Author + information
- Received December 7, 1995
- Revision received August 29, 1996
- Accepted September 16, 1996
- Published online January 1, 1997.
- ↵*Dr. Yasuhiro Nishikawa, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, P.O. Box 26509, Milwaukee, Wisconsin 53226-0509.
Objectives. The purpose of this study was to investigate the role of endothelium-dependent vascular regulation in the human coronary circulation during rest and hyperemic states.
Background. Evidence of the role of nitric oxide (NO) during metabolic demand is not consistent in animal and human coronary circulation.
Methods. NG-Monomethyl-l-arginine (l-NMMA), a specific inhibitor of NO synthesis, was infused into the left anterior descending coronary artery at rest and during rapid atrial pacing in 18 subjects—9 with normal coronary arteries (control) and 9 with atherosclerotic coronary arteries. The diameter of the epicardial coronary artery was measured by quantitative coronary angiography. Vasodilation of the coronary microcirculation was assessed using an intracoronary Doppler FloWire.
Results. Infusion of 25 μmol/min of l-NMMA reduced the diameter of the proximal and distal epicardial coronary artery segments by 8 ± 2% (mean ± SE) and 11 ± 2%, respectively (p < 0.05) in the control subjects. The coronary blood flow (CBF) decreased by 33 ± 13% during l-NMMA infusion. l-NMMA caused similar changes in the diameter of the distal epicardial segment and the CBF in patients with coronary artery disease. The proximal vessel diameter did not change significantly during infusion of l-NMMA. During pacing, infusion of l-NMMA caused the same changes in vessel diameter as before pacing in both groups, but did not affect CBF.
Conclusions. Our findings indicate that NO synthesis maintains basal vasomotor tone in both conduit and resistance vessels in the normal human coronary circulation. Although NO release was impaired in the large epicardial coronary arteries in patients with atherosclerosis, NO still regulated vascular tone in the small epicardial coronary arteries and arterioles. Our results suggest that vasodilation in arterioles during increased myocardial oxygen demand is mediated by metabolic or myogenic mechanisms, or both, rather than by endothelium-dependent production of NO.
(J Am Coll Cardiol 1997;29:85–92)>
The endothelium modulates many aspects of vascular function, including vascular growth, anticoagulant, fibrinolytic and antithrombotic properties, permeability and inflammatory and immune mechanisms in the vessel wall. Endothelial cells synthesize and release vasodilator substances, collectively referred to as endothelium-derived relaxing factor into the lumen and influence the tone of underlying smooth muscle (). Endothelium-derived relaxing factor has been identified as nitric oxide (NO) or related chemical compounds with the same biologic and pharmacologic properties. Release of a sufficient amount of NO appears to account for the many biologic actions of endothelium-derived relaxing factor ([2–4]). NG-Monomethyl-l-arginine (l-NMMA), a specific inhibitor of NO synthesis, inhibits endothelium-dependent relaxation in vitro ([5, 6]) and increases systemic blood pressure in the rat (), rabbit () and guinea pig () in vivo. Infusion of l-NMMA into the brachial artery of the human forearm reduced basal blood flow, and blood flow returned to the basal state after infusion of l-arginine (). These findings indicate that NO contributes to the maintenance of vascular tone and therefore to regulation of tissue blood flow in various species, including humans.
Although evidence indicates that NO is a significant regulator of tissue flow in the systemic circulation, the role of NO in the regulation of vascular tone in the coronary conductance and resistance vessels is inconsistent. Woodman and Dusting () showed that the inhibition of NO synthesis reduced the diameter of the coronary artery without affecting coronary vascular resistance in an acute anesthetized, canine model, which suggests that NO modulates basal vasomotion in the large epicardial coronary arteries but not in the microcirculation. Chu et al. ([12, 13]) found that although l-NMMA reduced both the diameter of proximal epicardial coronary arteries and coronary blood flow (CBF) in conscious dogs, its effects on flow were modest and higher doses of l-NMMA were required to significantly reduce the diameter of epicardial coronary arteries. Lefroy et al. () found that infusion of l-NMMA into normal human coronary arteries reduced the diameter of the distal portion of epicardial coronary arteries and CBF, but not the diameter of the proximal segments.
