Sarcosine1,glycine8 angiotensin II is an AT1 angiotensin II receptor subtype selective antagonist

Studies predating the discovery of the two major subtypes of angiotensin II (Ang II) receptors, AT(1) and AT(2), revealed anomalous characteristics of sarcosine(1),glycine(8) Ang II (Sar(1),Gly(8) Ang II). It competed poorly for I-125-Ang II binding in bovine brain but potently antagonized dipsogenic responses to intracerebroventricularly administered Ang II. Subsequent recognition that bovine brain contains AT(2) receptors, while dipsogenic responses to Ang II are mediated by AT(1) receptors, suggests that Sar(1),Gly(8) Ang II is AT(1) selective. Sar(1),Gly(8) Ang II competed for I-125-sarcosine(1),isoleucine(8) Ang II binding to AT(1) receptors in pituitary, liver and adrenal (the latter with the AT(2) selective antagonist PD 123,319) with K-i's of 0.66, 1.40 and 1.36 nM, respectively. In contrast, the K-i of Sar(1),Gly(8) Ang II for AT(2) receptors in rat adrenal (with the selective AT(1) antagonist losartan) was 52 nM. I-125-Sar(1),Gly(8) Ang II (0.5-3 nM) bound to AT(1) receptors in pituitary, liver, heart, adrenal, and hypothalamic membranes with high affinity (K-d=0.43, 1.6, 2.3, 0.96 and 1.8 nM, respectively), but showed no saturable binding to the adrenal AT(2) receptor. I-125-Sar(1),Gly(8) Ang II selectively labeled AT(1) receptors in sections of adrenal using receptor autoradiography. Thus, binding studies reveal Sar',Gly8 Ang II to be the first angiotensin peptide analog to show AT(1) receptor selectivity. I-125-Sar(1),Gly(8) Ang II offers a new means to selectively radiolabel AT(1) receptors and may help to characterize ligand docking sites and agonist switches for AT(1) versus AT(2) receptors. (C) 2003 Elsevier B.V. All rights reserved.