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(Circulation. 1996;94:130-134.)
© 1996 American Heart Association, Inc.

Articles

Effects of L-Arginine Supplementation on Endothelium-Dependent Coronary Vasodilation in Patients With Angina Pectoris and Normal Coronary Arteriograms

Kensuke Egashira, MD; Yoshitaka Hirooka, MD; Takeshi Kuga, MD; Masahiro Mohri, MD; Akira Takeshita, MD

the Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Correspondence to Kensuke Egashira, MD, PhD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan.

	Abstract

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Background The pathogenesis of impaired endothelium-dependent coronary vasodilation in angina pectoris and normal coronary arteriograms (microvascular angina pectoris) is not known. We examined whether supplementation with L-arginine, a precursor of endothelium-derived nitric oxide, improves endothelium-dependent coronary vasodilation in patients with microvascular angina.

Methods and Results The effect of intracoronary infusion of L-arginine (50 mg/min) on acetylcholine-induced coronary vasomotion was studied in eight patients with microvascular angina and eight control subjects. The responses of the large epicardial coronary artery diameter and coronary blood flow were measured with coronary arteriography and an intracoronary Doppler catheter, respectively. Acetylcholine increased coronary blood flow with modest vasoconstriction of the large coronary artery without altering arterial pressure and heart rate. The acetylcholine-induced increases in coronary blood flow were significantly less (P<.01) in patients than in control subjects. L-Arginine significantly augmented the coronary blood flow responses to acetylcholine in patients, but not in control subjects. L-Arginine did not alter responses of the large coronary artery in either group.

Conclusions Study results suggest that L-arginine improved endothelium-dependent vasodilation of coronary microcirculation in patients with microvascular angina pectoris.

Key Words: endothelium-derived factors • coronary disease • syndrome X • angina

	Introduction

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Endothelium-dependent dilation of coronary microcirculation in response to acetylcholine is impaired in patients with angina pectoris and normal coronary arteriograms (microvascular angina pectoris),^{1 2} in whom abnormal vasomotion of coronary microcirculation may contribute to myocardial ischemia.^{3 4} The results of these studies suggest the presence of endothelial dysfunction of coronary microcirculation in patients with microvascular angina; however, the mechanism of the microvascular endothelial dysfunction in these patients is not known.

L-Arginine is a precursor of endothelium-derived nitric oxide.⁵ Thus, supplementation with L-arginine may facilitate production of nitric oxide and augment endothelium-dependent vasodilation. In fact, it has been shown that supplementation with L-arginine improves attenuated endothelium-dependent coronary vasodilation in animals and humans with hypercholesterolemia.^{6 7 8 9} However, we recently demonstrated that intracoronary infusion of L-arginine did not alter attenuated acetylcholine-induced endothelium-dependent coronary vasodilation in patients with coronary artery disease and hypertension.¹⁰ Therefore, it appears that the mechanisms of endothelial dysfunction may differ depending on the cause and severity of vascular disease.^{11 12} It is not known whether L-arginine improves endothelial dysfunction in patients with microvascular angina.

In the present study, we examined the effects of intracoronary infusion of L-arginine on endothelium-dependent coronary vasodilation evoked with acetylcholine in patients with microvascular angina.

	Methods

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Study Population
Eight patients with angina pectoris and normal coronary arteriograms (microvascular angina) and eight control subjects with atypical chest pain and normal coronary arteriograms were studied (Table 1). The diagnostic criteria for microvascular angina were angina-like chest pain at rest and/or on effort, positive exercise tests (chest pain associated with ST-segment depression of >0.1 mV), normal coronary arteriograms, and no spasm of large epicardial coronary arteries provoked by acetylcholine. All patients exhibited evidence suggestive of myocardial ischemia (myocardial lactate production, chest pain, or ischemic ST-segment abnormalities) after intracoronary administration of papaverine (Table 2). The control subjects with atypical chest pain had normal exercise tests and normal coronary arteries without spasm in major coronary arteries. Thallium myocardial scintigraphy stress tests did not show positive results in either group. Patients with previous myocardial infarction, evidence of left ventricular dysfunction, or valvular heart disease were excluded. None of these patients had diabetes mellitus or any ST-segment abnormalities in their resting ECGs.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

View this table: [in this window] [in a new window]   Table 2. Myocardial Lactate Extraction Ratio, Symptoms, and ECG Changes With Intracoronary Papaverine

Study Protocol
The study protocols were approved by the Institutional Review Committee on Human Research of the Research Institute of Angiocardiology, Kyushu University School of Medicine. Written informed consent was obtained from each patient.

