(Circulation. 1996;94:266-272.)
© 1996 American Heart Association, Inc.
Articles |
Nitric Oxide Activity Is Deficient in Spasm Arteries of Patients With Coronary Spastic Angina
the Division of Cardiology, Kumamoto University School of Medicine, Kumamoto City, Japan.
Correspondence to Hirofumi Yasue, MD, Division of Cardiology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City, 860 Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background Coronary spasm can be induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact by releasing nitric oxide (NO). Coronary spasm is promptly relieved by nitroglycerin, which vasodilates through its conversion to NO. It is thus possible that NO release may be deficient in the spasm arteries in patients with coronary spastic angina (CSA). The aim of this study was to determine whether NO release is deficient in coronary arteries of patients with CSA.
Methods and ResultsNG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, was infused into coronary arteries in 21 patients with coronary spastic angina (CSA) and in 28 control patients. Coronary spasm was induced by intracoronary injection of acetylcholine and was documented angiographically in all patients with CSA. L-NMMA dose-dependently decreased basal luminal diameter of coronary arteries in control patients, whereas it had no effect on basal diameter of the spasm arteries in patients with CSA. L-NMMA abolished the dilator response to acetylcholine and enhanced the constrictor response to acetylcholine in control arteries, whereas it had no effect on the constrictor response to acetylcholine in spasm arteries. Intracoronary infusion of L-arginine did not affect the diameter of spasm or control arteries. The dilator response to nitroglycerin was increased markedly in spasm arteries compared with control ar-teries, whereas response to diltiazem did not differ between them.
Conclusions There is a deficiency in endothelial NO activity in spasm arteries, which leads to the supersensitivity of the artery to the vasodilator effect of nitroglycerin and to the vasoconstrictor effect of acetylcholine in patients with CSA. This deficient endothelial NO activity plays an important role in the pathogenesis of coronary spasm.
Key Words: endothelium-derived factors • vasoconstriction • vasodilation • vasospasm
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Coronary artery spasm has been shown to play an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, including other forms of angina pectoris, acute myocardial infarction, and sudden death.1 2 However, the precise mechanism(s) by which coronary spasm occurs remains unknown. We have shown that intracoronary injection of ACh induces coronary spasm in patients with coronary spastic angina,3 4 5 whereas it causes coronary vasodilation in young subjects with normal coronary arteries.6 It is well known that ACh causes vasodilation by releasing NO when the endothelium is intact, whereas it causes vasoconstriction by its direct effect on vascular smooth muscle when the endothelium is removed or damaged.7 8 9 10 11 It is thus possible that NO release in response to ACh may be deficient in the coronary arteries of patients with coronary spastic angina and that NO deficiency may be related to the pathogenesis of coronary spasm.
NO is produced from L-arginine by way of the enzyme NOS.11 12 13 The constitutive NOS in the arterial endothelium continuously generates NO, which has been shown to maintain basal vascular tone in animals and hu-mans.14 15 16 17 We and others1 18 19 20 21 have shown that the basal tone of the coronary arteries is increased and the artery dilates markedly in response to nitroglycerin and that the increased basal tone contributes importantly to the circadian variation of the attack in patients with coronary spastic angina. Recently, it has been demonstrated22 that nitrovasodilators including nitroglycerin cause vasodilation by way of their conversion to NO. It is thus possible that the basal endothelial release of NO is deficient in the coronary arteries and that the artery may be hypersensitive to nitrovasodilators because of deficient NO production in patients with coronary spastic angina.
Our purpose in the present study was to elucidate the mechanism(s) of coronary spasm by investigating whether endogenous endothelial NO production is deficient in the spasm arteries of patients with coronary spastic angina.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Patients
The study included 29 patients with coronary spastic angina (mean age, 61 years; range, 33 to 74 years; 17 men and 12 women) in whom episodes of spontaneous angina occurred at rest. Twelve patients showed transient ST-segment elevation and the remaining 17 patients showed ST-segment depression during the spontaneous attacks. All patients with coronary spastic angina showed angiographically documented coronary spasm associated with ischemic ST-segment changes with or without chest pain after intracoronary injection of ACh as reported previously.3 4 5 All patients with coronary spastic angina had no organic stenosis angiographically.
The present study also included 37 control patients with atypical chest pain (mean age, 60 years; range, 30 to 77 years; 20 men and 17 women). These control patients underwent diagnostic cardiac catheterization for evaluation of chest pain. They had angiographically normal or nearly normal coronary arteries and did not show coronary spasm after intracoronary injection of ACh.
