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(Circulation. 1998;97:576-580.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Amlodipine Releases Nitric Oxide From Canine Coronary Microvessels

An Unexpected Mechanism of Action of a Calcium Channel–Blocking Agent

Xiaoping Zhang, MD; ; Thomas H. Hintze, PhD

From the Department of Physiology, New York Medical College, Valhalla, NY.

Correspondence to Thomas H. Hintze, PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas-Hintze{at}NYMC.edu

	Abstract

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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.

Methods and 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-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.

Key Words: nifedipine • bradykinin • calcium channels • endothelium-derived factors

	Introduction

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Recent studies suggest that calcium channel blockers in general may not be beneficial in the treatment of heart failure even if effective in the treatment of other vascular diseases, including hypertension and vasospasm.^{1 2 3} The mechanism of these effects may be a negative inotropic action, particularly if there is some abrogation of the reflex sympathetic actions caused by these drugs due to the disappearance of sympathetic nerve endings in the heart as a part of the heart failure process.⁴ In contrast to these views, amlodipine has been reported in the PRAISE-1 trial to have a substantial beneficial effect in a subgroup of patients with dilated cardiomyopathy who underwent posthoc analysis.⁵ For instance, there was a 31% reduction in fatal events in a subgroup of patients with nonischemic dilated cardiomyopathy who were treated with amlodipine.⁵

Our recent data suggested that a portion of the beneficial effects of ACE inhibitors in the treatment of heart failure may be due to the release of NO⁶ secondary to the generation of kinins locally.^{6 7 8} These data support a large number of other studies,^{9 10} and it is now widely believed that NO contributes importantly to the mechanism of action of ACE inhibitors used in the treatment of all disease states. The release of NO by amlodipine or other calcium channel blockers would not be expected because there are no known receptors for calcium channel blockers in endothelial cells and because calcium is a cofactor for NO synthase and required for activation of NO synthase.^{11 12} However, because both ACE inhibitors and organic nitrates release NO and are useful in the treatment of heart failure, we reasoned that perhaps amlodipine releases NO from blood vessels and that kinins mediate the release of NO.^{6 7 8} Thus, the goal of our study was to compare and contrast the ability of amlodipine and two other calcium channel blockers to release NO with that of a group of compounds, the ACE inhibitors, which are already known to release NO.

	Methods

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Nineteen male mongrel dogs (body weight, 23 to 30 kg) were used in the study. Hearts were obtained immediately from pentobarbital-anesthetized dogs and kept in ice-cold PBS containing 0.1% bovine serum albumin, pH 7.4. All of the studies in dogs were approved by the Institutional Animal Care and Use Committee of New York Medical College and conform to current National Institutes of Health and American Physiological Society guidelines for the use and care of laboratory animals.

Isolation of Coronary Microvessels
Isolation of coronary microvessels from the left ventricle of the dog heart was performed using the method originally developed by Gerritsen and Printz.¹³ Coronary microvessels were obtained free of both large arteries and veins and also of myocytes by a series of steps involving sequential dissection, homogenization, sieving, and glass bead purification. We have previously used these methods.^{6 7 8 14 15 16}

Incubation of Coronary Microvessels
Microvessels were placed in a small package of 80-µm nylon mesh, transferred into a tissue bath containing PBS, and oxygenated with 95% O₂/5% CO₂ for 30 minutes. About 20 mg (wet weight) of tissue was placed in 5-mL plastic tubes that contained 500 µL of PBS as control or 450 µL of PBS and 50 µL of drugs dissolved in PBS used to stimulate (eg, amlodipine and ramiprilat) or inhibit (eg, L-NAME) NO formation. All drugs were incubated with tissue for 20 minutes. At the end of the incubation time, the tubes were removed from the tissue bath, and sulfanilamide (450 µL of 1%) and N-(1-naphthyl)-ethylenediamine (50 µL of 0.2%) were added to each tube for diazotization of sulfanilic acid by NO. After 5 to 10 minutes' incubation at room temperature, the supernatant was removed from each tube. Formation of NO was measured as nitrite that is the major metabolite of NO in aqueous solution. Nitrite was measured using a spectrophotometer (Uvikon 930 Spectrophotometer; Kontron Instruments) as the increase in absorbance at 540 nm and compared with known concentrations of nitrite. L-NAME was used to block NO synthase. HOE-140 (Icatibant) was used to block the kinin₂ receptor, and DCIC used to block the action of kinin-forming enzymes. We described these methods recently.^{14 15 16}

