Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ETA-Receptor Complexes

Endothelin-1 (ET-1), a long-acting paracrine mediator, is implicated in cardiovascular diseases but clinical trials with ET-receptor antagonists were not successful in some areas. We tested whether the quasi-irreversible receptor-binding of ET-1 (i) limits reversing effects of the antagonists and (ii) can be selectively dissociated by an endogenous counterbalancing mechanism.-receptor complexes.-receptors by ET-1 (i) occur at an antagonist-insensitive site of the receptor and (ii) are selectively terminated by endogenously released CGRP. Hence, natural stimuli of sensory-motor nerves that stimulate release of endogenous CGRP can be considered for therapy of diseases involving ET-1

Endothelin-1 and-2: Two amino acids matter

AbstractAimsEndothelin-1 (ET-1) and endothelin-2 (ET-2; Trp6Leu7ET-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 methodsWe 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 (Trp6ET-1 and Leu7ET-1).Key findingsET-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 (pKB: 7.1±0.2 versus 5.6±0.4). However, 1μM BQ123 relaxes maximal contractile responses to ET-2 more markedly than those to ET-1. Leu7ET-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 256nM Trp6ET-1 did not cause contraction and did not antagonize arterial responses to ET-1.SignificanceArterial 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