title: Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries.
abstract: The effect of big endothelin-1 (big ET-1) and its conversion to endothelin-1 (ET-1) in rabbit cerebral arteries were examined. Big ET-1 and ET-1 induced concentration-dependent contractions in the basilar artery; ET-1 was approximately 8 times more potent than big ET-1. The metalloprotease inhibitor phosphoramidon (30 mumol/l) almost abolished the contractile response to big ET-1, whereas the ET-1-induced contraction was unaffected. Removal of the endothelium did not attenuate the big ET-1-induced contraction. ET-1 was approximately 14 times more potent than endothelin-3 (ET-3) to elicit contraction. The contractions induced by big ET-1, ET-1 and ET-3 were all inhibited by ET(A) receptor antagonist BQ 123 (3 mumol/l). The ET(B) receptor antagonist IRL 1038 (3 mumol/l) had no effect on the contractile responses to big ET-1 and ET-1, but produced a small inhibition of the ET-3-induced contraction. Formation of ET-1 was demonstrated in membrane fractions of cerebral arteries incubated with big ET-1 as measured by high pressure liquid chromatography followed by radioimmunoassay. These results suggest that externally applied big ET-1 is converted to ET-1 by a phosphoramidon-sensitive "endothelin converting enzyme" present in the vascular smooth muscle cells. The ET-1 formed subsequently mediates the big ET-1-induced contraction by activation of mainly ET(A) receptors, although a small contribution of ET(B) receptors cannot be excluded.
authors.affiliation: Department of Neurology, University Hospital, Malmö, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Petersson
authors.forename: G C
authors.initials: GC
authors.lastname: Hanson
authors.forename: B F
authors.initials: BF
authors.lastname: Lindberg
authors.forename: E D
authors.initials: ED
authors.lastname: Högestätt
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019334:Endothelin-3 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011817:Rabbits; D017466:Receptors, Endothelin / Q000502:physiology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D016232:Endothelins; D006020:Glycopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011498:Protein Precursors; D017466:Receptors, Endothelin; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); D008666:Metalloendopeptidases; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon