title: Endothelium-derived bradykinin: implications for angiotensin-converting enzyme-inhibitor therapy.
abstract: The effects of angiotensin-converting enzyme (ACE) inhibitors on endothelial autacoid formation were determined in human cultured endothelial cells and in endothelium-intact bovine coronary arteries under resting conditions and after stimulation with bradykinin. Incubation of cultured human endothelial cells with moexiprilat or ramiprilat (0.3 microM) caused a maintained increase in resting intracellular calcium [Ca2+]i, which was prevented by the selective B2-receptor antagonist Hoe 140 (0.1 microM). Both ACE inhibitors also significantly enhanced the increase in [Ca2+]i elicited by bradykinin (3 nM). In parallel with their effect on resting [Ca2+]i, moexiprilat and ramiprilat both induced an increase in intracellular cyclic GMP (cGMP). This increase was prevented by Hoe 140 (0.1 microM) and was abolished by NG-nitro-L-arginine (30 microM), indicating a kinin-induced nitric oxide (NO) formation in this response. The elevation in [Ca2+]i also led to an enhanced production of prostacyclin (PGI2), as indicated by an increase in the concentration of 6-keto prostaglandin F1 alpha (PGF1 alpha) in the cell supernatant. Similar effects of the ACE inhibitors on endothelial autacoid production were observed in endothelium-intact bovine coronary arteries. Like bradykinin (30 nM), moexiprilat (0.3 microM) elicited a nearly twofold increase in the cGMP content of these arteries, which was abolished by both NG-nitro-L-arginine and removal of the endothelium. The functional consequences of this ACE inhibitor-induced increase in vascular cGMP were reflected by a distinct relaxation of arteries preconstricted with PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Applied Physiology, University of Freiburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Busse
authors.forename: I
authors.initials: I
authors.lastname: Fleming
authors.forename: M
authors.initials: M
authors.lastname: Hecker
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019335:Nitroarginine; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D044005:Tetrahydroisoquinolines; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D019335:Nitroarginine; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; C052549:ramiprilat; D001120:Arginine; D011464:Epoprostenol; D006152:Cyclic GMP; C059506:moexiprilat; D017257:Ramipril; D001920:Bradykinin; D002118:Calcium