AT 2 Receptor-Mediated Relaxation Is Preserved After Long-Term AT 1 Receptor Blockade

Abstract

Angiotensin II type 2 receptor (AT 2 R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT 1 R) antagonists, given that AT 1 R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT 2 R. Thus, we first directly assessed whether or not there is desensitization to AT 2 R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT 1 R stimulation. Second, we examined if AT 2 R-mediated vasorelaxation is preserved after long-term treatment with the AT 1 R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT 2 R stimulation, with either Ang II (with AT 1 R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT 2 R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT 2 R antagonist PD123319. By contrast, AT 1 R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT 1 R-mediated contraction was abolished, whereas AT 2 R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT 2 R-mediated vasorelaxation during short-term and long-term AT 1 R blockade. Such preservation of AT 2 R function is a prerequisite for the consideration of physiological role(s) of AT 2 R during AT 1 R blockade.