title: Carvedilol and its metabolites suppress endothelin-1 production in human endothelial cell culture.
abstract: Carvedilol (0.25-25 microM), an antihypertensive drug is shown here to reduce endothelin-1 (ET-1) production in cultured human umbilical cord endothelial cells. Two of its metabolites, M14 and M21 (2.5-25 microM) also suppressed ET-1 production, less potently, however, than carvedilol. Carvedilol is a multiple-acting compound with non-selective beta-adrenoceptor and selective alpha 1-adrenoceptor blocking activity, calcium channel blocking and anti-oxidant activity. To study whether these activities were related to suppressed ET-1 production, endothelial cells were treated with a beta 1-blocker, metoprolol (1-10 microM), a non-selective beta-blocker, propanolol (1-10 microM), an alpha 1-blocker, prazosin (1-10 microM), a calcium channel antagonist, nicardipine (1-10 microM), or with the antioxidative compounds probucol (1-100 microM) and ascorbic acid (1-100 microM). None of these compounds modified ET-1 production. The inhibitory effects of carvedilol, M14 or M21 on ET-1 production were not reversed by N Nitro-L-arginine methyl ester (L-NAME) (1.9 mM), or by indomethacin (1.5 microM), suggesting that mechanisms other than the stimulation of nitric oxide or prostacyclin production were involved.
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki University Central Hospital, Finland.
authors.forename: O
authors.initials: O
authors.lastname: Saijonmaa
authors.forename: K
authors.initials: K
authors.lastname: Metsärinne
authors.forename: F
authors.initials: F
authors.lastname: Fyhrquist
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002227:Carbazoles / Q000378:metabolism* / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008790:Metoprolol / Q000494:pharmacology; D009529:Nicardipine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism* / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D002227:Carbazoles; D019332:Endothelin-1; D011412:Propanolamines; D000077261:Carvedilol; D011433:Propranolol; D009529:Nicardipine; D008790:Metoprolol; D011341:Probucol; D001205:Ascorbic Acid; D011224:Prazosin