Endothelin-1 and -2: two amino acids matter

Abstract 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 endothelin A (ET A )-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 ET A -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 (ET A -antagonist) reduces sensitivity to ET-1 more potently than that to ET-2 (pK B : 7.1 ± 0.2 versus 5.6 ± 0.4). However, 1 μM 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 ET A -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.