Angiotensin II receptors in the normal and failing heart

Abstract

Mammalian myocardium expresses two major subtypes of angiotensin II receptors, namely, AT1 and AT2. These two subtypes mediate a diverse set of Ang II actions on the myocardium in multiple types of cells. AT1 receptors mediate most of the conventionally known angiotensin II actions such as vasoconstrictive, inotropic, chronotropic, and trophic–mitogenic effects. The function(s) of AT2 receptors remains obscure in the myocardium. Expression of the two receptor subtypes appears to be developmentally regulated, with high expression in the fetus followed by decreased expression in the early postnatal period. In end-stage failing human heart, expression of the two subtypes is differentially regulated, with selective downregulation of the AT1 subtype and unchanged or relative upregulation of the AT2 subtype. The selective AT1 receptor downregulation in failing human ventricular myocardium is similar to the behavior of β1-adrenergic receptors, and is “chamber-specific” or only present in failing chambers in the failing human heart. AT1 receptor downregulation in failing ventricular myocardium is likely caused directly or indirectly by activation of the cardiac renin–angiotensin system. Cardiac AT1 receptor downregulation is present in subjects treated with angiotensin-converting enzyme inhibitors, which suggests that blockade of AT1 receptors may be necessary to optimally inhibit adverse effects of angiotensin II. The overall effectiveness of selective AT1 receptor antagonist therapy will likely depend on the probable enhancement of unblocked AT2 receptor-mediated effects of Ang II in the failing human heart, the consequences of which are yet to be elucidated.