some are mostly reabsorbed: bicarbonates & some electrolytes, some are mostly reabsorbed in the electrolytes, some are mostly reabsorbed in the presence of hormones:water reabsorption increases presence of hormones:water reabsorption increases in presence of antidiuretic hormone, sodium ions in presence of antidiuretic hormone, sodium ions reabsorption in presence of aldosterone and\or reabsorption in presence of aldosterone and\or angiotensin II hormones.angiotensin II hormones.

Many substances are reabsorbed along with other Many substances are reabsorbed along with other substances like chloride ions which follow sodium substances like chloride ions which follow sodium ions, sodium chloride salt which follows water. ions, sodium chloride salt which follows water. Some substances 50% reabsorbed (50% excreted) Some substances 50% reabsorbed (50% excreted) like urea. Some substances completely excreted like like urea. Some substances completely excreted like creatinine and some drugs and poisons.creatinine and some drugs and poisons.

There is glomerulotubular balance, when GFR There is glomerulotubular balance, when GFR increases; tubular reabsorption increases. But increases; tubular reabsorption increases. But active transport processes may be saturated when active transport processes may be saturated when tubular lumen overloaded. Maximum tubular load tubular lumen overloaded. Maximum tubular load just before saturation is just before saturation is transport maximum (Tm)transport maximum (Tm). . Maximum plasma conc. before a substance starts Maximum plasma conc. before a substance starts to appear in urine is its to appear in urine is its renal thresholdrenal threshold=Tm\GFR=Tm\GFR

Tm of glucose(TmG) is about Tm of glucose(TmG) is about 325 mg\min325 mg\min, its ideal , its ideal renal threshold is 325\125 =2.6 mg\ml = renal threshold is 325\125 =2.6 mg\ml = 260 mg\dL260 mg\dLBut actual renal threshold for glucose is about But actual renal threshold for glucose is about 180 180 mg\dLmg\dL, this difference may be due to that not all of , this difference may be due to that not all of renal tubules have the same Tm and that some of renal tubules have the same Tm and that some of the filtered glucose molecules before Tm bypass the filtered glucose molecules before Tm bypass reabsorption.reabsorption.

Factors affecting tubular reabsorptionFactors affecting tubular reabsorption

TR = Kf * (net reabsorption pressure)TR = Kf * (net reabsorption pressure) = Kf * (Pif – Pc + Πc - Πif)= Kf * (Pif – Pc + Πc - Πif) = Kf * (6 – 13 + 32 – 15) mmHg respectively= Kf * (6 – 13 + 32 – 15) mmHg respectively = Kf * (+10 mmHg)= Kf * (+10 mmHg)Kf Kf is constant depends on surface area, thickness & is constant depends on surface area, thickness & permeability, permeability, PP is hydrostatic pr., is hydrostatic pr., ΠΠ is osmotic pr. is osmotic pr. of colloids, of colloids, cc is peritubular capillaries, and is peritubular capillaries, and ifif is is interstitial fluidinterstitial fluid

Control of tubular reabsorptionControl of tubular reabsorption

1- Sympathetic activity1- Sympathetic activity: increases Na: increases Na++ reabsorption reabsorption2- Hormonal activity: 2- Hormonal activity: A-AldosteroneA-Aldosterone: : adrenal cortex, acts on principal adrenal cortex, acts on principal cells of distal tubules, increase Nacells of distal tubules, increase Na++ reabsorption & reabsorption & KK++ excretion. It increases permeability of luminal excretion. It increases permeability of luminal membrane to Namembrane to Na++ & stimulates Na & stimulates Na++-K-K++ pump in pump in basolateral membrane. Adrenal insufficiency basolateral membrane. Adrenal insufficiency (Addison's disease) results in excessive Na(Addison's disease) results in excessive Na++ loss & loss & KK++ retention while adrenal hyperactivity (Cushing retention while adrenal hyperactivity (Cushing syndrome) results in Nasyndrome) results in Na++ retention & K retention & K++ depletion depletion

B-Angiotensin-IIB-Angiotensin-II: Produced by lungs from : Produced by lungs from angiotensin-I (produced in liver from angiotensino-angiotensin-I (produced in liver from angiotensino-gen or called renin). Renin is formed in kidneys. It gen or called renin). Renin is formed in kidneys. It acts directly (or indirectly after stimulation of acts directly (or indirectly after stimulation of aldosterone) to increase sodium ions reabsorption. aldosterone) to increase sodium ions reabsorption. C-Antidiuretic hormone (vasopressin)C-Antidiuretic hormone (vasopressin): produced : produced from posterior pituitary gland and it acts on distal from posterior pituitary gland and it acts on distal and collecting tubules and ducts to increase water and collecting tubules and ducts to increase water reabsorption and urine concentration. reabsorption and urine concentration.

