Modulation by endothelium of the responses induced by endothelin‐1 and by some of its analogues in rat isolated aorta

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Abstract
The contractile effects of endothelin‐1 and various analogues were studied in rat isolated aortic rings. The potency order of the peptides studied was endothelin‐1 > sarafotoxin S6b > [Ala3,11]endothelin‐1 > [Ala1,15]endothelin‐1. [Ala1,3,11,15]endothelin‐1 was neither agonist nor antagonist. The concentration of endothelin‐1 required to induce contractions equal to 50% of those induced by 1 μm noradrenaline was reduced from 5.8 nm when the vascular endothelium was present to 1.4 nm after it had been mechanically removed. Contractions elicited by [Ala3,11]endothelin‐1, [Ala1,15]endothelin‐1 and sarafotoxin S6b were not modulated by the endothelium. Endothelin‐1 increased the tissue content of guanosine 3′,5′‐cyclic monophosphate (cyclic GMP) in rat aortic segments with endothelium by about 4 fold, suggesting that it increased the release of endothelium‐derived relaxing factor. Sarafotoxin S6b did not reduce, or significantly increase, tissue cyclic GMP levels and therefore had little effect on EDRF release. The concentration of sodium nitroprusside required to relax half‐maximally aortae denuded of endothelium was 430 nm if the aortae had been precontracted with 10 nm endothelin‐1 and 35 nm if 10 nm sarafotoxin S6b was used as the spasmogen. This indicates that differential sensitivities of the smooth muscle to cyclic GMP cannot explain differences between responses to endothelin‐1 and sarafotoxin S6b in the presence of. endothelium. It is concluded that endothelin‐1 contractions of rat aorta are modified by the endothelium, probably by enhancing the release of endothelium‐derived relaxing factor (EDRF) and not by affecting the sensitivity of the smooth muscle to EDRF. This suggests that a stimulated release of an adequate amount of EDRF is necessary to modulate contractile responses to these peptides.