AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade

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 R (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 naive 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.