P2Y2 receptor activation decreases blood pressure and increases renal Na+ excretion

ATP and UTP are endogenous agonists of P2Y2/4receptors. To define the in vivo effects of P2Y2receptor activation on blood pressure and urinary excretion, we compared the response to INS45973, a P2Y2/4receptor agonist and UTP analog, in wild-type (WT) and P2Y2receptor knockout (P2Y2−/−) mice. INS45973 was administered intravenously as a bolus injection or continuous infusion to determine effects on blood pressure and renal function, respectively. Within seconds, bolus application of INS45973 (0.1 to 3 mg/kg body wt) dose-dependently decreased blood pressure in WT (maximum response −35 ± 2 mmHg) and to a similar extent in endothelial nitric oxide synthase knockout mice. By contrast, blood pressure increased in P2Y2−/− (maximum response +18 ± 1 mmHg) but returned to basal levels within 60 s. Continuous infusion of INS45973 (25 to 750 μg·min−1·kg−1body wt) dose-dependently increased urinary excretion of Na+in WT (maximum response +46 ± 15%) but reduced Na+excretion in P2Y2−/− (maximum responses of −45 ± 15%) mice. In renal clearance experiments, INS45973 did not affect glomerular filtration rate but lowered blood pressure and increased fractional excretion of fluid, Na+, and K+in WT relative to P2Y2−/− mice. The blood pressure responses to INS45973 are consistent with P2Y2receptor-mediated NO-independent vasodilation and implicate responses to endothelium-derived hyperpolarizing factor, and P2Y2receptor-independent vasoconstriction, probably via activation of P2Y4receptors on smooth muscle. Systemic activation of P2Y2receptors thus lowers blood pressure and inhibits renal Na+reabsorption, effects suggesting the potential utility of P2Y2agonism in the treatment of hypertension.