In‐vivo effects of endothelin‐1 and ET_a receptor blockade on arterial, venous and capillary functions in skeletal muscle

Abstract

Results from in vitro studies have indicated that endothelin-1 is a main candidate for endothelium-derived contracting factors. The aim of this in vivo study was to describe in quantitative terms the effects of endothelin-1 (ET-1), and of ETA receptor blockade, on vascular tone (resistance) in large-bore arterial resistance vessels (> 25 microns), small arterioles (< 25 microns) 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 ETA receptor antagonist FR 139317 was found to be fully effective in vivo, insofar as it abolished the constrictor response to endothelin-1. ETA receptor 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 tone in vivo, perhaps especially during pathophysiological conditions.

Effects of selective ETB‐receptor stimulation on arterial, venous and capillary functions in cat skeletal muscle

“…The present result, demonstrating that ETBreceptor stimulation leads to a constrictor response, could a priori suggest that the vasoconstrictor response to ET-1 can be mediated by both receptor subtypes in skeletal muscle in vivo. However, we have previously demonstrated that the ET-1-mediated vasoconstriction in muscle in vivo can be abolished by selective ETA-receptor blockade alone (FR 139317;Ekelund et al, 1993). Further, in the present in vitro study, FR139317 competitively inhibited the ET-l-induced contraction of the femoral artery and vein.…”

“…The initial transient vasodilator responses to IRL 1620 and BQ 3020 were not significantly different from those elicited by the endothelins (Ekelund et al, 1993;Ekelund, 1994) with regard to amplitude, duration and time to peak dilatation. This finding seems to support our previous tentative conclusion (Ekelund, 1994) that the dilator responses to the endothelins are mediated via the ETB-receptor.…”

“…Our previous investigations, demonstrating quite unusual haemodynamic and capillary effects of the endothelins in muscle tissue (Ekelund et al, 1993;Ekelund, 1994), suggested that they might be of importance in long-term, rather than short-term, regulation of vascular tone in vivo, perhaps especially during pathophysiological conditions. From the present results, it may be concluded that ETB-receptor stimulation is responsible for the dilator response, and can contribute to the constrictor response, elicited by the endothelins in skeletal muscle in vivo.…”

“…In some recent studies (Ekelund et al, 1993;Ekelund, 1994), the vascular effects in vivo of ET-1, ET-2 and ET-3 were analysed in cat skeletal muscle with the same technical approach as was used in the present investigation. The results showed that all three endothelins elicited a transient dilatation followed by a slowly developing pronounced vasoconstrictor response.…”

“…In previous studies (Ekelund et al, 1993;Ekelund, 1994) on this muscle preparation in vivo, we have demonstrated that FR139317, administered i.a. at the dose of lmgkg-' min-', entirely abolished the vasoconstrictor response to ET-1 (400 ng kg' min'1, i.a.).…”