AT 2 receptor-mediated vasodilatation is unmasked by AT 1 receptor blockade in conscious SHR

Abstract

1 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. 2 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 μg kg -1 i.v.) alone, the AT 2 receptor agonist, CGP42112 (1 μg kg -1 min -1) alone and candesartan plus CGP42112. 3 Low-dose candesartan (5 μg 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 μg kg -1 min -1), with the candesartan and CGP42112 combination. PD123319, given alone, increased MAP and reduced renal and mesenteric conductances. 4 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. 5 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.