P2Y₂ receptor activation decreases blood pressure and increases renal Na⁺ excretion - PubMed (original) (raw)

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

Timo Rieg et al. Am J Physiol Regul Integr Comp Physiol. 2011 Aug.

Abstract

ATP and UTP are endogenous agonists of P2Y(2/4) receptors. To define the in vivo effects of P2Y(2) receptor activation on blood pressure and urinary excretion, we compared the response to INS45973, a P2Y(2/4) receptor agonist and UTP analog, in wild-type (WT) and P2Y(2) receptor knockout (P2Y(2)-/-) 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 P2Y(2)-/- (maximum response +18 ± 1 mmHg) but returned to basal levels within 60 s. Continuous infusion of INS45973 (25 to 750 μg·min(-1)·kg(-1) body wt) dose-dependently increased urinary excretion of Na(+) in WT (maximum response +46 ± 15%) but reduced Na(+) excretion in P2Y(2)-/- (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 P2Y(2)-/- mice. The blood pressure responses to INS45973 are consistent with P2Y(2) receptor-mediated NO-independent vasodilation and implicate responses to endothelium-derived hyperpolarizing factor, and P2Y(2) receptor-independent vasoconstriction, probably via activation of P2Y(4) receptors on smooth muscle. Systemic activation of P2Y(2) receptors thus lowers blood pressure and inhibits renal Na(+) reabsorption, effects suggesting the potential utility of P2Y(2) agonism in the treatment of hypertension.

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Figures

Fig. 1.

Representative original recordings of the blood pressure (BP) response to INS45973 in a wild-type (WT) and a P2Y2 knockout mouse (P2Y2−/−). In WT, application of INS45973 dose-dependently and rapidly decreased blood pressure, which started to partially recover during drug application. In contrast, INS45973 in P2Y2−/− dose-dependently and rapidly increased blood pressure, which was sustained during drug application and thereafter recovered to baseline within 1–2 min, consistent with the short half-life of INS45973.

Fig. 2.

Maximal responses in blood pressure (A) and heart rate (B) to acute bolus application of INS45973 in wild-type (WT, n = 7) and P2Y2 knockout mice (P2Y2−/−, n = 8). In WT mice, application of INS45973 dose-dependently decreased blood pressure, whereas in P2Y2−/− mice blood pressure increased. In both genotypes, heart rate was unaffected. Error bars are covered. *P < 0.05 vs. WT same dose, §P < 0.05 vs. vehicle.

Fig. 3.

Representative recordings of the acute blood pressure (BP) response to INS45973 in endothelial NO synthase knockout mice (eNOS−/−). INS45973 dose-dependently and rapidly decreased blood pressure. The initial decrease was followed by a sustained (3–5 min) increase in blood pressure above basal values.

Fig. 4.

Maximal responses in blood pressure and heart rate to acute bolus application of INS45973 in endothelial NO synthase knockout mice (eNOS−/−, n = 5). In eNOS−/− mice, administration of INS45973 induced a dose-dependent, rapid decrease in blood pressure (left, early phase). In contrast to wild-type mice, eNOS−/− mice show a dose-dependent rise in blood pressure above basal values following the initial decrease (right). Heart rate was unaffected.

Fig. 5.

Responses in urinary excretion of fluid (A), Na+ (B), and K+ (C) to continuous infusion of INS45973 in wild-type (WT, n = 7) and P2Y2 knockout mice (P2Y2−/−, n = 8). The responses in urinary excretion of fluid, Na+ and K+ excretion in response to continuous infusion of INS45973 for 15 min were significantly different between WT and P2Y2−/− mice, as determined over the last 10 min. *P < 0.05 vs. WT.

Fig. 6.

Response in blood pressure, GFR, and renal reabsorption to continuous infusion of INS45973 (INS, 250 μg·min−1·kg−1 body wt) in wild-type (WT, n = 5) and P2Y2 knockout mice (P2Y2−/−, n = 5) in two-period clearance experiments. INS45973 decreased blood pressure (A and B) in WT mice, which was different from the response in P2Y2−/− mice. C: INS45973 did not alter GFR in either genotype. WT and P2Y2−/− mice showed opposite responses to INS45973 in fluid (D and G), Na+ (E and H), and K+ (F and I) excretion, such that responses in absolute and fractional Na+ and K+ excretion were significantly different between genotypes. *P < 0.05 vs. WT.

Fig. 7.

A proposed model of blood pressure responses of wild-type mice, P2Y2 receptor, and eNOS knockout mice to the P2Y2/4 receptor agonist, INS45793. Displayed on top are original recordings showing the response to a dose of 1 mg/kg body wt. The bars reflect infusion of the drug over 25 s. Left: in wild-type mice, INS45793 lowers blood pressure by inducing P2Y2 receptor-mediated endothelial NO-independent vasodilation, implicating a role for endothelial derived hyperpolarization factor (EDHF) (1). Activation of smooth muscle P2Y4 receptors results in vasoconstriction (2), which is counterbalanced by P2Y4 receptor-induced endothelial NO formation and release (3). Middle: in P2Y2 receptor knockout mice INS43793 increases blood pressure by activating P2Y4 receptors on smooth muscle cells (2), which is counterbalanced by NO release following endothelial P2Y4 receptor activation (3). Right: in eNOS−/− mice, INS43793 decreases blood pressure via P2Y2 receptor-induced EDHF (1). The increase in blood pressure due to P2Y4 receptor activation on smooth muscle cells (2) is enhanced and sustained compared with wild-type and P2Y2 receptor knockout mice due to the lack of P2Y4 receptor-induced NO release from endothelial cells.

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P2Y₂ receptor activation decreases blood pressure and increases renal Na⁺ excretion - PubMed (original) (raw)