D- Atrial natriuretic peptide (ANP)D- Atrial natriuretic peptide (ANP): Produced by : Produced by cardiac atria in response to any increase in Bd vol. cardiac atria in response to any increase in Bd vol. & acts especially on collecting ducts to decrease & acts especially on collecting ducts to decrease sodium and water reabsorption and so, increase sodium and water reabsorption and so, increase urine excretion to restore normal Bd vol. urine excretion to restore normal Bd vol. E-Parathyroid hormonesE-Parathyroid hormones:Produced by parathyroid :Produced by parathyroid glands & act especially on TAHL (& DCT) to glands & act especially on TAHL (& DCT) to increase calcium and magnesium ions reabsorption increase calcium and magnesium ions reabsorption and decrease phosphate reabsorption.and decrease phosphate reabsorption.

Regulation of ECF osmolarityRegulation of ECF osmolarity

Normal ECF osmolarity is about 280-300 mosm\L Normal ECF osmolarity is about 280-300 mosm\L and it is mostly dependant on sodium ions conc. and it is mostly dependant on sodium ions conc. (142 mEq\L). Normal daily sodium ions intake (142 mEq\L). Normal daily sodium ions intake must equals its daily output = 10-20 mEqmust equals its daily output = 10-20 mEq

Na+ intake ECF volume Blood pressure Angiotensin II Baroreceptors Na+ excretion Pressure natriuresis Brain stem Aldosterone Na+ reabsorption Sympathetic activity

Plasma osmolarity (PPlasma osmolarity (Posmosm) calculated from plasma ) calculated from plasma

sodium conc. (Psodium conc. (PNaNa++)…. P)…. Posmosm = 2.1 * P = 2.1 * PNaNa++

But, in patients with renal diseases, plasma conc.s But, in patients with renal diseases, plasma conc.s of urea & glucose are also calculated.of urea & glucose are also calculated.When PWhen Posmosm decreases; excretion of large amounts of decreases; excretion of large amounts of

diluted urine (down to 50 mosm\L) while when Pdiluted urine (down to 50 mosm\L) while when Posmosm

increases; excretion of small amounts of highly increases; excretion of small amounts of highly conc. urine (up to 1200 mosm\L).conc. urine (up to 1200 mosm\L).

Human body must get rid of not less than 600 Human body must get rid of not less than 600 mosm of metabolic wastes per day. So, it is very mosm of metabolic wastes per day. So, it is very necessary to excrete not less than 0.5 liters of necessary to excrete not less than 0.5 liters of highly concentrated urine daily:highly concentrated urine daily:

600 mosm\day = 0.5 L\day this is the minimum obligatory urine volume 1200 mosm\L

According to equation, when no conc. urine; the According to equation, when no conc. urine; the minimum obligatory urine volume will increase minimum obligatory urine volume will increase resulting in excessive loss of body fluids (diabetes resulting in excessive loss of body fluids (diabetes insipidus). Excessive intake of hyperosmotic fluids insipidus). Excessive intake of hyperosmotic fluids like sea water will seriously increase Plike sea water will seriously increase Posmosm & min. & min.

obligatory urine vol. even with maximum urine obligatory urine vol. even with maximum urine conc. resulting in death from dehydration. conc. resulting in death from dehydration.

Ability of kidney to conc. urine requires presence Ability of kidney to conc. urine requires presence of hyperosmotic medulla created by of hyperosmotic medulla created by countercurrent mechanism & urea recirculation & countercurrent mechanism & urea recirculation & ADH. ADH.

Countercurrent mechanismCountercurrent mechanism

Descending & ascending limbs of Henle's loop and Descending & ascending limbs of Henle's loop and vasa recta run long distance parallel, counter & in vasa recta run long distance parallel, counter & in close proximity to each other. Descending limbs are close proximity to each other. Descending limbs are called countercurrent multipliers because they called countercurrent multipliers because they continuously bring new NaCl to medulla while continuously bring new NaCl to medulla while ascending vasa recta are called countercurrent ascending vasa recta are called countercurrent exchangers because they continuously draw back exchangers because they continuously draw back water from medulla to the systemic circulation. water from medulla to the systemic circulation.

