In-vivo effects of endothelin-1 and ETA receptor blockade on arterial, venous and capillary functions in skeletal muscle.
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.
Ekelund
U
U
Department of Physiology & Biophysics, University of Lund, Sweden.
Albert
U
U
Edvinsson
L
L
Mellander
S
S
D000818:Animals; D001158:Arteries / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D002415:Cats; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D006940:Hyperemia / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D009129:Muscle Tonus / Q000187:drug effects; D009132:Muscles / Q000098:blood supply* / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D013562:Sympathectomy; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014680:Veins / Q000187:drug effects
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D006020:Glycopeptides; D007211:Indoles; C079574:FR 139317; D015260:Neprilysin; C008890:phosphoramidon