title: P2Y₂ receptor activation decreases blood pressure and increases renal Na⁺ excretion.
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.
authors: Department of Medicine, University of California San Diego, La Jolla, California 92161, USA. trieg@ucsd.edu
authors: Timo
authors: T
authors: Rieg
authors: Maria
authors: M
authors: Gerasimova
authors: José L
authors: JL
authors: Boyer
authors: Paul A
authors: PA
authors: Insel
authors: Volker
authors: V
authors: Vallon
references: J Pharmacol Exp Ther. 2000 Jun;293(3):755-60
references: 10869373
references: Br J Pharmacol. 2007 Mar;150(5):604-12
references: 17262017
references: Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):866-73
references: 10712415
references: J Pharmacol Exp Ther. 2005 Apr;313(1):403-9
references: 15590766
references: Eur J Biochem. 2003 Jul;270(14):2971-8
references: 12846830
references: Br J Pharmacol. 2005 Sep;146(2):288-95
references: 15997227
references: Br J Pharmacol. 1998 Jun;124(4):703-10
references: 9690862
references: Br J Pharmacol. 2010 Aug;160(8):1953-62
references: 20649593
references: Am J Physiol. 1996 Sep;271(3 Pt 2):H1109-16
references: 8853348
references: Hypertension. 1999 Jan;33(1 Pt 2):329-34
references: 9931125
references: Br J Pharmacol. 1999 Oct;128(3):549-55
references: 10516631
references: Blood Vessels. 1985;22(3):145-55
references: 2988672
references: Annu Rev Physiol. 2010;72:377-93
references: 20148681
references: J Physiol Pharmacol. 2003 Jun;54(2):163-73
references: 12832719
references: FASEB J. 2010 Jun;24(6):2056-65
references: 20097874
references: Purinergic Signal. 2009 Dec;5(4):481-9
references: 19306075
references: Br J Pharmacol. 2003 Apr;138(8):1451-8
references: 12721100
references: Br J Pharmacol. 2010 Jun;160(4):987-97
references: 20590593
references: Purinergic Signal. 2005 Jun;1(2):183-91
references: 18404503
references: Cardiovasc Res. 2010 Jan 1;85(1):204-13
references: 19640930
references: Circ Res. 1991 Dec;69(6):1583-90
references: 1659504
references: Circulation. 1997 Nov 18;96(10):3570-8
references: 9396457
references: BMC Pharmacol. 2003 May 9;3:4
references: 12737633
references: Pharmacol Rev. 2006 Sep;58(3):281-341
references: 16968944
references: Am J Physiol. 1990 Jul;259(1 Pt 2):H243-7
references: 2375411
references: Trends Pharmacol Sci. 1998 Mar;19(3):99-107
references: 9584626
references: Eur J Pharmacol. 1999 Apr 9;370(2):139-43
references: 10323262
references: Biochem J. 1998 Dec 15;336 ( Pt 3):513-23
references: 9841859
references: J Biol Chem. 2008 Dec 26;283(52):36599-607
references: 18981175
references: J Biol Chem. 1999 Sep 10;274(37):26454-60
references: 10473605
references: Purinergic Signal. 2009 Dec;5(4):447-60
references: 19294530
references: Br J Pharmacol. 1996 May;118(2):428-34
references: 8735648
references: Am J Physiol Regul Integr Comp Physiol. 2002 Nov;283(5):R1033-40
references: 12376395
references: Am J Physiol Renal Physiol. 2008 Jan;294(1):F10-27
references: 17977905
references: Br J Pharmacol. 1996 Apr;117(8):1797-802
references: 8732294
references: Br J Pharmacol. 2006 Mar;147(5):569-74
references: 16415908
references: Stroke. 1990 Feb;21(2):305-9
references: 1968294
references: Stroke. 2002 Sep;33(9):2285-91
references: 12215600
references: Mol Pharmacol. 2008 Sep;74(3):777-84
references: 18523137
references: J Am Soc Nephrol. 2002 Jan;13(1):10-18
references: 11752016
references: Am J Physiol Heart Circ Physiol. 2001 Feb;280(2):H767-76
references: 11158976
references: Am J Physiol Regul Integr Comp Physiol. 2009 Feb;296(2):R419-27
references: 19020292
references: Fertil Steril. 2003 Feb;79(2):393-8
references: 12568851
references: Thromb Haemost. 2001 May;85(5):875-81
references: 11372682
references: Circulation. 1991 Jul;84(1):1-14
references: 1647896
references: J Cardiovasc Pharmacol. 2002 Jan;39(1):142-9
references: 11743236
references: Am J Physiol. 1997 Aug;273(2 Pt 2):H878-85
references: 9277506
references: J Physiol Pharmacol. 2008 Mar;59(1):129-37
references: 18441393
references: FASEB J. 2007 Nov;21(13):3717-26
references: 17575258
references: Br J Pharmacol. 2010 Oct;161(3):530-40
references: 20880394
references: J Physiol. 2009 Jul 15;587(Pt 14):3651-63
references: 19451200
references: Naunyn Schmiedebergs Arch Pharmacol. 1987 Nov;336(5):556-60
references: 3437923
references: Nat Med. 2005 Feb;11(2):223-7
references: 15665829
references: Am J Physiol. 1999 Mar;276(3):H1091-7
references: 10070096
references: Acta Physiol Scand. 2002 Apr;174(4):301-9
references: 11942917
references: Naunyn Schmiedebergs Arch Pharmacol. 1990 Jun;341(6):538-46
references: 2118236
references: Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):42-8
references: 11788459
references: Drug News Perspect. 2003 Apr;16(3):133-40
references: 12819811
references: J Am Soc Nephrol. 2008 Apr;19(4):731-42
references: 18235098
references: Naunyn Schmiedebergs Arch Pharmacol. 2004 Oct;370(4):320-3
references: 15549274