Cardiac catheterization was performed with the participant in the fasting state after premedication with 5 mg diazepam PO. Antianginal medications were discontinued for 24 hours before the study (Table 1).

Thirty minutes after the diagnostic coronary arteriography was completed, the following studies were performed while the diameter of the large epicardial coronary arteries and coronary blood flow (CBF) were measured: (1) acetylcholine at the graded doses (1, 3, 10, and 30 µg/min; 2 minutes each) was infused into the Doppler catheter, and coronary arteriography was performed after each dose of acetylcholine; (2) 10 minutes later, L-arginine (50 mg/min for 10 minutes) was infused into the left coronary artery through the guiding catheter, and coronary arteriography was performed; (3) the acetylcholine study was repeated while L-arginine was simultaneously infused; (4) 10 minutes after the infusion of L-arginine was stopped, isosorbide dinitrate (2 mg) was administered through the guiding catheter, and coronary arteriography was performed 2 minutes later; and (5) papaverine (10 mg) was injected through the guiding catheter, and coronary arteriography was performed 2 minutes later.

In all eight patients and in five control subjects, a catheter was inserted into the coronary sinus vein. Paired samples of arterial and coronary venous blood were taken before and 2 minutes after papaverine administration for measurement of plasma lactate. The plasma lactate concentration was measured immediately after sampling with a calibrated lactate analyzer (OMRON Inc).

Arterial pressure, heart rate, and ECGs were continuously monitored and recorded with the use of a polygraph system (Nihon-Kohden).

Quantitative Coronary Arteriography
The diameter at the proximal segment of the left anterior descending coronary artery distal to the Doppler catheter was determined with the use of a videodensitometric analysis system as we described previously.^{1 10 13 14 15} After selection of the view that allowed the best visualization of the left anterior descending coronary artery, coronary angiograms were recorded with a Siemens angiographic system.

The diameter measurements were done three times in a blinded manner without knowledge of the clinical characteristics of the patients, and the averaged value was used for analysis. Two or more branch points were determined to allow assessment of serial changes in the diameter of the same arterial site in response to drugs. The size of a Judkins catheter was used to calibrate the arterial diameter.

Measurements of CBF and Velocity
An 8F angioplasty guiding catheter was introduced into the left main coronary artery via the femoral approach. A 3F Doppler flow velocity catheter (model DC-201, Millar Instruments) was introduced into the proximal left anterior descending coronary artery. Blood flow velocity signals were obtained with a Millar DC-101 Velocimeter. The increases in CBF in response to acetylcholine and nitrate were estimated on the basis of the product of the mean CBF velocity and the cross-sectional area of the proximal left anterior descending coronary artery segment distal to the tip of the Doppler catheter.^{1 10 13 14 15} The increase in CBF in response to papaverine was assessed from the product of mean blood flow velocity and the baseline cross-sectional area. Changes in estimated CBF in response to drugs were expressed as percent changes from the baseline value.

Statistical Analysis
Data are given as mean±SD. The effects of L-arginine on acetylcholine-induced changes in hemodynamic parameters were compared with the use of two-way ANOVA with repeated measures followed by Bonferroni's multiple-comparison tests. Clinical characteristics such as age and cholesterol levels were compared with the use of a Student's t test.

The effects of clinical characteristics on the CBF response to acetylcholine were examined. Simple linear regression analysis was used to examine the effects of continuous variables (eg, age, cholesterol levels). The Student's t test was used to examine the effects of sex, smoking habit, and hypertension. Finally, the effects of these factors were examined through multiple linear regression analysis. A probability level of <.05 was considered statistically significant.

	Results

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Patient Characteristics
Table 1 shows clinical characteristics such as age, sex, serum cholesterol levels, and presence of arterial hypertension and smoking habit, which were comparable between control subjects and patients with angina and normal coronary arteriograms. The use of antianginal drugs was similar between the two groups.