The evidence for the role of NO during increased metabolic demand is less consistent in previous studies. Persson et al. () found that l-NMMA did not alter the hyperemic response to exercise in isolated rabbit skeletal muscle. In a chronic canine model, l-NMMA was reported not to influence the increase in CBF produced by pacing to ∼200 beats/min (), whereas Jones et al. () showed inhibition of NO-attenuated coronary dilation during pacing in open chest dogs. The flow response to l-NMMA in the human forearm during exercise was unchanged in a study by Wilson and Kapoor (), but was reduced in a study by Gilligan et al. (). Recently, Quyyumi et al. () reported that cardiac pacing produced less microvascular and epicardial coronary artery dilation after l-NMMA, suggesting that the release of NO contributes significantly to metabolic vasodilation in the coronary circulation. The discrepancies concerning the role of NO in metabolic vasodilation in the coronary circulation in these studies may be related to differences in basal blood flow. Endothelial cells respond to increases in blood flow through a vessel by increasing NO production ([21, 22]). Thus, the basal level of flow may affect the response to l-NMMA. In other words, the response to inhibition of NO synthesis depends on the flow-dependent, NO-mediated baseline vasodilation in the vessel. Furthermore, changes in vasomotion through endothelium-independent mechanisms triggered by the protocols themselves may modify the response to l-NMMA.
The purpose of this study was to investigate whether the vascular tone of conduit and resistance vessels in the human coronary circulation is mediated by NO in both baseline and hyperemic states. We evaluated the responses to intracoronary infusion of l-NMMA before and during rapid atrial pacing in control subjects and patients with coronary artery disease (CAD).
1.1 Study group.
1.1.1 Control subjects.
The control group consisted of nine patients with angiographically normal coronary arteries (eight men and one woman; mean age 48 years) who were being evaluated for atypical chest pain and who had negative exercise tests (Table 1). Control subjects had normal sinus rhythm. Patients with hypertension (≥160/90 mm Hg), diabetes mellitus or hypercholesterolemia (≥220 mg/dl) were excluded. All control subjects had angiographically normal, smooth coronary arteries and normal left ventricular angiograms.
1.1.2 Patients with CAD.
We assessed nine patients (six men and three women; mean age 59 years) who had angiographic evidence of coronary atherosclerosis. All patients with CAD had >50% lumen narrowing of the right coronary artery or the left circumflex coronary artery, or both. Patients with hemodynamically significant stenosis of the left anterior descending coronary artery (LAD) were excluded. None of these patients showed any ischemic ST-T segment changes on the anterior chest leads during a treadmill test or any evidence of persistent or reversible defects in the perfusion area of the LAD on a thallium exercise test. Written informed consent was obtained from all patients before cardiac catheterization.
1.2 Study protocol.
Vasoactive medications, including calcium channel blockers, angiotensin-converting enzyme inhibitors and long-acting nitrates, were discontinued at least 24 h before the study. Diagnostic cardiac catheterization was performed by the standard percutaneous femoral approach in the fasting state after premedication with oral diazepam (5 to 10 mg). After completion of routine diagnostic catheterization, subjects received an additional 5,000 U of heparin administered intravenously. A steerable Doppler guide wire (FloWire, Cardiometrics) was introduced through a 6F Judkins catheter and placed in the proximal LAD. The tip of each FloWire was preshaped into a mild J curve to ensure stable signals. The Doppler crystal was placed in the proximal segment of the LAD. Once strong, stable signals were obtained, the position of the FloWire was left unchanged. A 5F bipolar pacing catheter was placed in the right atrium. We used atrial pacing rather than ventricular pacing because it allows arterial pressure to remain higher, resulting in greater myocardial oxygen consumption and CBF.