The major bulk of tubular reabsorption of water & The major bulk of tubular reabsorption of water & solutes (about 65%) occurs in proximal tubules. So, solutes (about 65%) occurs in proximal tubules. So, tubular fluid reaches the thin segments within its tubular fluid reaches the thin segments within its original osmolarity (300 mosm\L).original osmolarity (300 mosm\L).

About 15% of water reabsorption occurs in tDHL About 15% of water reabsorption occurs in tDHL which is carried back to the systemic circulation which is carried back to the systemic circulation via ascending vasa recta. But tDHL is impermeable via ascending vasa recta. But tDHL is impermeable to solutes which stay within thin segment not to solutes which stay within thin segment not reabsorbed. So, tubular fluid reaches the ascending reabsorbed. So, tubular fluid reaches the ascending limbs highly hyperosmotic (1200 mosm\L).limbs highly hyperosmotic (1200 mosm\L).

Starting from tAHL, all the following segments are Starting from tAHL, all the following segments are impermeable to water in absence of ADH but very impermeable to water in absence of ADH but very little amounts of solutes are passively reabsorbed in little amounts of solutes are passively reabsorbed in tAHL. So, tubular fluid reaches the following tAHL. So, tubular fluid reaches the following segment still hyperosmotic (900 mosm\L).segment still hyperosmotic (900 mosm\L).

The major active reabsorption of electrolytes The major active reabsorption of electrolytes occurs in TAHL (about 30%) which is mainly due occurs in TAHL (about 30%) which is mainly due to 1Na+-2Cl¯-1K+ active cotransport process to 1Na+-2Cl¯-1K+ active cotransport process which works against as much as 200 mosm\L conc. which works against as much as 200 mosm\L conc. gradient. So, tubular fluid reaches distal tubules gradient. So, tubular fluid reaches distal tubules hypoosmotic (100 mosm\L). hypoosmotic (100 mosm\L).

Remaining reabsorption processes of electrolytes Remaining reabsorption processes of electrolytes (about 5%) occur in distal segments. Net result is (about 5%) occur in distal segments. Net result is hyperosmotic medulla which favours further water hyperosmotic medulla which favours further water reabsorption (about 19%) from collecting ducts in reabsorption (about 19%) from collecting ducts in presence of ADH & only about 1% of filtered presence of ADH & only about 1% of filtered water excreted in urine. While in absence of ADH, water excreted in urine. While in absence of ADH, about 20% of filtered water is excreted.about 20% of filtered water is excreted.

Urea recirculation is responsible for about 40% of Urea recirculation is responsible for about 40% of the process of urine concentration when urea is the process of urine concentration when urea is reabsorbed from medullary colleting tubules to the reabsorbed from medullary colleting tubules to the medullary interstitium to be secreted again from medullary interstitium to be secreted again from the tubular cells of thin segments to their lumen the tubular cells of thin segments to their lumen where the cycle is repeated again and again.where the cycle is repeated again and again.

Body control of ECF osmolarityBody control of ECF osmolarity

1-Osmoreceptors-ADH feedback1-Osmoreceptors-ADH feedback2-Thirst center in brain stem2-Thirst center in brain stem3-Salt appetite center in brain stem3-Salt appetite center in brain stem

Osmoreceptor cellsOsmoreceptor cells lie in anterior hypothalamus & lie in anterior hypothalamus & sensitive to any increase in Nasensitive to any increase in Na++ conc., send signals conc., send signals to supraoptic nuclei to stimulate posterior pituitary to supraoptic nuclei to stimulate posterior pituitary gland to increase secretion of ADH (vasopressin) to gland to increase secretion of ADH (vasopressin) to increase water reabsorption. ADH is stimulated by increase water reabsorption. ADH is stimulated by decreased Bd vol., decreased BP, nausea, vomiting, decreased Bd vol., decreased BP, nausea, vomiting, morphine & nicotine & vice versa. ADH inhibited morphine & nicotine & vice versa. ADH inhibited by alcohol intake.by alcohol intake.

Thirst centerThirst center in brain stem increases the desire for in brain stem increases the desire for water intake & increase secretion of ADH. Thirst water intake & increase secretion of ADH. Thirst center is also stimulated by decreased ECF volume, center is also stimulated by decreased ECF volume, decreased BP, angiotensin II & dryness of mouth, decreased BP, angiotensin II & dryness of mouth, pharynx & esophagus & vice versa. Inhibited also pharynx & esophagus & vice versa. Inhibited also by gastric distension.by gastric distension.Salt appetiteSalt appetite center in the brain stem increases the center in the brain stem increases the desire for salt intake.desire for salt intake.

