Stimulation of angiotensin AT2 receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

• Published in: British journal of pharmacology 2010-02, Vol.159 (3), p.709-716
• Main Authors: Bosnyak, S, Welungoda, IK, Hallberg, A, Alterman, M, Widdop, RE, Jones, ES
• Format: Article
• Language: English
• Subjects: angiotensin; angiotensin AT2 receptor; Animals; Aorta - drug effects; Arterial hypertension. Arterial hypotension; Benzimidazoles; Biological and medical sciences; Blood and lymphatic vessels; blood pressure; Blood Pressure - physiology; Blood Vessels - drug effects; Cardiology. Vascular system; Cardiovascular System - drug effects; Compound 21; Consciousness - drug effects; Imidazoles; Male; Medical sciences; Mice; Mice, Inbred Strains; Peptides - pharmacology; Pharmacology. Drug treatments; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2 - physiology; Research Papers; spontaneously hypertensive rats; Tetrazoles; vascular function; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2009.00575.x

Background and purpose:  Angiotensin type 2 receptor (AT2 receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT1 receptors). Recently, a novel non‐peptide AT2 receptor agonist, Compound 21, was described, which exhibited high AT2 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 AT2 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 AT1 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 AT2 receptor antagonist PD123319. Conclusion and implications:  Collectively, our results indicate that acute administration of Compound 21 evoked blood pressure reductions via AT2 receptor stimulation. Thus Compound 21 can be considered an excellent drug candidate for further study of AT2 receptor function in cardiovascular disease.