All infusions were administered into the LAD through the Judkin’s catheter at a rate of 2 ml/min. The CBF velocity was measured and coronary arteriography was performed after a 2-min infusion of 0.9% physiologic saline solution (baseline before pacing). For coronary arteriography, 6 to 8 ml of nonionic contrast material was infused manually for 2 to 3 s. In a preliminary study, infusion of 0.9% saline had no significant effect on the diameter of either the proximal (−2 ± 1%, n = 5) or distal coronary artery segments (−2.9 ± 1%, n = 5). Rapid atrial pacing was then started, and the heart rate was increased until atrioventricular conduction block was reached (149 ± 12 beats/min). If the pacing rate caused the systolic blood pressure to decrease by ≥10 mm Hg, the heart rate was allowed to fall to minimize the decrease in systolic blood pressure. Measurements were again obtained 1 min after initiation of pacing (baseline during pacing). After discontinuation of pacing and confirming that CBF velocity and aortic blood pressure returned to the state before pacing, l-NMMA (Wako, Osaka, Japan) was infused at a rate of 10 μmol/min for 4 min. The CBF velocity was measured and coronary angiography was performed 2 min after initiation of the l-NMMA infusion, after which rapid atrial pacing was again initiated. The CBF velocity was measured and coronary angiography was performed after 1 min of pacing. The same protocol was repeated during infusion of l-NMMA at a rate of 25 μmol/min. We did not administer acetylcholine or nitroprusside deliberately to determine to what extent endothelium-dependent and -independent vasodilation was impaired. This is because 1) although the duration of action of both agents is short, several injections of these agents could modify systemic and coronary vascular tonus enough to result in a different response to subsequent l-NMMA infusion; and 2) coronary angiography, which should be performed after each injection, has the potential to alter the position of the tip of FloWire, resulting in changes in flow pattern and flow velocity. We used the same dose of l-NMMA for intracoronary infusions as in the study by Lefroy et al. ().
1.3 Data analysis.
1.3.1 Quantitative coronary angiography.
Coronary angiography was performed using a Hitachi cineangiographic system (Hitachi, Tokyo, Japan). Angiography was performed in the right anterior oblique view with the LAD near the isocenter. The angle and position of the image intensifier were kept constant during the study.
The epicardial vessel diameter was determined quantitatively using an automated edge detection analysis system (Baxter, Tokyo, Japan). An end-diastolic frame from a high quality angiogram was selected and programmed into the analyzer and digitized with two- to fourfold magnification. Side branches of the arteries were used as a reference guide to assess serial changes in the diameter at the same site of the coronary artery. Previous studies have shown that there is significant segmental variation in the responses of the proximal and distal segments of epicardial coronary arteries to vasoactive stimuli ([23, 24]). We separately analyzed the responses of the proximal (American Heart Association [AHA] segment 6 or 7) and distal segments (AHA segment 8) of the LAD. Reproducibility using this quantitative analysis system was very high, with a mean coefficient of 0.98.
1.3.2 Coronary blood flow velocity.
The CBF velocity was measured using FloWire. Coronary blood flow was estimated from the product of the time-averaged peak velocity and the cross-sectional area calculated by π × diameter2/4.
All hemodynamic data are expressed as the mean value ± SD. Vessel diameter and CBF are expressed as the mean value ± SE. Changes in CBF in response to l-NMMA are expressed as the percent change compared with the baseline data at rest before l-NMMA. Two-way repeated-measures analysis of variance (ANOVA) was used to compare the effects of the two doses of l-NMMA infusions before and during pacing in each group (normal subjects and patients with CAD). If ANOVA indicated a significant differences, a paired ttest with an appropriate Bonferroni correction was used. Differences in diameter between before and during pacing were compared with the paired ttest. A nonpaired ttest was used for data between normal subjects and patients with coronary artery disease. A value p < 0.05 was considered significant.
The procedure was well tolerated by all patients. There were no episodes of chest pain, undesirable side effects or ischemic ST-T segment changes on electrocardiograms.
2.1 Changes in hemodynamic variables.
Intracoronary infusion of l-NMMA caused no significant changes in heart rate, mean aortic blood pressure or rate-pressure product before or during pacing in control subjects or patients with CAD (Table 2). Atrial pacing significantly increased heart rate in both control subjects and patients with CAD (p < 0.01). Although the mean aortic blood pressure decreased slightly, by ∼4%, during pacing, the rate-pressure product (heart rate–systolic pressure product) increased by ∼110% during pacing in both groups.
2.2 Changes in coronary artery diameter.
Before pacing, infusion of 10 μmol/min of l-NMMA caused no significant change in the diameter of the proximal segment of the LAD, but infusion of 25 μmol/min significantly reduced its diameter in the control subjects by 7.8% (p < 0.05) (Fig. 1, left). Pacing produced a mean 50% increase in CBF. The diameter of the proximal segments of the LAD during pacing increased from 4.20 ± 0.8 to 4.43 ± 0.79 mm (p < 0.01). The diameter during pacing decreased significantly after infusion of l-NMMA (p < 0.05). The percent change in diameter of the proximal segment in response to l-NMMA during pacing was significantly higher than before pacing (11.2 vs. 7.8% at a dose of 25 μmol/min of l-NMMA), suggesting that sustained release of NO in the proximal epicardial coronary arteries is greater during an increase in myocardial oxygen demand than at baseline.
