AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade.
Angiotensin II type 2 receptor (AT2R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT1R) antagonists, given that AT1R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT2R. Thus, we first directly assessed whether or not there is desensitization to AT2R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT1R stimulation. Second, we examined if AT2R-mediated vasorelaxation is preserved after long-term treatment with the AT1R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT2R stimulation, with either Ang II (with AT1R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT2R 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 AT2R antagonist PD123319. By contrast, AT1R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT1R-mediated contraction was abolished, whereas AT2R-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 AT2R-mediated vasorelaxation during short-term and long-term AT1R blockade. Such preservation of AT2R function is a prerequisite for the consideration of physiological role(s) of AT2R during AT1R blockade.
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology*; D015203:Reproducibility of Results; D013777:Tetrazoles; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C060894:CGP 42112A; C077793:candesartan cilexetil