IN-VIVO EFFECTS OF ENDOTHELIN-2, ENDOTHELIN-3 AND ET(A) RECEPTOR BLOCKADE ON ARTERIAL, VENOUS AND CAPILLARY FUNCTIONS IN CAT SKELETAL-MUSCLE

This study describes, in quantitative terms, the effects of endothelin -2 and endothelin-3 on vascular tone (resistance) in large-bore arteri al resistance vessels ( > 25 mu m), small arterioles( < 25 mu m) and t he veins, as well as on capillary pressure and fluid exchange in cat g astrocnemius muscle in vivo. Infusion of endothelin-2 or endothelin-3 (200-1600 ng kg(-1) min(-1), i.a.) elicited an initial transient dilat ion, followed by a dose-dependent, slowly developing constrictor respo nse, 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 bo th peptides was preferentially located to the small arterioles. Endoth elin-2 also constricted the veins and, hence, evoked a pronounced capa citance response, whereas endothelin-3 was devoid of any venoconstrict or effect. This difference, via effects on the pre-/post-capillary res istance ratio, led to a more pronounced fall of capillary pressure in response to endothelin-3 than to endothelin-2. The new specific compet itive ET(A) receptor antagonist, FR 139317, abolished the vasoconstric tor response to both endothelin-2 and endothelin-3 In vivo, whereas th e preceding vasodilator responses were unaffected. These results, take n together with those of our previous analogous study of the effects o f endothelin-1, indicated that all three endothelins were approximatel y 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 tissu e oedema formation. The results further indicated that the vasoconstri ctor responses to all endothelins in skeletal muscle were mediated by the ET(A) receptor, whereas the initial transient vasodilator response s seemed to be mediated by the ET(B) receptor.