title: Synergy of amlodipine and angiotensin-converting enzyme inhibitors in regulating myocardial oxygen consumption in normal canine and failing human hearts.
abstract: The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.
authors.affiliation: Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mital
authors.forename: K E
authors.initials: KE
authors.lastname: Loke
authors.forename: J P
authors.initials: JP
authors.lastname: Slater
authors.forename: L
authors.initials: L
authors.lastname: Addonizio
authors.forename: W M
authors.initials: WM
authors.lastname: Gersony
authors.forename: T H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D017311:Amlodipine / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002648:Child; D003374:Coumarins / Q000494:pharmacology; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D049934:Isocoumarins; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010101:Oxygen Consumption / Q000187:drug effects*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D002121:Calcium Channel Blockers; D003374:Coumarins; D049934:Isocoumarins; C110881:S-nitro-N-acetylpenicillamine; D015842:Serine Proteinase Inhibitors; D017311:Amlodipine; C046235:3,4-dichloroisocoumarin; C052549:ramiprilat; C065679:icatibant; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D017257:Ramipril; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester