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(Hypertension. 2002;40:516.)
© 2002 American Heart Association, Inc.

Scientific Contributions

AT₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT₁ Receptor Blockade

From the Department of Pharmacology, Monash University (R.E.W.), Melbourne, Victoria, Australia; INSERM U541, IFR Circulation-Paris-Nord, Paris VII University (K.M., D.H.), Paris, France; and the Department of Physiology, AP-HP-Hôpital Lariboisière (B.I.L.), Paris, France.

Correspondence to Dr Robert Widdop, Department of Pharmacology, PO Box 13E, Monash University, Melbourne, Victoria 3800, Australia. E-mail robert.widdop{at}med.monash.edu.au

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.

Key Words: receptors, angiotensin • muscle, smooth, vascular • vasodilation

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