AT2 receptor-mediated vasodilatation is unmasked by AT1 receptor blockade in conscious SHR.
In the present study, we investigated the role of the angiotensin II type 2 receptor (AT(2)) receptor in the regulation of regional haemodynamics in spontaneously hypertensive rats (SHR). We tested the hypothesis that AT(2) receptor activation directly causes vasodilatation. Mean arterial pressure (MAP), renal, mesenteric and hindquarters flows and conductances were measured in various groups of conscious rats that received the following drug combinations on separate days: the AT(1) receptor antagonist, candesartan (5 or 10 microg kg(-1) i.v.) alone, the AT(2) receptor agonist, CGP42112 (1 microg kg(-1) min(-1)) alone and candesartan plus CGP42112. Low-dose candesartan (5 microg kg(-1)) caused renal vasodilatation, while CGP 42112 alone caused minimal haemodynamic effects. In the presence of candesartan, CGP42112 caused a marked depressor effect together with generalised vasodilatation that was abolished by the coinfusion of the AT(2) receptor antagonist, PD123319 (50 microg kg(-1) min(-1)), with the candesartan and CGP42112 combination. PD123319, given alone, increased MAP and reduced renal and mesenteric conductances. We also confirmed that the enhanced vasodilatation evoked by candesartan plus CGP42112 was not due to additional AT(1) receptor blockade, since angiotensin II-mediated vasoconstriction was inhibited by a similar magnitude in the combination treatment compared with candesartan alone. Analogous experiments in Wistar-Kyoto rats did not demonstrate significantly enhanced effects due to candesartan plus CGP42112. Collectively, these data suggest that, in SHR, AT(2) receptors tonically modulate vascular tone and that direct AT(2) receptor-mediated vasodilatation was unmasked by AT(1) receptor blockade.
Li
Xiao C
XC
Department of Pharmacology, PO Box 13E, Monash University, Victoria 3800, Australia.
Widdop
Robert E
RE
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D012039:Regional Blood Flow / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C060894:CGP 42112A; C081643:candesartan