Before pacing, the diameter of the distal segments decreased significantly during l-NMMA infusion in control subjects (p < 0.05) (Fig. 1, left). Pacing increased the diameter of the distal segments of the LAD (from 1.9 ± 0.3 to 2.02 ± 0.41 mm, p < 0.05). l-NMMA decreased the diameter of the distal segments during pacing (p < 0.05), the same as before pacing.
Cardiac pacing did not affect the diameter of the proximal epicardial segment of the LAD in patients with CAD. l-NMMA caused no significant change in the diameter of the proximal segment of the LAD from baseline either before or during pacing in patients with CAD (Fig. 1, right panel). The diameter of the distal segment decreased significantly during l-NMMA infusion before pacing in patients with CAD (p < 0.05). Pacing increased the diameter of the distal segments from 1.92 ± 0.31 to 2.05 ± 0.43 mm (p < 0.05). l-NMMA decreased the diameter of the distal segments during pacing (p < 0.05), the same as before pacing. These data clearly indicate a difference between the response to NO inhibition in the proximal segment and the distal segment of the coronary arteries of the patients with CAD. There was no difference in change in the diameter of the distal segment in response to l-NMMA in the two groups (p = NS), suggesting that tonic release of NO is not impaired in the distal segment in patients with CAD.
2.3 Changes in coronary blood flow.
Fig. 2shows representative Doppler tracings of flow velocity during l-NMMA infusion before and during rapid pacing in a control subject. Before pacing, infusion of both 10 and 25 μmol/min of l-NMMA significantly reduced the CBF in control subjects (Fig. 3, left panel). l-NMMA infusion caused no significant change in the CBF from baseline during pacing. In patients with CAD, infusion of l-NMMA significantly reduced the CBF before pacing (Fig. 3, right panel). During pacing, l-NMMA had no significant effect on the CBF in patients with CAD.
In control subjects, infusion of l-NMMA reduced the diameters of the proximal and distal segments of the epicardial coronary artery and the blood flow at baseline, indicating that sustained release of NO from the vascular endothelium regulates the vascular tone of coronary arteries of all sizes, ranging from arterioles with a diameter of 100 to 200 μm, which mainly determine coronary vascular resistance, to the epicardial conduit vessels. In patients with CAD, inhibition of NO reduced both the diameter of the distal epicardial coronary artery and the blood flow without a change in the diameter of the proximal segments, indicating that even though coronary atherosclerosis was associated with impairment of endothelial NO production in the large epicardial coronary arteries, NO still played a role in the regulation of rest vascular tone in the small epicardial coronary arteries and resistant coronary vessels. During the hyperemic state induced by rapid pacing, l-NMMA reduced the diameter of the epicardial coronary artery, but did not affect the CBF. Thus, we conclude that NO did not regulate vascular resistance when myocardial blood flow was increased by rapid pacing.
Lefroy et al. (), who first reported the effects of l-NMMA on human coronary arteries, showed that infusion of 25 μmol/min of l-NMMA caused a significant reduction in the diameter of the distal segment (5.9%), but not the proximal segment, of the LAD. One possible explanation for the difference in the response of the proximal segment of the epicardial coronary artery to l-NMMA is that their () group of patients may have had more atherosclerotic lesions than did our control subjects. The control subjects in the present study were about 10 years younger than those in the study by Lefroy et al. (). There is evidence that coronary atherosclerosis impairs endothelial cell function ([25–27]). El-Tamimi et al. () showed that the endothelium-dependent dilator acetylcholine induced both dilation and constriction in adjacent segments of the same coronary artery with angiographically minimal atherosclerosis (), suggesting that even a minor difference in the degree of atherosclerosis may have a significant effect on NO production by endothelial cells and that the severity of endothelial dysfunction is not uniform in the same coronary artery. Chu et al. () found that systemic infusion of l-NMMA reduced the diameter of the proximal epicardial coronary artery by 8% in conscious dogs, which is consistent with our hypothesis. The pathologic changes associated with coronary atherosclerosis should be less severe in dogs than in humans.