Isolation of Large Coronary Artery and Aorta
Either the left circumflex or left anterior descending coronary artery was removed and cut into rings 20 mg in weight. In addition, pieces of the descending thoracic aorta (20 mg) were removed and studied. Rings were incubated in a fashion similar to microvessels. We used this technique previously.^{15 16}

Comparison of Effects of Amlodipine, Ramiprilat, and Diltiazem on NO Production
The effects of increasing doses of amlodipine (10^-10 to 10^-5 mol/L) on nitrite production were compared with those of ramiprilat (10^-10 to 10^-8 mol/L). The highest dose of amlodipine or ramiprilat was examined after preincubation of the microvessels with L-NAME, HOE-140, or DCIC. A standard dose-response curve for bradykinin (10^-8 to 10^-5 mol/L) was also examined. A comparison of the effects of amlodipine on large coronary arteries, ascending aorta, and coronary microvessels was performed. To make a comparison with another water-soluble calcium channel blocker, the effects of increasing doses of diltiazem (10^-10 to 10^-5 mol/L) on NO production were determined in microvessels from five dogs.

Comparison of Effects of Amlodipine, Nifedipine, and Enalaprilat on NO Production
We compared the ability of amlodipine to release NO with that of nifedipine. However, unlike amlodipine and diltiazem, nifedipine is not soluble in aqueous solution. Therefore, we compared the actions of nifedipine, amlodipine, and enalaprilat with all of the drugs dissolved in 0.01% DMSO (n=7). In coronary microvessels, the effects were assessed of increasing doses of amlodipine, nifedipine, and enalaprilat on NO production. The effects of the highest dose of each of these was also assessed after preincubation of the microvessels with L-NAME, HOE-140, or DCIC.

Drugs and Chemicals
The PBS used in these studies consisted of 139 mmol/L NaCl, 2.7 mmol/L KCl, 8.1 mmol/L NaHPO₄, 1.5 mmol/L KH₂PO₄, 0.68 mmol/L CaCl₂, 0.49 mmol/L MgCl₂, and 0.1% bovine serum albumen. L-NAME is an inhibitor of NO synthase; HOE-140 (Icatibant) is a bradykinin₂ receptor antagonist; and DCIC is a serine protease inhibitor that blocks the activity of kinin-forming enzymes (serine proteases). Drugs (bradykinin, enalaprilat, diltiazem) and chemicals (L-NAME, DCIC, and nitrite) were purchased from Sigma Chemical. Amlodipine and nifedipine were generously supplied by Pfizer Pharmaceutical (Groton, CT). Ramiprilat and HOE-140 were generously supplied by Hoechst-Roussel Inc (Somerville, NJ). In only one study, amlodipine, nifedipine, and enalaprilat were dissolved in 0.01% DMSO and PBS. In all of the other studies, the drugs were dissolved in PBS.

Statistical Analysis and Calculation
To construct a standard curve for nitrite, a stock solution of NaNO₂ (10^-5 mol/L), was prepared and diluted each day. Sulfanilamide (450 µL of 1%) and N-(1-naphthyl) ethylene diamine (50 µL of 0.2%) were added to each tube and mixed well. The tubes were allowed to stand at room temperature for 5 to 10 minutes for full color (pink) development and absorbance of nitrite measured at 540 nm. Absorbance was computed and converted to a straight line using a regression analysis (y=ax+b, r>.99). Nitrite production was calculated using the linear regression formula and resulting values computed. Data were expressed as mean±SEM in pmol · mg of wet weight^-1 · 20-min incubation^-1. Differences in nitrite production from control were determined with ANOVA. A value of P<.05 was considered statistically significant. Statistical analysis and graphs were produced on a 486 computer (Everex) using commercially available software (Lotus1,2,3; GB STAT; Slide Write). The differences between individual data points were determined using Tukey's test (GB STAT).

	Results

Top Abstract Introduction Methods Results Discussion References

 
The average weight of the heart in these dogs was 211±7 g, the LV free wall weight was 83±3 g, and the amount of microvessels collected was 2.0±0.1 g per heart. The average weight of rings of coronary arteries was 21±2 mg, and the weight of pieces of the aorta was 20±4 mg. The average body weight of the dogs was 27±0.5 kg. The data in the figures are the actual changes in nitrite production in pmol · mg of wet weight^-1 · 20-min incubation^-1, whereas the data in the text are the actual values.

