Big endothelin-1 and big endothelin-3 are constrictor agents in the microvasculature: evidence for the local phosphoramidon-sensitive conversion of big endothelin-1.
The effect of local administration of big endothelin-1 (1-38, big ET-1) has been investigated on blood flow in the skin of anaesthetised rats, measured by 133Xe clearance. The local effects of big ET-1 and big endothelin-3 (1-41, big ET-3) have also been determined on microvessel diameter by intravital microscopy of the cheek pouch of anaesthetised hamsters. Big ET-1 (i.d.) caused a dose-dependent decrease in skin blood flow and was 10 times less potent than endothelin-1 (ET-1). Phosphoramidon (30 nmol/site i.d.) did not effect blood flow but when coinjected selectively attenuated the effect of big ET-1 (1 and 3 pmol/site, P < 0.05). In the cheek pouch big ET-1 (100 pmol) induced an intense and long-lasting arteriolar constriction. Phosphoramidon (100 nmol) abolished constriction to big ET-1 (100 pmol) but not to ET-1 (10 pmol). The modest constriction induced by big ET-3 (300 pmol) was not inhibited by phosphoramidon (100 nmol). Results suggest that a phosphoramidon-sensitive endothelin-converting enzyme situated close to microvascular vessels is important in the conversion of big ET-1. The mechanism for activity of big ET-3 in the microcirculation is unclear.
Lawrence
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Biomedical Sciences Division, King's College, London, UK.
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D000818:Animals; D006224:Cricetinae; D004347:Drug Interactions; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000098:blood supply*; D013820:Thermolysin / Q000037:antagonists & inhibitors*; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D006020:Glycopeptides; D013820:Thermolysin; C008890:phosphoramidon