Angiotensin Receptors & Mechanism of Action

ANGIOTENSIN RECEPTORS & MECHANISM OF ACTION

Angiotensin II receptors are widely distributed in the body. Like the receptors for other peptide hormones, ANG II recep-tors are G protein-coupled and located on the plasma membrane of target cells, and this permits rapid onset of the various actions of ANG II. Two distinct subtypes of ANG II receptors, termed AT₁ and AT₂, have been identified on the basis of their differential affinity for antagonists and their sensitivity to sulfhydryl-reducing agents. AT₁ receptors have a high affinity for the inhibitor losartan and a low affinity for PD 123177 (an experimental nonpeptide antagonist), whereas AT₂ receptors have a high affinity for PD 123177 and a low affinity for losar-tan. Angiotensin II and saralasin  bind equally to both subtypes. The relative proportion of the two subtypes var-ies from tissue to tissue: AT₁ receptors predominate in vascular smooth muscle. Most of the known actions of ANG II are mediated by the AT ₁ receptor, a G_q protein-coupled receptor. Binding of ANG II to AT₁ receptors in vascular smooth muscle results in activation of phospholipase C and generation of inositol trisphosphate and diacylglycerol . These events, which occur within seconds, result in smooth muscle contraction.

The AT₂ receptor has a structure and affinity for ANG II similar to those of the AT₁ receptor. In contrast, however, stimulation of AT₂ receptors causes vasodilation that may serve to counteract the vasoconstriction resulting from AT₁ receptor stimulation. AT₂ receptor-mediated vasodilation appears to be nitric oxide-dependent and may involve the bradykinin B₂ receptor-nitric oxide-cGMP pathway. AT₂ receptors are present at high density in all tissues during fetal development, but they are much less abundant in the adult where they are expressed at high concentration only in the adrenal medulla, reproduc-tive tissues, vascular endothelium, and parts of the brain. AT₂ receptors are up-regulated in pathologic conditions including heart failure and myocardial infarction. The functions of the AT₂ receptor appear to include fetal tissue development, inhi-bition of growth and proliferation, cell differentiation, apopto-sis, and vasodilation.