Comparison of Effects of Amlodipine, Ramiprilat, and Diltiazem on NO Production
The effects of increasing doses of amlodipine and ramiprilat in coronary microvessels (n=7) are shown in Fig 1. Both agents caused a substantial increase in nitrite production; however, ramiprilat was significantly more potent. The highest dose of amlodipine increased nitrite production from 74±5 to 130±8 pmol/mg. and this was reduced to 60±7 pmol/mg in the presence of L-NAME, to 76±10 pmol/mg in the presence of HOE-140, and to 90±8 pmol/mg in the presence of DCIC (all P<.05 from amlodipine, Fig 2). In contrast, diltiazem did not increase NO production at any dose studied (Fig 1). Bradykinin caused a dose-dependent increase (n=7) in nitrite production with 10^-5 mol/L, increasing from 78±8 to 153±9 pmol/mg. The increase in nitrite was entirely blocked by L-NAME (to 85±11 pmol/mg) and HOE-140 (to 82±9 pmol/mg, both P<.05; baseline, 89±8 pmol/mg).

View larger version (17K): [in this window] [in a new window]   Figure 1. Increase in nitrite production due to amlodipine, ramiprilat, and diltiazem in isolated coronary microvessels. Although amlodipine and ramaprilat caused a dose-dependent increase in nitrite production, diltiazem had no significant effect at any dose.

View larger version (22K): [in this window] [in a new window]   Figure 2. Role of NO, bradykinin2 receptor, and local kinin formation in the production of nitrite. The production of nitrite in coronary microvessels was entirely blocked by L-NAME, indicating that nitrite production reflects NO synthesis. The enhanced nitrite production was also blocked by HOE-140 and DCIC, indicating that NO production was a consequence of stimulation of the bradykinin 2 receptor and the formation of kinins, respectively.

As shown in Fig 3, amlodipine caused a significant, comparable, and dose-dependent increase (n=7) in nitrite production in large coronary arteries, aorta, and coronary microvessels. NO production was blocked by L-NAME (from 145±17 to 110±14), by HOE-140 (from 145±17 to 92±10), or by DCIC (from 145±17 to 98±8; baseline, 80±4 pmol/mg) in large coronary artery (all P<.05) and by L-NAME (from 140±18 to 90±11 pmol/mg), by HOE-140 (from 140±18 to 102±14 pmol/mg), and by DCIC (from 140±18 to 97±14; baseline, 88±9 pmol/mg) in aorta (all P<.05). At no dose did diltiazem significantly increase nitrite production in large coronary artery or aorta.

View larger version (18K): [in this window] [in a new window]   Figure 3. Amlodipine caused similar increases in nitrite production in large coronary arteries, aorta, and coronary microvessels.

Comparison of Effects of Amlodipine, Nifedipine, and Enalaprilat on NO Production
When dissolved in DMSO (n=7), enalaprilat and amlodipine both increased NO production in a dose-dependent manner (Fig 4). Amlodipine increased nitrite production from 76±5 to 153±12 pmol/mg, and enalaprilat increased nitrite production from 80±7 to 146±11 pmol/mg. There was no statistical difference in the peak response to these agents. In marked contrast, at no dose did nifedipine cause a statistically significant increase in NO production in coronary microvessels (Fig 4) or in large coronary arteries (117±12 to 107±10 pmol/mg) and aorta (90±8 to 102±10 pmol/mg, n=7). The increase in nitrite production to amlodipine and enalaprilat was reduced to 76±7 and 72±12 pmol/mg by L-NAME, to 77±7 and 81±10 pmol/mg by HOE-140, and to 87±11 and 77±15 pmol/mg by DCIC, respectively.

View larger version (17K): [in this window] [in a new window]   Figure 4. Amlodipine and enalaprilat caused similar and dose-dependent increases in nitrite production in coronary microvessels. In marked contrast, nifedipine had no effect on nitrite production at any dose studied. The vehicle for all these drugs was DMSO because nifedipine is not soluble in aqueous solution.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The most significant finding of the present study was that unlike the other calcium channel–blocking agents, nifedipine and diltiazem, amlodipine causes the release of NO from large and small coronary arteries and aorta. The magnitude of the stimulation of NO at the highest dose studied is not different from that of ACE inhibitors. It is interesting that the same mechanism that is responsible for ACE inhibitor-induced NO production (ie, a kinin-dependent mechanism) appears also to be responsible for the ability of amlodipine to release NO. It is therefore very likely that part of the difference between amlodipine and nifedipine or diltiazem stems from the unexpected property of amlodipine to release NO.

