Pharmacology 20: Volume Regulation
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Fluid in vascular compartment determines extent of tissue perfusion
2/3 of body water = intracellular and 1/3 = extracellular (3/4 in interstitial space, ¼ in plasma)
Between plasma and interstitial compartments, capillary permeability (jxns between cells),
oncotic pressure (molecular solute components) and hydrostatic pressure allows exchange
o Fluid filtration = Kf (Pc – Pif) – (πc – πif)
o Hydrostatic and oncotic gradient terms have opposing vectors
o At arterial end of capillary bed, plasma filtration favored. At venous end, balanced or
favors flow from interstitium to capillary bed.
 Liver returns fluids via lymphatic flow
Low-pressure vascular volume sensors = atria and pulmonary vasculature
o Low wall stress signals PNS to transmit signal to noradrenergic neurons in medulla ->
hypothalamus -> increase ADH/vasopressin secretion
o Increased wall stress, atria secreted natriuretic peptide -> vasodilation and natriuresis
High-pressure vascular volume sensors = baroreceptors in aortic arch, carotid sinus, and JGA
apparatus
o Modulate hypothalamic control of ADH secretion and sympathetic outflow, renin
Neurohormonal response (volume regulators) = renin-angiotensin-aldosterone system (RAAS),
natriuretic peptides, ADH, and renal sympathetic nerves
Renin produced and secreted by juxtaglomerular apparatus (JGA) -> vasoconstriction and Na+
retention, maintaining tissue perfusion and increase ECF volume
o Direct pressure-sensing mechanism of afferent arteriole increases renin with decrease
wall tension
o Sympathetic innervation of JGA cells promotes renin via β1-adrenoreceptor signal
o Tubuloglomerular feedback senses distal nephron Cl or Na delivery modulating renin
 distal end of thick ascending limb apposed to JGA (rapid regulation)
 Macula densa of thick ascending limb respond to increased NaCl delivery
(increase extracellular adenosine activating A1 receptors on JGA to decrease
renin). Decreased NaCl -> prostaglandin signaling cascade with renin release
 NaCl concentration senses by receptors in monocilia of macula densa.
 Luminal fluid flow rate sensed by direct bend of monocilia.
Renin cleaves angiotensinogen to generate angiotensin I cleaved by angiotensin converting
enzyme (ACE I) to active angiotensin II (AT II)
o ACE I in pulmonary vascular endothelium and coronary circulation but regulates ATII
production in all vascular beds
o ACE is aka as kininase II (broad proteolytic specificity including kinins)
ATII binds to AT II receptor subtype I (AT1R) -> stimulates aldosterone secretion (zona
glomerulosa cells in adrenal glands), increased NaCl reabsorption in proximal tubule, stimulation
of thirst and ADH, arteriolar vasoconstriction
o Aldosterone increases distal-tubule Na reabsorption
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AT1R (G-protein) activates phospholipase C -> Ca release (increase vascular smooth
muscle contractility, vascular resistance)
AT2R is more prominent in fetal than adult tissue (vasodilatory role)
Natriuretic peptides (atria, ventricles and vascular endothelium) released w/ overload
o A-type (ANP) = primarily by atria
o B-type (BNP) = primarily by ventricles
o C-type (CNP) = by vascular endothelial cells
o Uroguanylin (UGN) = enterocytes in response to dietary salt
o Vascular NPs released in response to increased intravascular volume (stretch of cells)
 Bind to NPR-A, NPR-B, and NPR-C
 NPR-A & B -> transmembrane protein with cytoplasmic guanylyl cyclase
(increase cGMP). ANP and BNP bind to NPR-A; CNP binds to NPR-B.
 NPR-C -> no guanylyl cyclase; decoy or bugger to reduce NPs. Binds all 3
NPs
 UGN bins transmembrane guanylyl cyclase C in renal proximal tubule cells and
enterocytes, undefined receptor in renal collecting ducts
NPs affect cardiovascular, kidney, and CNS
o relaxes vascular smooth muscle -> dephos of myosin light chain via cGMP; increases
capillary permeability
o promotes ↑ GFR (efferent arteriole constriction, dilation of afferent) and naturesis
(antagonism of ADH)
o decreased thirst, ADH and sympathetic tone (via CNP expressed high in brain)
ADH or vasopressin is nonpeptide hormone from posterior pituitary from increased plasma
osmolality or hypovolemia -> constricts vasculature and ↑ H2O reabsorption
o V1 receptor -> in smooth muscle cells; vasoconstriction (Gq)
o V2 receptor -> in collecting duct cells; H2O reabsorption (Gs -> cAMP -> PKA ->
phosphorylated aquaporin 2 -> porin fusion in apical membrane)
 Regulation of renal H2O reabsorption in collecting duct modulates urine and
plasma osmolality
Renal sympathetic nerves in afferent and efferent arterioles -> decrease GFR (with low volume)
with constriction of afferent > efferent arteriole -> decreased natriuresis
o Increase renin by β1 adrenergic receptors in JGA
To alter body fluid volume, alter renal Na reabsorption
o NaCl reabsorption is key for water retention
Glomerulus produces ultrafiltrate of plasma processed by nephron (solute and H2O
reabsorption, waste product and exnobiotic excretion)
o Substrate-specific transporters and channels in luminal tubular epithelial cells alter
[solute] altered by channels and transporters on contraluminal side
Segments of nephron: proximal tubule, thick ascending limb (TAL) of loop of henle, distal
convoluted tubule (DCT), and cortical collecting duct (CCD)
o Transport of solute and water through transcellular transporters, of ions via paracellular
tight junctions
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Proximal tube (PT) is first reabsorptive site (2/3 of Na reabsorption, 90% HCO3 reabsorption,
60% of Cl reabsorption).
o Symporters drive reabsorption of all glucose, AAs, phosphate and sulfate
o Secretion and reabsorption of weak acids/bases (symport or antiport)
o HCO3 reabsorption:
 2/3 of proton efflux exchanged for Na influx via NHE3 Na/H exchanger and 1/3
by vacuolar H-ATPase.
