Tolvaptan (vasopressin V2 receptor antagonist) is used in polycystic kidney disease (ADPKD) and hyponatremia. Which specific cellular mechanism in the renal collecting duct does it block?

• A Tolvaptan blocks V1a receptors on vascular smooth muscle causing systemic vasodilation
• B Tolvaptan inhibits AQP2 channels directly by competitive binding
• C Tolvaptan reduces vasopressin synthesis in the hypothalamus via feedback inhibition
• D Tolvaptan blocks V2 receptors on principal cells → reduced Gs coupling → less cAMP → less PKA activation → less aquaporin-2 (AQP2) phosphorylation and trafficking to apical membrane → reduced water permeability (aquaresis without natriuresis) ✓

Explanation

Vasopressin (ADH) acts on V2 receptors on renal principal cells, activating Gs protein → adenylyl cyclase → cAMP → PKA. PKA phosphorylates AQP2 on Ser256, promoting vesicle fusion with the apical membrane and dramatically increasing water permeability. Tolvaptan competitively blocks V2 receptors, reducing cAMP and preventing AQP2 membrane insertion. This causes 'aquaresis' — free water excretion without significant electrolyte loss — used for SIADH (euvolemic/hypervolemic hyponatremia). In ADPKD, V2 blockade also reduces intracellular cAMP in cystic epithelial cells, slowing cyst growth.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.