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Stimulation of angiotensin AT(2) receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2010 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 159, no 3, 709-716 p.Article in journal (Refereed) Published
Abstract [en]

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 center dot kg-1 center dot 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 center dot kg-1 center dot 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 center dot kg-1 center dot min-1) still evoked a significant depressor response in adult SHR (similar to 30 mmHg) when combined with different doses of candesartan (0.01 or 0.1 mg center dot kg-1). Moreover, the Compound 21-evoked depressor effect was abolished when co-infused (50 mu g center dot kg-1 center dot 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.

Place, publisher, year, edition, pages
2010. Vol. 159, no 3, 709-716 p.
Keyword [en]
Compound 21, angiotensin, angiotensin AT(2) receptor, spontaneously hypertensive rats, blood pressure, vascular function
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-137863DOI: 10.1111/j.1476-5381.2009.00575.xISI: 000274407400020PubMedID: 20128808OAI: oai:DiVA.org:uu-137863DiVA: diva2:378624
Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2017-12-11Bibliographically approved

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