title: Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts.
abstract: Recently, we found that amlodipine can release nitric oxide (NO) from canine coronary microvessels, which raises the question of whether amlodipine can also promote coronary NO production in failing human hearts. The goal of this study was to define the effect of amlodipine on NO production in failing human hearts and to determine the role of kinins in the control of NO production induced by amlodipine. Six explanted human hearts with end-stage heart failure were obtained immediately at transplant surgery. Coronary microvessels were isolated as previously described, and nitrite, the stable metabolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite production in coronary microvessels in a dose-dependent manner. The increase in nitrite in response to the highest dose of amlodipine (79%) was similar in magnitude to either that of the angiotensin-converting enzyme inhibitor ramiprilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) and thiorphan (72%). Interestingly, the increase in nitrite production induced by amlodipine was entirely abolished by N(omega)-nitro-L-arginine methyl ester and also HOE-140 (a bradykinin-2 antagonist) and dichloroisocoumarin (a serine protease inhibitor that blocks kallikrein activity). These results indicate that amlodipine can promote coronary NO production in failing human hearts and that this effect is dependent on a kinin-mediated mechanism.
authors.affiliation: Department of Physiology and Pharmacology, New York Medical College, Valhalla 10595, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: M R
authors.initials: MR
authors.lastname: Kichuk
authors.forename: S
authors.initials: S
authors.lastname: Mital
authors.forename: M
authors.initials: M
authors.lastname: Oz
authors.forename: R
authors.initials: R
authors.lastname: Michler
authors.forename: A
authors.initials: A
authors.lastname: Nasjletti
authors.forename: G
authors.initials: G
authors.lastname: Kaley
authors.forename: T H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008833:Microcirculation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000037:antagonists & inhibitors; D011803:Quinine / Q000378:metabolism*; D017257:Ramipril / Q000031:analogs & derivatives / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015244:Thiorphan / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D002121:Calcium Channel Blockers; D006020:Glycopeptides; D009573:Nitrites; D015842:Serine Proteinase Inhibitors; D017311:Amlodipine; D009569:Nitric Oxide; C052549:ramiprilat; C065679:icatibant; D011803:Quinine; D015244:Thiorphan; D008666:Metalloendopeptidases; D017257:Ramipril; D001920:Bradykinin; C008890:phosphoramidon; D019331:NG-Nitroarginine Methyl Ester