The lactate extraction ratio [(arterial lactate concentration minus venous lactate concentration)/arterial lactate concentrationx100 (%)] before and after intracoronary papaverine administration is presented in Table 2. Papaverine caused myocardial lactate production in all of the patients but not in the control subjects tested. Five of the eight patients developed chest pain, and five patients developed ischemic ST-segment changes, whereas none of the control subjects had myocardial lactate production, chest pain, or ischemic ST-segment changes.

Effects of L-Arginine on Acetylcholine-Induced Changes in Coronary Artery Diameter and CBF
Table 3 shows changes in the diameter of large epicardial coronary arteries in response to intracoronary infusion of acetylcholine before and during simultaneous infusion of L-arginine at 50 mg/min. The baseline arterial diameter (2.6±0.2 and 3.0±0.1 mm, P=NS), mean arterial pressure (84±6 and 86±4 mm Hg, P=NS), and heart rate (66±4 and 63±4 bpm, P=NS) did not differ between control subjects and patients. Before L-arginine, the diameter of the large epicardial coronary arteries decreased slightly but significantly (P<.05) in response to the high dose (30 µg/min) of acetylcholine in control subjects and patients. The responses of the large epicardial coronary arteries to acetylcholine were similar between the two groups. The infusion of L-arginine did not alter the baseline diameter of the large epicardial coronary artery, mean arterial pressure, or heart rate. L-Arginine had no effect on responses to acetylcholine in either group.

View this table: [in this window] [in a new window]   Table 3. Responses of the Large Epicardial Coronary Artery to Acetylcholine Before and During L-Arginine Infusion

Acetylcholine significantly (P<.01) increased CBF in a dose-dependent manner in control subjects but not in the patients (Figure). Before L-arginine infusion, the percent increases in CBF evoked with acetylcholine were significantly less (P<.01) in the patients than in control subjects. The percent increase in CBF evoked with papaverine was 332±43% in control subjects and 298±48% in patients (NS). The percent increase in CBF evoked with isosorbide dinitrate was 116±22% in control subjects and 130±34% in patients (NS).

View larger version (16K): [in this window] [in a new window]   Figure 1. Effect of intracoronary infusion of L-arginine on acetylcholine-induced coronary vasodilation in control subjects (left) and patients with angina pectoris and normal coronary arteriograms (right). MVA indicates microvascular angina. P<.01 vs before L-arginine by two-way ANOVA and multiple comparison tests.

Intracoronary infusion of L-arginine did not alter the CBF responses to acetylcholine in control subjects (Figure). In contrast, in patients with angina and normal coronary arteriograms, L-arginine infusion significantly (P<.01 by two-way ANOVA) augmented the CBF responses to acetylcholine (Figure). However, the increases in CBF responses to acetylcholine during L-arginine infusion were less (P<.05 by two-way ANOVA) in the patients than in the control subjects.

In either the patients or control subjects, the maximal increase in CBF evoked with acetylcholine did not significantly correlate with age, cholesterol level, or other clinical characteristics. Multiple linear regression analysis revealed that the presence of microvascular angina was an independent factor (P<.01) for predicting impaired CBF response to acetylcholine.

	Discussion

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The results of the present study confirmed our previous findings that the increases in CBF in response to acetylcholine were markedly less in patients with microvascular angina than in control subjects and that intracoronary infusion of papaverine induced myocardial lactate production in the presence of increased CBF in the patients but not in the control subjects.¹ These findings indicate that myocardial ischemia might be caused by microvascular disorders in these patients. The new finding of the present study is that intracoronary infusion of L-arginine significantly improved the CBF response to acetylcholine in patients with microvascular angina but not in control subjects. The present data suggest that L-arginine improved endothelium-dependent vasodilation of coronary microcirculation in patients with microvascular angina.

Effects of L-Arginine on Coronary Microcirculation
It has been shown that acetylcholine-induced vasodilation of coronary microcirculation is impaired in various pathophysiological states,^{11 12 13 14 15 16 17} including microvascular angina.^{1 2} However, the effects of L-arginine on endothelium-dependent dilation of coronary arteries have not been investigated in patients with microvascular angina.

L-Arginine is the precursor of endothelium-derived nitric oxide.⁵ Thus, supplementation with L-arginine may facilitate production of nitric oxide and improve endothelium-dependent vasodilation. In fact, it has been shown that L-arginine improves defective endothelium-dependent vasodilation in patients with hypercholesterolemia^{6 9} and those who have undergone cardiac transplantation¹⁸ but not in patients with coronary artery disease and hypertension.¹⁰

This study demonstrated for the first time that intracoronary infusion of L-arginine improves acetylcholine-induced vasodilation of coronary microcirculation in patients with microvascular angina. Since acetylcholine-induced coronary vasodilation in patients is mediated by endothelium-derived nitric oxide,^{19 20} it is reasonable to assume that impaired acetylcholine-induced endothelium-dependent vasodilation of coronary microcirculation in patients with microvascular angina resulted from defective synthesis and/or release of nitric oxide. However, the mechanism by which L-arginine improved endothelium-dependent vasodilation of coronary microcirculation is not known. L-Arginine supplementation may have effects at several levels in the L-arginine/nitric oxide pathway.²¹ L-Arginine supplementation might have increased nitric oxide synthesis by increasing the availability of L-arginine for the reaction mediated by nitric oxide synthase, caused upregulation of nitric oxide synthase activity, and inhibited augmented inactivation of nitric oxide by superoxide anions. L-Arginine might have reduced the effects of augmented release of endothelium-derived vasoconstrictors. Further studies are needed to investigate the mechanisms by which L-arginine supplementation improves microvascular endothelial function in these patients.

The fact that reversal of acetylcholine-induced coronary vasodilation by L-arginine was incomplete in the patients may be related to the following possibilities. First, endothelium-derived hyperpolarizing factor might be involved.¹² Second, the dose or duration of L-arginine supplementation may have been inadequate. Third, the incomplete reversal by L-arginine might be due to the presence of structural changes in coronary microcirculation (the reduced capillary density and microvascular luminal narrowing due to medial thickening and endothelial swelling) in patients.²²

The effect of L-arginine on acetylcholine-induced vasodilation of coronary microcirculation might not be nonspecific, because it was reported that D-arginine did not affect acetylcholine-induced vasodilation of forearm blood vessels in humans.²³

Effects of L-Arginine on Large Epicardial Coronary Artery
The degrees of the vasoconstriction in response to acetylcholine were similar between the patients and control subjects. Although normal humans should exhibit acetylcholine-induced vasodilation of large epicardial coronary artery,²⁴ acetylcholine is reported to induce vasoconstriction of angiographically normal segments of coronary arteries in patients with risk factors for coronary artery disease.^{13 14 15 16 17} Our patients had risk factors such as age of >50 years, smoking, arterial hypertension, and mild hypercholesterolemia.

L-Arginine did not affect acetylcholine-induced vasomotion of large epicardial coronary artery in patients with microvascular angina or control subjects in the present study. The reason why L-arginine did not improve acetylcholine-induced vasomotion of large epicardial coronary arteries in these patients is not known, but it might be related to different stages of arteriosclerotic process in the large epicardial and resistance coronary arteries.

Study Limitations
Many of our patients and control subjects had coronary risk factors. However, it is unlikely that the presence of the risk factors influenced the present results, because the incidence of those factors did not differ between the two groups. The presence of microvascular angina was an independent factor predicting impaired CBF response to acetylcholine.

Conclusions
This study demonstrated that L-arginine improved endothelium-dependent dilation of coronary microcirculation in patients with microvascular angina, suggesting that endothelial dysfunction of coronary microcirculation in these patients may be related to the defective synthesis and/or release of nitric oxide. Further studies are needed to elucidate the cause-and-effect relationship between the defective release of nitric oxide and myocardial ischemia in patients with microvascular angina.

	Acknowledgments

 
This study was supported by grants-in-aid for Scientific Research from the Japanese Ministry of Education, Science and Culture, Tokyo; Research Developing Award from the Naito Memorial Foundation, Tokyo; Research Grant from the Japan Heart Foundation, Tokyo; Research Grant from the Japan Cardiovascular Foundation, Osaka; and Research Developing Award from the Uehara Memorial Foundation, Tokyo, Japan.

Received January 10, 1995; revision received November 21, 1995; accepted December 10, 1995.

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