 Luminal membrane has glycosylphosphatidylinositol-linked exoenzyme carbonic
anhydrase IV (CAIV) -> converts HCO3 to CO2 and OH (enter cell)
 CO2 rehydratede to HCO3 via carbonic anhydrase II (CAII) -> cotransported with
Na across membrane of epithelial cell (Na/HCO3 co-transporter NBCe1 -> 3
HCO3 for 1 Na)
o Iso-osmotic solute absorption (H2O accompanies to maintain osmotic balance)
 Aquaporins (AQP1) -> transcellular water flow in proximal and thin descending
limb of loop of Henle
Thick ascending limb (TAL) + distal convoluted tubule (DCT) + connecting tubule (CNT) = “diluting
segment”
TAL receives hypertonic fluid with high NaCl concentration
o Devoid of aquaporins (reabsorb NaCl and urea without water) -> solute that generates
corticomedullary osmotic gradient of kidney (“countercurrent multiplier”)
o Reabsorbs 25-35% of filtered Na by luminal Na/K/2Cl cotransporter NKCC2
 Cl exits via CLC-K2 channel and Na via Na/K ATPase ((both on basolateral side)
 Apical ROMK recyvles K back into lumen
 Generate lumen-positive electrical potential for paracellular ion absorption
o 50% Na reabsorption via paracellular path (allows Na to flow without E waste)
o Ca and Mg reabsorbed via cation-channels (paracellins or claudin) in tight jxns
DCT reabsorbs 2-10% of NaCl filtered
o Luminal Na enters via NCC Na/Cl cotransporter and exits via Na/K ATPase and
electrogenic Cl channels and electroneutral K/Cl cotransport
o Ca and Mg reabsorbed via TRPV5 (Ca) and TRPM6 (Mg) in apical membrane
 Ca exits via NCX Na/Ca exchanger and Ca ATPase
Terminal nephron = cortical, outer medullary and inner medullary collecting duct (CD).
o Cortical and outer medullary CD cells
 Principal cells -> reabsorb 1-5% of filtered Na depending on aldosterone (Na
enters via Na channels (ENaC) and exit via Na/K ATPase). Secrete K into lumen,
have ADH-responsive water channels (Gs V2 receptor inserts AQP2)
 intercalated cells -> express H-ATPase, mediate K absorption by luminal H/K
ATPase and NH4 secretion by Rh antigen proteins
 Type A IC secrete protons via apical H-ATPase, reabsorb HCO3 via
basolateral Cl/HCO3 exchanger (kidney AE1)
 Type B IC secrete HCO3 via apical Cl/HCO3 exchanger pendrin and
reabsorb protons via basolateral H-ATPase
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 NonA, nonB IC reabsorbs CL via pendrin
Edema = accumulation of fluid in interstitial space
o Exudative (high protein; inflamm response) or transudative (low protein; pathologic
renal Na retention)
Return to physiologic homeostasis mediated by: osmotic force, lumphatic drainage, and longterm volume sensors
o Pathophysiology of transudative edema formation almost always requires an element of
pathologic renal Na retention
o Heart failure, cirrhosis and nephrotic syndrome -> all deranged Na reabsorption
Heart failure (HF) = inability of heart to perfuse tissues/organs -> congestion in venous
“capacitance” vessels *increase capillary hydrostatic pressure)
o RHF -> peripheral edema; LHF -> pulmonary edema
o Cause of Na retention is perceived volume depletion (high-pressure volume receptors) ->
increased renin-angiotensin-aldosterone system (endothelin and prostaglandins, too)
 Low-pressure NP and neural response sense increased pressure promoting
natriuresis but disrupted in HF (too much sympathetic response)
o Diuretics and ACE inhibitors can be used
Cirrhosis = hepatic parenchymal fibrosis from chronic inflammation or hepatotoxic insult
o Portosystemic shunt from liver into systemic circulation; decreased albumin,
contributors to plasma oncotic pressure, and coagulation factors
o Underfill model -> obstruction of venous outflow increases intrahepatic hydrostatic
pressure increasing transudation overwhelming lymphatic flow -> ascites
 ↓ intravascular volume, Q, and activation of baroreceptors (↑ Na retention)
o Overflow model -> ascites from primary renal Na retention. Obstruction activates
hepato-renal reflex (↑ Na retention)
Nephrotic Syndrome = massive proteinuria, edema, hypoalbuminemia, hypercholesterolemia
o Primary cause = glomerular dysfunction
o Massive proteinuria -> ↓ plasma oncotic pressure ->fluid transudation into interstitium
-> ↓ intravascular volume -> volume sensors enhance Na retention
o May be caused by change in capillary jxnal permeability or primary Na retention
(localized to distal nephron)
o Treat with diuretics but correct glomerular disorder