Regulation of blood volume and pressureRegulation of blood volume and pressure

Small increase in Bd vol., large increase in CO....Small increase in Bd vol., large increase in CO....Small increase in CO, large increase in BP.. Small Small increase in CO, large increase in BP.. Small increase in BP, large increase in urine excretion. increase in BP, large increase in urine excretion. Acute increase in BP balanced by direct increase in Acute increase in BP balanced by direct increase in NaNa++ excretion due to increase GFR & decrease in excretion due to increase GFR & decrease in NaNa++ reabsorption with increase in Na reabsorption with increase in Na++ leak back to leak back to tubular lumen (pressure natriuresis) which is tubular lumen (pressure natriuresis) which is always accompanied by pressure diuresisalways accompanied by pressure diuresis

Chronic increase in BP is balanced by decrease in Chronic increase in BP is balanced by decrease in angiotensin II production which results in decrease angiotensin II production which results in decrease NaNa+ + reabsorption directly or indirectly by decreas-reabsorption directly or indirectly by decreas-ing aldosterone production from adrenal cortex.ing aldosterone production from adrenal cortex.

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Renal system

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Body regulation of acid-base balanceBody regulation of acid-base balance

Any change in [HAny change in [H++] will affect all cellular and body ] will affect all cellular and body functions due to its effects on many reactions. functions due to its effects on many reactions. Normal [HNormal [H++] in ECF is only 0.00000004 mol\L, so; ] in ECF is only 0.00000004 mol\L, so; it is better to use pH (which is –log [Hit is better to use pH (which is –log [H++] = 7.4).] = 7.4).Nobody can survive more than hours when pH Nobody can survive more than hours when pH raises to 8.0 or falls to 6.8 Regulation of [Hraises to 8.0 or falls to 6.8 Regulation of [H++] is by ] is by one or more of the following systems: one or more of the following systems: Chemical Chemical acid-base buffer systems in body fluids, respiratory acid-base buffer systems in body fluids, respiratory and renal regulation of acid-base balanceand renal regulation of acid-base balance.`.`

Buffer systemsBuffer systems::1-Bicarbonate buffer system1-Bicarbonate buffer system: the most important : the most important buffer system in ECF. when [Hbuffer system in ECF. when [H++] is increased:] is increased:HH++ +HCO +HCO33

¯̄ → H → H22COCO33 → H → H22O + COO + CO22 (expired) (expired)

While when [OH-] is increased:While when [OH-] is increased:OH¯ + HOH¯ + H22COCO33 → H → H22O + HCOO + HCO33¯̄ (excreted) (excreted)

The power of dissociation constant (pK) for this The power of dissociation constant (pK) for this system is 6.1, so Henderson-Hasselbalch equation:system is 6.1, so Henderson-Hasselbalch equation:pH = 6.1 + log [HCOpH = 6.1 + log [HCO33¯]\0.03 PCO¯]\0.03 PCO22

When HCOWhen HCO33¯ decreases; metabolic acidosis ¯ decreases; metabolic acidosis

When PCOWhen PCO22 increases; respiratory acidosis increases; respiratory acidosis

When HCOWhen HCO33¯ increases; metabolic alkalosis¯ increases; metabolic alkalosis

When PCOWhen PCO22 decreases; respiratory alkalosis decreases; respiratory alkalosis

2-Phosphate buffer system2-Phosphate buffer system: important buffer in : important buffer in intracellular & renal tubular fluids. Its pK is 6.8 intracellular & renal tubular fluids. Its pK is 6.8 When [H+] increases: When [H+] increases: HH++ + HPO + HPO44

22¯ → H¯ → H22POPO44¯̄When [OH¯] is increased: When [OH¯] is increased: OH¯ + HOH¯ + H22POPO44¯ → HPO¯ → HPO44

22¯ + H¯ + H22OO

3-Protein buffer systems3-Protein buffer systems:the most available intra-:the most available intra-cellular systems but also work extracellularly. the cellular systems but also work extracellularly. the most important is hemoglobin in RBCs.most important is hemoglobin in RBCs. HH++ + Hb → HHb + Hb → HHb

4-Ammonium buffer system4-Ammonium buffer system:: the last choice system the last choice system in renal tubules when bicarbonate and phosphate in renal tubules when bicarbonate and phosphate systems are saturated. Ammonium is formed from systems are saturated. Ammonium is formed from metabolism of glutamine inside renal tubular cells. metabolism of glutamine inside renal tubular cells. When [H+] increases: When [H+] increases: HH++ + NH + NH33 → NH → NH44

