Urinary System and Blood Volume Regulation

• Diuretics are multiple classes with multiple sites of action
• There are mechanisms and pharmacology of blood volume control
• The Angiotensin-Renin control system includes ACE inhibitors and ANP
• Therapeutic benefits of pharmacological interventions in control of blood volume

Urinary System

• The urinary system includes the kidneys, ureters, bladder, and urethra
• The kidney cortex, medulla, renal pelvis, and capsule are major structures

Nephron Function

• The nephron is the functional unit of the kidney
• Kidneys receive about 20% of cardiac output at rest which is about 1 liter/min

Glomeruli Details

• Glomeruli contain:
  • Capillaries and podocytes
  • Fenestrated endothelial cells of capillary

Kidney Functions

• Blood filtration results in loss of materials with MW <50kDa, ~10% of blood volume
• Secretion example is organic acids
• Reabsorption is the uptake of ions and glucose
• Normal GFR values are 120±25 mls/min = 7 liters per hour (ca.10% of perfusion flow)
• Kidneys impact:
  • Urine production rates
  • Acid-base balance
  • Secretin and production of Renin-Angiotensin-Aldosterone System

Urine Formation Stages

• A Na+ gradient generated by the Na+/K+ pump of proximal tubule epithelial cell walls is used to drive reabsorption of glucose and amino acids
• The osmotic gradient leads to H₂O reabsorption – ca. 50%, mainly paracellular H₂O in the proximal tubule
• Basic energetics consume ATP by Na+/K+ pump in active transport at the Ascending Limb of Loop of Henle
• Na and Cl reabsorption requires Na-K-2Cl co-transporter in secondary active transport
• Countercurrent mechanism driven by active extrusion of Na+ produces hypertonic conditions in the medulla
• This supports creation of hypertonic urine by regulating water permeability of collecting duct which is regulated by ADH

Diuretics

• Blood filtration is not directly affected
• Secretion is a necessary route for some diuretics to act on the epithelial cell of nephron
• Reabsorption represents a primary modification
• Urine production rate and composition can be modified
• Salt/water balance and blood volume can be modified

Electrolytes and Kidney

• Electrolytes and molecules handled by kidneys include: Na+, Cl-, H+, Ca+2, HCO3, Alb, Glucose, H₂O, K+, aa

Sodium Functions

• Sodium (Na+) assists with:
  • Normal nerve function
  • Fluid balance
  • Normal muscle function
  • Blood pressure and volume

Key Values

• Na reabsorption is at about 99.5%
• Proximal tubule: 65%
• Loop (thick ascending): 25%
• Distal convoluted tubule: 5%
• Collecting duct: 3%
• Clearance includes Inulin and Glomerular Filtration Rate

Reabsorption Control

• Forces controlling reabsorption of solutes in the nephron:
  • Active transport
  • Secondary active transport
  • Solute gradient (mainly Na+)

Diuretic Structures and Types

• Sulphonamides were 1920s antibiotics with diuresis side-effect
• Carbonic Anhydrase Inhibitors represent 1950s development from sulphonamides
• Thiazide- Blocks Na Cl symporter are a further development from sulphonamides with thiazide ring
• Loop Diuretics block Na/K/2Cl co-transporter were developed in the -1960s. Further development with greater diuretic capacity but lose K+ - actively secreted as organic acid
• Aldosterone blockers are K+ sparing diuresis

Diuretic Sites of Action

• Proximal tubule: Osmotic and Carbonic anhydrase inhibitors
• Distal tubule: Thiazide diuretics
• Loop: Loop diuretics
• Collecting duct: Na/K, K+ sparing diuretics

Proximal Tubule Diuretics

• Osmotic (solute) function using Mannitol:
  • Non-metabolisable enters tubule and via osmotic effects prevents reabsorption of water
  • Main action involves water movement that is largely paracellular in the proximal tubule
  • Usage is in the treatment of cerebral edema and raised intra-ocular pressure

Carbonic Anhydrase Inhibitors (CAIs)

• Na gradient drives H+ efflux into tubule
• Combines with HCO3- via Carbonic anhydrase to produce CO2 and H20 (lost)
• CO2 into epithelial cell combines with H20 in cell to produce HCO; and H+ via Carbonic anhydrase
• HCO3- plus Na+ via cotransporter to blood
• Normally reabsorbs Bicarb and H2O
• An example is Acetazolamide, reduces the reabsorption of bicarbonate.
• CAIs are Weak diuretics and used mainly in the treatment of glaucoma, prophylaxis against mountain sickness and epilepsy.
• Loop Diuretics (Loop of Henle) block Na-K-2Cl co-transporter

