Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent.
BACKGROUND
Recent studies suggest that amlodipine may reduce mortality in patients with heart failure, especially those with dilated cardiomyopathy. In general, drugs that release NO, such as organic nitrates and ACE inhibitors, have been shown to be of substantial benefit in the treatment of heart failure.


RESULTS
We hypothesized that a portion of the beneficial actions of amlodipine may involve the release or action of NO. Coronary microvessels were isolated from the heart of normal dogs and incubated with increasing doses of the calcium channel blockers nifedipine, diltiazem, and amlodipine or the ACE inhibitors enalaprilat and ramiprilat. Neither nifedipine nor diltiazem increased nitrite production at any dose studied. In marked contrast, amlodipine caused a dose-dependent increase in nitrite production from 74+/-5 to 130+/-8 pmol/mg (by 85+/-21%,10(-5) mol/L, P<.05) that was similar in magnitude to that of either of the ACE inhibitors. Amlodipine also increased nitrite production in large coronary arteries and in aorta. N(omega)-Nitro-L-arginine methyl ester, HOE-140, and dichloroisocoumarin essentially abolished the increase in nitrite production, indicating that (1) nitrite production reflected NO formation, (2) nitrite production was dependent on stimulation of the kinin2 receptor, and (3) nitrite production is most likely secondary to the formation of local kinins.


CONCLUSIONS
Thus, unlike nifedipine and diltiazem, amlodipine releases NO from blood vessels.
Zhang
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X
Department of Physiology, New York Medical College, Valhalla 10595, USA.
Hintze
T H
TH
D017311:Amlodipine / Q000494:pharmacology*; D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015773:Enalaprilat / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D017257:Ramipril / Q000031:analogs & derivatives / Q000494:pharmacology; D012044:Regression Analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D017311:Amlodipine; D009569:Nitric Oxide; C052549:ramiprilat; D004110:Diltiazem; D015773:Enalaprilat; D017257:Ramipril