Effects of receptor blockade on metabolism and renal actions of vasopressin in conscious dogs

Vasopressin – but not the V₂ receptor agonist [deamino-cis1,D-Arg8]-vasopressin (dDAVP) – may mediate natriuresis in dogs. The present study investigated this phenomenon by use of nonpeptide antagonists to V_1a and V₂ receptors 1-{1-[4- (3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2 (1H)-quinolinone (OPC-21268) and 5-dimethylamino-1-{4- (2-methylbenzoylamino)-benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (OPC-31260), respectively) hypothesising that only V_1a inhibition would reduce the natriuresis. In conscious dogs vasopressin secretion was suppressed by water loading (2% body weight) and replaced by infusion of vasopressin (50 pg min^?1 kg^?1) resulting in physiological plasma concentrations (plasma levels of AVP (pAVP) = 2.0 ± 0.1 pg mL^?1). In this setting, OPC-21268 did not change the rate of sodium excretion. OPC-31260 increased water excretion 12-fold without significant changes in sodium excretion. Heart rate, mean arterial blood pressure, glomerular filtration rate, and clearance of endogenous Li⁺ were unchanged. During vasopressin infusion, both antagonists increased pAVP, OPC-21268 by 20% and OPC-31260 by 100% (2.0 ± 0.2–4.0 ± 0.3 pg mL^?1). In the absence of vasopressin infusion, OPC-31260 did not increase pAVP. Thus, the increase in pAVP appeared to be due to a decrease in metabolic clearance rate. The results indicate that the present dose of V_1a receptor inhibitor OPC-21268 does not reduce sodium excretion and that both vasopressin antagonists inhibit vasopressin metabolism.