Although NG-nitro-l-arginine methyl ester (l-NAME), another inhibitor of NO production, did not alter the rest CBF in conscious dogs (), other studies have found that the rest regional blood flow decreases after l-NMMA administration. l-NMMA reduced the rest blood flow in the human forearm by 25% to 50% ([10, 18, 19]), the CBF velocity in chronic canine model by 18% () and the CBF calculated by oximetry in humans by 6% (). In the present study, the CBF decreased by 11% after infusion of 25 μmol/min of l-NMMA in rest control subjects. Our data confirm the hypothesis that NO synthesis contributes substantially to rest vasomotion in the human coronary microcirculation.
An important potential influence on the response to NO inhibition is a basal level of NO activity. An increase in CBF increases the shear stress, stimulating production of NO in endothelial cells associated with coronary vasodilation ([21, 22]). In the present study, the percent change in the proximal LAD in response to l-NMMA was greater during pacing than before pacing in control subjects (Fig. 1), supporting the hypothesis that elevated basal NO activity may be associated with an enhanced response to l-NMMA. Infusion of l-NMMA before and during pacing did not affect the proximal segment of the epicardial coronary artery in the patients with CAD, indicating that even in a high flow state, atherosclerotic proximal vessels did not have the ability to produce NO in response to increases in shear stress—in other words, the ability of endothelial cells to act as flow sensors, adjusting the diameter to changes in regional flow, was severely impaired in patients with CAD.
3.1 Effects of l-NMMA on the coronary arteries of patients with CAD.
Zeiher et al. () found that the pathophysiologic manifestations of atherosclerosis extend to the coronary microcirculation: patients with evidence of epicardial atherosclerosis exhibited profound impairment of the ability to increase blood flow in response to acetylcholine. A decrease in blood flow after l-NMMA in patients with CAD in the present study does not contradict the findings of Zeiher et al. (). Although the flow response to acetylcholine represents the receptor-stimulated dilator capacity of vessels mediated by NO, the vasomotor response to l-NMMA reflects the level of sustained release of NO by endothelial cells. Thus, the ability of endothelial cells to increase production of NO in response to several stimulants, such as acetylcholine, bradykinin, substance P ([30, 31]) and increases in shear stress ([21, 22]), is a separate phenomenon from the baseline release of NO. The present data indicate that the ability to produce NO in the rest state is preserved in both the small epicardial vessels and the microcirculation of coronary arteries in patients with CAD, despite the fact that atherosclerosis impairs the endothelial function of the large epicardial vessels. These findings are consistent with previous data, in that the proximal segment is more prone to atherosclerosis and endothelial dysfunction evaluated from the response to acetylcholine in patients with angiographically normal coronary arteries ().
3.2 Effects of l-NMMA on coronary arteries during pacing.
Although NO plays a significant role in the regulation of basal vasomotion, previous data in animal ([15–17]) and human studies ([18–20]) have shown inconsistent results concerning the effects of NO inhibition on metabolic vasodilation. Our data suggest that the release of NO is not an important factor in pacing-induced arteriolar dilation in the human coronary circulation.
Gilligan et al. () have shown that inhibition of NO synthesis reduces exercise-induced vasodilation in the human forearm. However, they did not present any data indicating that vascular resistance and blood flow after termination of control exercise (before l-NMMA infusion) returned to the rest value. If any vessel-constricting factors persisted during exercise after l-NMMA, this could have resulted in the smaller decrease in vascular resistance during exercise after l-NMMA than before l-NMMA. Thus, this could lead us to incorrectly conclude that NO plays a role in exercise-induced vasodilation. A recent report by Quyyumi et al. () has shown evidence of a significant role of NO in coronary microvascular and epicardial vasodilation in humans. This study also lacks data indicating that all of the hemodynamic variables and CBF returned to baseline levels. These investigators performed several infusions of acetylcholine, sodium nitroprusside and adenosine before l-NMMA infusion, which may have affected coronary vascular tone. In the present study, we simplified the protocol to exclude the possible effects of various vasoactive agents on coronary vascular tone and to minimize the effects of frequent infusion of coronary angiographic contrast material on the position of the tip of the FloWire. The present study clearly demonstrates that coronary flow autoregulation in response to metabolic flow recruitment during rapid pacing is mediated by myogenic or metabolic mechanisms, rather than by a flow-mediated, endothelium-dependent pathway through NO production. Although numerous metabolic factors, including adenosine, lactate, hypoxia, phosphate, potassium, osmolarity and prostaglandins (), have been implicated in the regulation of CBF, the precise role of these mediators remains controversial. More than one factor is probably involved, so that even if one of the mediators is blocked, other mediators are able to compensate for its absence.
