Endothelins (ET-1, ET-2 and ET-3) are a family of 21-amino acid peptides. ET-1 represents the most potent vasoconstrictor known to date. It binds on at least two subtypes of G-protein coupled receptors with seven transmembrane spanning domains, named ETA and ETB, whereas ETB receptors display similar potency for all three isopeptides[1]. Ro 46-8443, a pyrimidyl sulfonamide, displayed a binding potency in the μM range. It competed for the binding of [125I]ET-1 on cultured human vascular smooth muscle cells, rat mesangial cells and membranes of baculovirus infected insect cells expressing human recombinant ETA receptor resulting in monophasic competition binding curves with average IC50 values of 2.2, 0.9 and 6.8 μM, respectively. Ro 46-8443 competed for the binding of [125I]ET-1 on membranes of CHO cells carrying recombinant human ETB receptor and microsomal membranes from human placenta with monophasic binding curves resulting in IC50 values of 69 nM and 34 nM, respectively. Thus, Ro 46-8443 displays 300-2000-fold selectivity for these constricting ETB receptor over the above mentioned ETA receptor preparations[1]. Ro 46-8443 dose dependently inhibited release of arachidonic acid with an apparent IC50 value of 110 ± 30 nM in CHO cells carrying recombinant human ETB receptor[1]. The potency of Ro 46-8443 to inhibit the sarafotoxin S6c mediated constriction of rat tracheal rings was also assessed as a measure of inhibitory potency on ETB receptor. Ro 46-8443 caused a dose dependent parallel rightwards shift of the dose response curves resulting in a pA2 value of 7.1 ± 0.2. The ET-1 induced constriction of rat aortic rings, mediated via ETAreceptors, was inhibited with a pA2 value of 5.7 ± 0.06[1].
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