Stimulation of angiotensin AT 2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Abstract

Background and purpose: Angiotensin type 2 receptor (AT 2 receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT 1 receptors). Recently, a novel non-peptide AT 2 receptor agonist, Compound 21, was described, which exhibited high AT 2 receptor selectivity. Experimental approach: Functional cardiovascular effects of the drug candidate Compound 21 were assessed, using mouse isolated aorta and rat mesenteric arteries in vitro and in conscious spontaneously hypertensive rats (SHR). Key results: Compound 21 evoked dose-dependent vasorelaxations in aortic and mesenteric vessels, abolished by the AT 2 receptor antagonist, PD123319. In vivo, Compound 21 administered alone, at doses ranging from 50 to 1000 ng·kg -1·min -1 over 4 h did not decrease blood pressure in conscious normotensive Wistar-Kyoto rats or SHR. However, when given in combination with the AT 1 receptor antagonist, candesartan, Compound 21 (300 ng·kg -1·min -1) lowered blood pressure in SHR only. Further analysis in separate groups of conscious SHR revealed that, at a sixfold lower dose, Compound 21 (50 ng·kg -1·min -1) still evoked a significant depressor response in adult SHR (∼30 mmHg) when combined with different doses of candesartan (0.01 or 0.1 mg·kg -1). Moreover, the Compound 21-evoked depressor effect was abolished when co-infused (50 μg·kg -1·min -1 for 2 h) with the AT 2 receptor antagonist PD123319. Conclusion and implications: Collectively, our results indicate that acute administration of Compound 21 evoked blood pressure reductions via AT 2 receptor stimulation. Thus Compound 21 can be considered an excellent drug candidate for further study of AT 2 receptor function in cardiovascular disease. © 2010 The British Pharmacological Society.