3.3 Study limitations.
There are several potential limitations to the present study. First, although we paced the heart to obtain the maximal increase in the heart rate–systolic pressure product, the increase in flow during pacing was ∼40% to 50%. It is possible that the contribution of NO to metabolic vasodilation may be more important when there is a greater increase in CBF and therefore a greater increase in the shear stress on endothelial cells, which stimulates NO production ([21, 22]). Thus, we cannot rule out the possibility that because of the modest increase in metabolic demand in the present study, metabolic or myogenic vasodilation, or both, in the coronary microcirculation may have overcome NO-mediated vasodilation. However, Wilson and Kapoor () found that l-NMMA did not inhibit the five- to sixfold exercise-induced increase in the flow response in the forearm, suggesting that even at higher flow rates, mediators other than NO regulate flow recruitment during hyperemic conditions.
The heart rate during pacing in this study was a little less than that in the study of Quyyumi et al. () (128 vs. 141 beats/min). However, we adjusted the pacing heart rate to minimize the decrease in systolic blood pressure, resulting in a similar increase in CBF to Quyyumi’s study. Thus, the small difference in pacing heart rate cannot explain the different response of blood flow to l-NMMA in the two studies.
The dose of l-NMMA used in the present study was lower than that in Quyyumi’s study. Thus, a possible explanation for the discrepancy in response to pacing-induced vasodilation in resistant vessels may simply be the incomplete inhibition of NO production. Generally, we cannot determine whether complete inhibition of NO synthesis occurs in resistant vessels by injection of acetylcholine, because acetylcholine may act on resistant vessels through the release of vasoactive substances other than NO from the endocardium, such as adenosine and endothelium-derived hyperpolarizing factor (). It is unlikely that an insufficient dose of l-NMMA could modify blood flow data in our study. First, the dose of l-NMMA we used has been shown to inhibit NO production completely in the epicardial coronary arteries (), and there has been no evidence indicating that activity of NO synthetase is significantly different between conductance and resistant vessels. Second, considering that Japanese patients have a smaller perfusion territory of the LAD compared with white or black patients (the mean body weight of our patients was <60 kg for men and 45 kg for women), the difference in concentration of l-NMMA in the heart should be smaller. Our data strongly support the view that NO has a minor role in pacing-induced vasodilation of coronary resistant vessels.
Previous studies have shown inconsistent results with regard to the role of NO in metabolic vasodilation. The discrepancies appear not to be due to different doses of l-NMMA or l-NAME, but to the effects of various interventions performed in the protocols that could have changed the vasotone of the vessels, resulting in the different responses to inhibition of NO production.
During ischemia, endothelium-dependent NO is one of the important mediators responsible for minimizing coronary vascular resistance ([16, 34]), suggesting that in the presence of myocardial ischemia, when other vasodilating factors may be depleted, endothelial vasodilation by NO may be a more important mechanism of increased tissue perfusion than under nonischemic conditions. Therefore, although we did not observe any significant changes in myocardial blood flow in response to l-NMMA during pacing, blockade of NO synthesis may worsen the oxygen supply-demand relation in the presence of critical epicardial stenosis and increased metabolic demands.
The present findings show that sustained release of NO played a role in the control of rest vascular tone in epicardial coronary conduit and resistance vessels in patients with normal coronary arteries. In patients with CAD, basal synthesis of endothelial NO was unimpaired in the coronary circulation, except in the large epicardial coronary artery, in which administration of l-NMMA had no effect on the rest vasomotor tone. Inhibition of NO synthesis did not affect coronary resistance vessel tone when the myocardial blood flow was increased during rapid pacing, suggesting that CBF autoregulation in response to metabolic flow recruitment during pacing is mediated by myogenic or metabolic mechanisms, rather than by endothelium-dependent production of NO.
We thank the nursing and technical staff of the Cardiac Catheterization Laboratory at Ichikawa General Hospital for their expert help in conducting this study.
- American Heart Association
- coronary artery disease
- coronary blood flow
- left anterior descending coronary artery
- NG-nitro-l-arginine methyl ester
- nitric oxide
- Received December 7, 1995.
- Revision received August 29, 1996.
- Accepted September 16, 1996.
- The American College of Cardiology
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