In‐vivoeffects of endothelin‐1 and ETareceptor blockade on arterial, venous and capillary functions in skeletal muscle

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Abstract
Results fromin vitrostudies have indicated that endothelin‐1 is a main candidate for endothelium‐derived contracting factors. The aim of thisin vivostudy was to describe in quantitative terms the effects of endothelin‐1 (ET‐1), and of ETareceptor blockade, on vascular tone (resistance) in large‐bore arterial resistance vessels (> 25 μm), small arterioles (< 25 μm) and the veins, as well as on capillary pressure and fluid exchange in cat gastrocnemius muscle. Endothelin‐1 (100–1600 ng kg‐1 min‐1, i.a.) elicited, after an initial transient dilation, a strong dose‐dependent constrictor response in all three consecutive vascular sections, yet with a preferential action on the small arterioles and the veins. The vasoconstriction developed very slowly over about 1 h and was also long‐lasting after cessation of the infusion. Our main quantitative analysis refers to effects elicited by 20 min long i.a. infusions of ET‐1 at a dose of 400 ng kg‐1 min‐1. At the end of this period, the peptide caused, on average, a three‐fold increase in total regional vascular resistance, in turn explained by a 70% increase in large‐bore arterial resistance, a 280% increase in arteriolar resistance and a 220% increase in venous resistance. The latter effect was also manifested as a pronounced capacitance response, and as a decrease in the pre‐ to post‐capillary resistance ratio leading regularly to a rise in capillary pressure, net transcapillary fluid filtration and oedema formation which is unusual for a vasoconstrictor. The new specific competitive ETAreceptor antagonist FR 139317 was found to be fully effectivein vivo, insofar as it abolished the constrictor response to endothelin‐1. ETAreceptor blockade, or administration of phosphoramidon, an inhibitor of ET‐1 production, did not influence the level of basal vascular tone, indicating no significant endogenous release of ET‐1 under resting conditions. This contrasts to the established pronounced endogenous release of endothelium‐derived nitric oxide. Finally, vascular myogenic regulation was found not to be mediated by ET‐1. The results, taken together, suggest a possible role of ET‐1 in long‐term, rather than short‐term, regulation of vascular tonein vivo, perhaps especially during pathophysiological conditions.

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