++

When [OH-] is increased: When [OH-] is increased: OH¯ + NH4+ → NH4OHOH¯ + NH4+ → NH4OH

Respiratory regulationRespiratory regulation:: stimulation of respiratory stimulation of respiratory center by central chemosensitive areas which are center by central chemosensitive areas which are bilateral aggregations of neurons beneath ventral bilateral aggregations of neurons beneath ventral surface of medulla sensitive to changes in Hsurface of medulla sensitive to changes in H++&P&PCO2CO2

Double alveolar ventilation reduces PDouble alveolar ventilation reduces PCO2CO2 & raises & raises

pH from 7.4 to 7.63 while 1\4pH from 7.4 to 7.63 while 1\4thth alveolar ventilation alveolar ventilation raises Praises PCO2CO2 & reduces pH to 6.95 & reduces pH to 6.95

c. Renal regulationc. Renal regulation: excretion of acidic or alkaline : excretion of acidic or alkaline urine. Daily renal secretion of Hurine. Daily renal secretion of H++ is 4400 mmol. is 4400 mmol. Bicarbonates system buffers 4320 mmol & other 80 Bicarbonates system buffers 4320 mmol & other 80 mmol buffered by phosphates & then ammonium mmol buffered by phosphates & then ammonium systems. Most renal tubular cells utilize secondary systems. Most renal tubular cells utilize secondary active transport to secrete Hactive transport to secrete H++ like Na like Na++-H-H++ antiport, antiport, but the intercalated cells of distal tubules utilize but the intercalated cells of distal tubules utilize primary active transport called proton pumpprimary active transport called proton pump

Physiology of micturitionPhysiology of micturition

Urine enters bladder in spurts synchronous with Urine enters bladder in spurts synchronous with regular peristaltic contractions of ureteric smooth regular peristaltic contractions of ureteric smooth muscles (1-5/minute), oblique insertion of ureters muscles (1-5/minute), oblique insertion of ureters into vicinity of bladder walls prevents back flow of into vicinity of bladder walls prevents back flow of urine. Bladder parasym.:S2, S3& S4 with pelvic urine. Bladder parasym.:S2, S3& S4 with pelvic nn. Sym. from L1, L2 &L3 via hypogastric nn after nn. Sym. from L1, L2 &L3 via hypogastric nn after relay in inferior mesenteric ganglion.relay in inferior mesenteric ganglion.Somatic sensory & motor from S2, S3 & S4 via Somatic sensory & motor from S2, S3 & S4 via pudendal nn. Sensory also via pelvic & hypogastricpudendal nn. Sensory also via pelvic & hypogastric

The first urge to void is felt at volume of 150 ml & The first urge to void is felt at volume of 150 ml & the marked sense of fullness is at 400 ml. But this is the marked sense of fullness is at 400 ml. But this is relieved by property of plasticity. Micturition is relieved by property of plasticity. Micturition is initiated after relaxation of muscles of pelvic floor, initiated after relaxation of muscles of pelvic floor, downward pull on detrusor muscle, excitation of downward pull on detrusor muscle, excitation of stretch receptors in its wall, reflex contraction. The stretch receptors in its wall, reflex contraction. The afferent & efferent limbs of voiding reflex run with afferent & efferent limbs of voiding reflex run with pelvic nerves to sacral cord, threshold is adjusted pelvic nerves to sacral cord, threshold is adjusted by activity of facilitatory (pons & posterior hypoth-by activity of facilitatory (pons & posterior hypoth-alamus) & inhibitory (midbrain) centers.alamus) & inhibitory (midbrain) centers.

The internal urethral sphincter, smooth muscles on The internal urethral sphincter, smooth muscles on either sides, plays no role in micturition, in male it either sides, plays no role in micturition, in male it prevents retrograde ejaculation (reflux of semen prevents retrograde ejaculation (reflux of semen into urinary bladder). External sphincter, skeletal into urinary bladder). External sphincter, skeletal muscle, contracts voluntarily, delay micturition or muscle, contracts voluntarily, delay micturition or interrupt its starting. Delay micturition is learning interrupt its starting. Delay micturition is learning ability of brain in adults. After micturition; female ability of brain in adults. After micturition; female urethra empties by gravity while male urethra by urethra empties by gravity while male urethra by several contractions of bulbocavernosus muscle. several contractions of bulbocavernosus muscle.