Angiotensin II type 2 receptor agonists: where should they be applied?

Abstract

Introduction: Angiotensin II, the active endproduct of the renin–angiotensin system (RAS), exerts its effects via angiotensin II type 1 and type 2 (AT₁, AT₂) receptors. AT₁ receptors mediate all well-known effects of angiotensin II, ranging from vasoconstriction to tissue remodeling. Thus, to treat cardiovascular disease, RAS blockade aims at preventing angiotensin II–AT₁ receptor interaction. Yet RAS blockade is often accompanied by rises in angiotensin II, which may exert beneficial effects via AT₂ receptors.

Areas covered: This review summarizes our current knowledge on AT₂ receptors, describing their location, function(s), endogenous agonist(s) and intracellular signaling cascades. It discusses the beneficial effects obtained with C21, a recently developed AT₂ receptor agonist. Important questions that are addressed are do these receptors truly antagonize AT₁ receptor-mediated effects? What about their role in the diseased state and their heterodimerization with other receptors?

Expert opinion: The general view that AT₂ receptors exclusively exert beneficial effects has been challenged, and in pathological models, their function sometimes mimics that of AT₁ receptors, for example, inducing vasoconstriction and cardiac hypertrophy. Yet given its upregulation in various pathological conditions, the AT₂ receptor remains a promising target for treatment, allowing effects beyond blood pressure-lowering, for example, in stroke, aneurysm formation, inflammation and myocardial fibrosis.

Keywords::

• angiotensin
• angiotensin II type 2 receptor agonist
• C21
• heterodimer
• hypertrophy
• inflammation
• Marfan's syndrome
• natriuresis
• neuroprotection
• vasorelaxation

Acknowledgements

This study has been performed within the framework of the Dutch Top Institute Pharma, project T2-301 (Renin-angiotensin system blockade beyond angiotensin II).

Notes

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