Loop Diuretics

• Furosemide acts on the thick ascending limb
• it blocks Na-K-2Cl co-transporter and thus prevents Na gradient-driven reabsorption of K
• This leads to losses of K+ and H₂O

Distal Tubule Diuretics

• Thiazide Diuretics are in action Distal Convoluted Tubule
• They block:
  • Na-Cl co-transporter
  • Increase Na and K loss

Potassium-sparing Diuretics

• Collecting duct normally- Impermeable to water in the absence of ADH (aquaporins) and to Na in the absence of Aldosterone (eNaC)
• Collecting Tubule requires eNaC blocked by amiloride (mineralocorticoid aldosterone increases eNaC and Na/Kpump retain Na+) resulting in K sparing diuretics

Aldosterone Blockers

• Spironolactone has limited action via blocking intracellular Aldosterone receptors and prevents upregulation of eNaC
• eNaC Blockers
• Antagonise Aldosterone effects (K+ sparing)
• Amiloride reduces Na reabsorption and K+ loss

Volume Regulation Control

• Antidiuretic hormone/Vasopressin is involved in blood volume and osmolarity control
• Kidney function REQUIRES good perfusion at SUFFICIENT blood pressure
• Circulation REQUIRES control of Blood Volume and Ionic concentrations in order to produce appropriate blood pressures to ensure SUFFICIENT tissue perfusion

RAAS System

• The Renin-Angiotensin-Aldosterone System is key for kidney function and control of circulation
• Renin from juxtaglomerular cells converts Angiotensinogen (from liver) into Angiotensin I, then ACE in lung can convert to active Angiotensin II

ACE System

• The juxtaglomerular cells secrete renin in response to:
  • Sympathetic stimulation (beta-1 adrenergic receptor)
  • Decrease in renal perfusion pressure
  • Decrease in NaCl concentration at the macula densa

Hypothalamic POSTERIOR System

• The hypothalmic system is responsible for secretion of antidiuretic hormone/Vasopressin
• Angiotensin II and Sympathetic stimulation are positive regulators for hormone release
• Hyperosmolarity, Hypovolemia, and Hypotension stimulate secretion

ACE Inhibitors

• ACE Inhibitors (ACEi) block ACE in the lungs
• ACEi reduce:
  • Angiotensin II, Aldosterone, and ADH levels
  • Vasoconstriction
• ACEi Increase Endovascular Volume
• ACEI's are used for correcting heart failure and hypertension

ACE Inhibitors

• ACE Inhibitors (ACEi) reduce degradation of Bradykinin, and this may produce cough
• ACE Inhibitors:
  • Are derived from snake venom
  • Were initially Venom Peptide Analogs
• Development from ACEi
  • Discovery of ACE-Angiotensin II ----1950s
  • Bothrops jararaca -------- 1968
  • 2000 compounds tested -------- 1970-1973
  • 60 carboxypeptidase A inhibitors tested ----1974

Atrial Natriuretic Peptide details

• Atrial Natriuretic Peptide is released from atrial myocytes in response to atrial stretch
• It counteracts Renin/Angiotensin
• It acts on Vascular smooth muscle
• Reduces:
  • Renin secretion
  • Aldosterone secretion

Action of ANP

• Cardiac distension, Sympathetic stimulation, and Angiotensin II increase GFR via Renin and ANP/BNP
• Ang II & Aldo are decreased
• Vasodilation happens
• Increased Natriuresis and Diuresis decrease:
  • Blood Pressure
  • Blood Volume

Summary of Salt/Water Balance

• Modifying Salt/Water Balance is beneficial in:
  • Heart Failure
  • Hypertension
  • Oedema such as Renal oedema

Types of Diuretics

• Mannitol causes diuresis by increasing osmotic pressure in proximal renal tubules
• Acetazolamide reduces the reabsorption of bicarbonate in proximal renal tubules, which results in diuresis of alkaline urine
• Loop diuretics interfere with the Na+-K+-2Cl- transporter in the Thick Ascending Limb of the loop of Henle, resulting diuresis
• Thiazide diuretics interfere with the Na+-Cl co-transporter in the early distal tubules
• K+ Sparing diuretics are either blocking eNaC or blocking aldosterone receptors
• ACEi inhibit the formation of Angiotensin II, used in hypertension and heart failure
• ANP analogues and Neutral Endopeptidase Inhibitor are promising candidates in the treatment of cardiac conditions

Explore the urinary system's components and their function. Learn about kidney's role in blood volume regulation with the Angiotensin-Renin system and ANP. Understand how diuretics and ACE inhibitors impact blood volume.