Endothelin-1 and-2: Two amino acids matter

[摘要] Aims: Endothelin-1 (ET-1) and endothelin-2 (ET-2; Trp(6)Leu(7)ET-1) are expressed by different cell types, but are considered to display identical pharmacological properties on endothelin receptors. We studied agonist-dependent aspects of endothelinA (ETA)-receptor function and the importance of amino acids 6 and 7 of ET-1 and ET-2 in this respect. Main methods: We used isolated rat mesenteric resistance arteries in wire myographs, in a setting that minimizes influences of endothelium and sensorimotor nerves, to study arterial smooth muscle ETA-receptor-mediated vasomotor responses, to ET-1, ET-2 and chimeras thereof (Trp(6)ET-1 and Leu(7)ET-1). Key findings: ET-1 and ET-2 cause arterial contractions with comparable sensitivities and maximal responses. BQ123 (ETA-antagonist) reduces sensitivity to ET-1 more potently than that to ET-2 (pK(B): 7.1 +/- 02 versus 5.6 +/- 0.4). However, 1 mu M BQ123 relaxes maximal contractile responses to ET-2 more markedly than those to ET-1. Leu(7)ET-1 is a contractile agonist with lower potency and similar maximal effect compared to ET-1 and greater sensitivity to BQ123 than ET-2. Up to 256 nM Trp(6)ET-1 did not cause contraction and did not antagonize arterial responses to ET-1. Significance: Arterial smooth muscle ETA-receptor function displays agonist-dependent aspects. This involves roles of amino acids on position 6 and 7 of the endothelin sequence. Agonist-dependent pathologies may benefit from the design of specific, agonist-selective ET-receptor antagonists. (c) 2012 Elsevier Inc. All rights reserved.

[发布日期] 2012-10-15

[效力级别]  Proceedings Paper

[关键词] Endothelin;Rat resistance arteries;Agonist-dependence;Allosteric modulation of receptor function;Structure activity relationships