Amlodipine enhances NO production induced by an ACE inhibitor through a kinin-mediated mechanism in canine coronary microvessels.
Our previous study found that angiotensin-converting enzyme (ACE) inhibitors and amlodipine induce NO release from coronary microvessels through a kinin-dependent mechanism. The goal of this study was to determine whether amlodipine could potentiate NO formation during ACE inhibition. Coronary microvessels were isolated from 16 mongrel dogs. Nitrite, the hydration product of NO, from coronary microvessels was quantified by using the Griess reaction. Bradykinin and kallikrein all significantly increased nitrite release from coronary microvessels in a concentration-dependent manner. The ACE inhibitor, ramiprilat, potentiated these effects. Amlodipine also markedly potentiated nitrite production by ramiprilat. For instance, amlodipine (10(-10) M) enhanced nitrite release induced by ramiprilat (10(-7) M) from 122 +/- 9 to 168 +/- 14 pmol/mg (p < 0.05 vs. ramiprilat). Nitrite release potentiated by ramiprilat and amlodipine was entirely blocked by N(omega)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase), HOE 140 (Icatibant, a specific B2-kinin receptor antagonist), and dichloroisocoumarin (DCIC, a serine protease inhibitor that blocks local kinin formation). These results clearly show that there is a synergistic effect on NO formation when amlodipine is combined with ACE inhibition. Our data suggest that kinin-mediated coronary NO production may contribute importantly to the beneficial therapeutic action of ACE inhibitors, especially in combination with amlodipine in the treatment of heart disease.
Zhang
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Department of Physiology, New York Medical College, Valhalla, New York 10595, USA.
Xu
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Nasjletti
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Hintze
T H
TH
D017311:Amlodipine / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003331:Coronary Vessels / Q000378:metabolism*; D003374:Coumarins / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066298:In Vitro Techniques; D007610:Kallikreins / Q000494:pharmacology*; D008833:Microcirculation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000032:analysis; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D003374:Coumarins; D009573:Nitrites; D017311:Amlodipine; D009569:Nitric Oxide; C052549:ramiprilat; C065679:icatibant; D007610:Kallikreins; D017257:Ramipril; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester