The pharmacological properties of the peptide, endothelin

Abstract

1 The effect of endothelin (ET-1) has been studied on isolated vascular and non-vascular preparations, using both functional and competition radioligand binding techniques. The effects of endothelin on blood pressure were studied in both anaesthetised, chemically denervated normotensive and spontaneously hypertensive rats (SHR). 2 Endothelin elicited contractile responses in the rat thoracic aorta, perfused mesenteric bed, rabbit mesenteric artery and portal vein. The maximal responses in the rat aorta were enhanced by removal of the endothelium, and were reduced in the presence of either a cyclo-oxygenase inhibitor (indomethacin) or a thromboxane receptor antagonist (SQ 29,548). In terms of potency, the most sensitive preparation was the rat endothelium-denuded aorta and rat perfused mesenteric bed (-log EC50 values = 8.2 + 0.07 and 8.2 + 0.12, mean + s.e.mean, n = 4, respectively). In the perfused mesenteric bed of the rat the maximum response to endothelin (219 + 12 mmHg, n = 4) was greater than that to either phenylephrine (maximal response = 67 + 9 mmHg; n = 4) or KCl (maximal response = 110 + 6 mmHg, n = 4).3 Endothelin elicited contractile responses of the guinea-pig isolated ileum, oesophageal muscularis mucosae and uterus. Responses were also observed in the rat fundic strip and paced left atria. The guinea-pig urinary bladder, trachea, rat vas deferens and anococcygeus exhibited little or no response to endothelin at the concentrations studied (1 x 10 -2-3.2 x 10 -8M). Of the above preparations, the ileum and oesophageal muscularis mucosae were the most sensitive to endothelin (-log EC50 = 8.5 + 0.11 and 8.4 + 0.06, n = 6, respectively), exhibiting potencies similar to those observed in the endothelium-denuded aorta of the rat. 4 In competition-radioligand binding studies, endothelin did not displace either [3H]-PN 210-100 or [125I]< -)-co-conotoxin GVIA from binding sites in membranes from rat cerebral cortex and, skeletal muscle or from guinea-pig cerebral cortex and hippocampus, respectively. This indicates a lack of direct interaction of endothelin at the dihydropyridine binding site and the N-type calcium channel, respectively. However, in functional studies, contractile responses to endothelin (1 x 10-8M) in the endothelium-denuded aorta of the rat were potently reversed by nifedipine, verapamil, and prenylamine (-log IC50 values = 8.0 + 0.13, 7.2 + 0.09 and 6.6 + 0.08, n = 4-8,

Pharmacological modulation of endothelin‐induced contraction of guinea‐pig isolated airways and thromboxane release

“…For example, ET-1 was found to be a more potent myotropic agent in the rat aorta than in the guinea-pig trachea (Hay, 1990). The maximal responses to ET-1 in the rat aorta were significantly reduced by indomethacin (1 pM) or a thromboxane receptor antagonist (Eglen et al, 1989). These findings are similar to our observations in the parenchyma.…”

Regional haemodynamic effects of endothelin‐1 and endothelin‐3 in conscious Long Evans and Brattleboro rats

“…While it is feasible that bolus doses of endothelin-1 or endothelin-3 cause hindquarters vasodilatation by releasing eicosanoids or endothelium-derived relaxing factor (De Nucci et al, 1989;Warner et al, 1989b), we have been unable to block this effect with either N0-monomethy-L-arginine, an inhibitor of nitric oxide synthesis by endothelial cells (Gardiner et al, 1989c), or with indomethacin (Gardiner, S.M., Compton, A.M. & Bennett, T., unpublished observations). Indeed, recent findings indicate that indomethacin reduces the contractile effects of endothelin-I on rat aorta (Eglen et al, 1989). In addition, it seems unlikely that the hindquarters hyperaemic responses to bolus doses of endothelin-1 are dependent upon release of atrial natriuretic peptide (Winquist et al, 1989), since bolus doses of this peptide do not cause significant increases in hindquarters blood flow in Brattleboro rats (Gardiner et al, 1988).…”

Differences in regional vascular sensitivity to endothelin‐1 between spontaneously hypertensive and normotensive Wistar‐Kyoto rats

“…Thus, no direct relaxation of arterial segments from a variety of species has ever been demonstrated (Cocks et al, 1989;Eglen et al, 1989;Saito et al, 1989). On the other hand, endothelin has been shown to dilate the rat perfused mesenteric vascular bed when tone was induced by methoxamine (Warner et al, 1989a,b;Randall et al, 1989) and to release the vasodilator eicosanoid, prostacyclin, from rat perfused lungs in vitro (de Nucci et al, 1988).…”