In vivo effects of endothelin-2, endothelin-3 and ETA receptor blockade on arterial, venous and capillary functions in cat skeletal muscle.

Abstract

This study describes, in quantitative terms, the effects of endothelin-2 and endothelin-3 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 in vivo. Infusion of endothelin-2 or endothelin-3 (200-1600 ng kg-1 min-1, i.a.) elicited an initial transient dilation, followed by a dose-dependent, slowly developing constrictor response, being maintained after cessation of the infusion. At the dose of 400 ng kg-1 min-1 (n = 9), infused i.a. during 20 min, endothelin-2 caused an average increase in total regional vascular resistance of 80%, and endothelin-3 of 35%, and the site of constrictor action of both peptides was preferentially located to the small arterioles. Endothelin-2 also constricted veins and, hence, evoked a pronounced capacitance response, whereas endothelin-3 was devoid of any venoconstrictor effect. This difference, via effects on the pre-/post-capillary resistance ratio, led to a more pronounced fall of capillary pressure in response to endothelin-3 than to endothelin-2. The new specific competitive ETA receptor antagonist, FR 139317, abolished the vasoconstrictor response to both endothelin-2 and endothelin-3 in vivo, whereas the preceding vasodilator responses were unaffected. These results, taken together with those of our previous analogous study of the effects of endothelin-1, indicated that all three endothelins were approximately equally as effective in eliciting the transient dilator response in skeletal muscle in vivo, whereas the order of vasoconstrictor activity was endothelin-1 > endothelin-2 > endothelin-3. Due to an especially pronounced venoconstrictor activity of endothelin-1, this peptide, in contrast to endothelin-2 and -3, evoked a rise in capillary pressure, with a consequent net transcapillary fluid filtration and muscle tissue oedema formation. The results further indicated that the vasoconstrictor responses to all endothelins in skeletal muscle were mediated by the ETA receptor, whereas the initial transient vasodilator responses seemed to be mediated by the ETB receptor.