Recent clinical studies have suggested that nifedipine is without benefit in the treatment of heart failure and have questioned its therapeutic use even when it may clearly be indicated and effective in disease states in which nifedipine causes vasodilation, such as hypertension or vasospasm. A preliminary study, PRAISE-1, however, has shown that amlodipine has clear beneficial actions in nonischemic dilated cardiomyopathy.⁵ In heart failure secondary to ischemia, amlodipine may also have no effect on mortality when compared with a placebo-treated group.⁵ The most widely used drugs in the treatment of heart failure are organic nitrates and ACE inhibitors.¹⁷ Both of these compounds release NO either chemically, as in the nitrates, or due to inhibition of kinin breakdown, by kininase II inhibition, as in the case of ACE inhibitors. These actions result in vasodilation, increased coronary blood flow, decreased peripheral vascular resistance, and other actions, such as inhibition of platelet aggregation.¹² In addition, the organic nitrates cause venous dilation to reduce preload and myocardial oxygen consumption.^{18 19 20} Because amlodipine releases NO and this may be mediated by a kinin mechanism, a portion of its cardiovascular actions should be similar to that of ACE inhibitors and organic nitrates. Indeed, amlodipine is a long-acting vasodilator, increasing blood flow in the coronary, renal, and mesenteric vascular beds.^{12 21 22} In addition, amlodipine reduces myocardial oxygen consumption.¹² Amlodipine caused a potent concentration-dependent relaxation of KCl-precontracted dog saphenous veins and, to a lesser extent, jugular veins in vitro.²³ Interestingly, there is an acute fall in peripheral resistance to amlodipine, whereas the maximum effects on peripheral resistance may not occur for 4 hours after its administration,¹² suggesting two mechanisms of action.

Ours is not the first study to investigate whether a portion of the actions of amlodipine is NO dependent. Bennett et al²⁴ compared the effects of chronic treatment of SH rats with amlodipine, ACE inhibitors, and hydralazine on endothelium-dependent vessel relaxation in vitro. These authors found that chronic ACE inhibitor therapy potentiated endothelium-dependent relaxation to ACH and bradykinin and that treatment with amlodipine did not. They concluded that a product from the endothelium did not play an important role in the action of amlodipine. On the other hand, Lyons et al²⁵ found that chronic treatment of patients with enalaprilat or amlodipine reduced blood pressure and that L-NMMA reduced forearm blood flow by 55% in the enalaprilat-treated group and by 59% in the amlodipine-treated group compared with only 33% in the placebo group. There was no statistical difference between the enalaprilat and amlodipine groups. Clearly, that study implicated altered vascular NO production in the mechanism of action of amlodipine. Finally, amlodipine may stimulate cellular cGMP production, an action shared by NO, although it was attributed to altered phosphodiesterase activity.²⁶

Our previous studies have indicated that a number of agents increase nitrite formation in vitro due to effects on local kinins.^{7 8 14 27} In those studies, nitrite production was inhibited by L-NAME, by HOE-140 (Icatibant), and by three different serine protease inhibitors. Furthermore, the actions of bradykinin and ACE inhibitors were blocked by a kinin antibody, indicating the formation of kinins locally.²⁸ The present study indicates that amlodipine stimulates NO production through a similar mechanism in that nitrite formation was entirely blocked by L-NAME, HOE-140, and, in particular, DCIC. These results suggest that a portion of the clinical benefit of ACE inhibitors, and perhaps amlodipine, can be attributed to altered local production or activity of kinins,²⁹ although clinical trials will be needed to confirm this hypothesis.

In summary, our data strongly suggest that amlodipine releases NO from (1) isolated coronary microvessels, (2) large epicardial coronary arteries, and (3) conduit vessels like the aorta. In addition, these actions are not shared by nifedipine and diltiazem. The mechanism responsible for the release of NO by amlodipine is similar to that of ACE inhibitors—that is, modulation of the actions or formation of kinins.

	Selected Abbreviations and Acronyms

 

DCIC = dichloroisocoumarin DMSO = dimethylsulfoxide L-NAME = N-nitro-L-arginine methyl ester

	Acknowledgments

 
This study was supported by grants PO-1-HL-43023, HL-50142, and HL-53053 from the National Heart, Lung, and Blood Institute and by Fellowship 96–103 (Dr Zhang) from the American Heart Association, New York Affiliate. We would like to thank Xiaobin Xu, MD, for assistance with this study.

Received July 31, 1997; revision received September 10, 1997; accepted September 30, 1997.

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