Original Articles
Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts

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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 Nω-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.

Section snippets

Procurement of human hearts

Explanted hearts were harvested from 6 patients with end-stage cardiac failure during orthotopic cardiac transplantation and immediately placed in iced normal saline solution. The apical portion of each heart (which includes a portion of the left ventricular free wall, the septum, and the right ventricular free wall) was removed for this study. Within 30 minutes after removal, the hearts were transported on ice to our laboratory, where microvessels were isolated. The hearts were placed in iced

Effects of amlodipine on NO production by coronary microvessels in failing human hearts

Amlodipine (10−10 to 10−5 mol/L) caused a significant and dose-related increase in nitrite production in coronary microvessels of explanted failing human hearts (Figure 1). Compared with control, the highest dose of amlodipine increased nitrite release from 71 ± 4 to 126 ± 8 pmol/mg (p <0.01). Nitrite release induced by the highest dose of amlodipine was markedly reduced after pretreatment with L-NAME and HOE-140 (75 ± 5 and 84 ± 7 pmol/mg, respectively; all p <0.01, as compared with the

Discussion

Amlodipine can significantly increase NO production in the coronary microvessels of explanted failing human hearts. Compared with angiotensin-converting enzyme and neutral endopeptidase inhibitors, amlodipine induced a similar maximal NO production, indicating that amlodipine has a potent effect on coronary microvessels to release NO even after the development of severe congestive heart failure. It is therefore very likely that the difference between amlodipine and other calcium antagonists in

Conclusion

In summary, amlodipine significantly increased nitrite production in isolated coronary microvessels of explanted failing human hearts. This effect was blocked by L-NAME, HOE-140, and 3 serine protease inhibitors. These results suggest that amlodipine is a potent NO-releasing agent, as potent as ramiprilat and more potent than 2 neutral endopeptidase inhibitors. Amlodipine stimulates NO production from endothelium, most likely by promoting the effect of local kinins. Thus, amlodipine

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      Laboratory studies have demonstrated that amlodipine has beneficial effects on endothelial dysfunction.42–44 One early investigation recorded the effects on human arterial vessels with the administration of different antihypertensive agents, including an ACE inhibitor and a calcium channel blocker.43 The aim of this study was to determine the effect of amlodipine on NO production in failing human hearts along with the role of kinins.

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    These studies were supported by grants PO-1-HL 43023, HL 50142, HL 18579#, and HL 53053 from the National Heart, Lung, and Blood Institute and by Fellowship 96-103 (XZ) from the New York Affiliate of the American Heart Association.

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