IN-VIVO EFFECTS OF ENDOTHELIN-1 AND ET(A) RECEPTOR BLOCKADE ON ARTERIAL, VENOUS AND CAPILLARY FUNCTIONS IN SKELETAL-MUSCLE

Results from in vitro studies have indicated that endothelin-1 is a ma in candidate for endothelium-derived contracting factors. The aim of t his in vivo study was to describe in quantitative terms the effects of endothelin-1 (ET-1), and of ET(A) receptor blockade, on vascular tone (resistance) in large-bore arterial resistance vessels (> 25 muM), sm all arterioles (< 25 muM) and the veins, as well as on capillary press ure and fluid exchange in cat gastrocnemius muscle. Endothelin-1 (100- 1600 ng kg-1 min-1, i.a.) elicited, after an initial transient dilatio n, a strong dose-dependent constrictor response in all three consecuti ve vascular sections, yet with a preferential action on the small arte rioles and the veins. The vasoconstriction developed very slowly over about 1 h and was also long-lasting after cessation of the infusion. O ur main quantitative analysis refers to effects elicited by 20 min lon g 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% increa se in large-bore arterial resistance, a 280% increase in arteriolar re sistance and a 220% increase in venous resistance. The latter effect w as also manifested as a pronounced capacitance response, and as a decr ease in the pre- to post-capillary resistance ratio leading regularly to a rise in capillary pressure, net transcapillary fluid filtration a nd oedema formation which is unusual for a vasoconstrictor. The new sp ecific competitive ET(A) receptor antagonist FR 139317 was found to be fully effective in vivo, insofar as it abolished the constrictor resp onse to endothelin-1. ET(A) receptor blockade, or administration of ph osphoramidon, an inhibitor of ET-1 production, did not influence the l evel of basal vascular tone, indicating no significant endogenous rele ase of ET-1 under resting conditions. This contrasts to the establishe d pronounced endogenous release of endothelium-derived nitric oxide. F inally, vascular myogenic regulation was found not to be mediated by E T-1. The results, taken together, suggest a possible role of ET-1 in l ong-term, rather than short-term, regulation of vascular tone in vivo, perhaps especially during pathophysiological conditions.