Synergy of amlodipine and angiotensin-converting enzyme inhibitors in regulating myocardial oxygen consumption in normal canine and failing human hearts.
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.
Mital
S
S
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Loke
K E
KE
Slater
J P
JP
Addonizio
L
L
Gersony
W M
WM
Hintze
T H
TH
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
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