Patients with coronary spastic angina and control patients were separated into two groups that were studied by two different protocols. All medications except sublingual nitroglycerin were withdrawn at least 3 days before the study. No study patient had taken nitroglycerin within 6 hours of the study. No patient had previous myocardial infarction, congestive heart failure, or other serious diseases. Written informed consent was obtained from all patients before the study. The study was in agreement with the guidelines approved by the ethics committee at our institution.
Quantitative Coronary Angiography
Coronary angiographic study was performed by use of the Judkins technique with contrast material (Ioxaglate, Guerbet SA) in the morning when the patients were fasting. Coronary angiograms were taken in the right and left anterior oblique positions with adequate angulations to allow clear visualization for the left and right coronary arteries, respectively, during the study period. The relations among focal spot, patient, and height of the image tube were kept constant during the angiographic study. When ACh was injected into the coronary artery to provoke coronary spasm, a tripolar electrode catheter (USCI) was placed in the right ventricular apex through the right femoral vein and was connected to a temporary pacemaker set at a rate of 50 bpm. Measurement of the luminal diameter of the coronary artery was performed quantitatively with the use of a computer-assisted coronary angiographic analysis system by two observers blinded to the study protocol. End-diastolic cinefilms that most clearly visualized the coronary segments were video digitized and stored in the cardiac image analysis system (Cardio 500, Kontron Instruments). Automated contour detection was performed by the geometric edge differentiation technique, described in previous studies in which the technique was validated.5 6 23 The size of a Judkins catheter was used to calibrate the arterial diameter in millimeters. The length of the coronary segment analyzed was 
10 mm; measurement was performed at three points, and the measured diameters were averaged within each segment. Each trunk of the three major coronary arteries in the control patients was divided into proximal and distal segments that were equal in length. The luminal diameter at the center of each segment was measured, and special care was taken to measure the diameter at the same site under each condition with use of anatomic references. In patients with coronary spastic angina, the luminal diameter was measured at the site of coronary spasm induced by intracoronary injection of ACh. Coronary spasm was defined as total or subtotal occlusion of the epicardial coronary arteries associated with signs of myocardial ischemia such as chest pain and ischemic ST-segment changes. When subtotal occlusion of the spasm occurred diffusely from the proximal to the distal segments of a coronary artery, the diameters were measured at both the proximal and distal segments of the spasm artery. Analysis of intraobserver and interobserver variability for measurement of coronary artery diameter showed high reproducibility (r=.99, SEE=0.05 mm, P<.001; and r=.99, SEE=0.04 mm, P<.001, respectively). Twelve ECG leads and arterial pressure were monitored continuously during the study period.
Study Protocols
The study protocols are shown in Fig 1
. We designed two protocols, protocol 1 and protocol 2, to examine NO activity at baseline and at ACh-stimulated conditions in the separate groups of the case patients and control patients, respectively.
|
Protocol 1
This protocol was designed primarily to examine the basal release of NO in patients with coronary spastic angina and in control patients. Twenty patients with coronary spastic angina (mean age, 60 years; 13 men and 7 women) and 25 control patients (mean age, 59 years; 14 men and 11 women) were included in this protocol. After baseline measurements of heart rate and blood pressure were obtained, angiography of the left and right coronary arteries was performed. The following drugs were then infused directly into the left coronary artery through the Judkins catheter. First, physiological saline (0.9% saline) was infused in all patients. Second, incremental doses of L-NMMA (25 and 50 µmol/min, each for 4 minutes) were infused into the left coronary artery in 12 patients with coronary spastic angina and in 16 control patients. In the other 8 patients with coronary spastic angina and in the other 9 control patients, L-arginine 125 mg/min was infused into the left coronary artery for 4 minutes. This dose of L-arginine was selected because its intracoronary infusion at this dose has been reported to correct endothelial dysfunction in the coronary microcirculation of hypercholesterolemic patients without causing a direct vasodilator effect on vascular smooth muscle.24 25 Each infusion was performed at a rate of 2 mL/min, and measurement of systemic hemodynamics and coronary angiography were repeated at the last 30 seconds of each infusion. All drug solutions were kept at 37°C.
Fifteen minutes after completion of the infusion of L-NMMA or L-arginine, by which time the coronary diameter had returned nearly to the baseline level as confirmed by coronary angiography, incremental doses of ACh were injected into the left coronary artery (50 and 100 µg) and subsequently into the RCA (20 and 50 µg) until coronary spasm was induced or the maximal doses were reached in all patients in both groups. Coronary spasm induced by this method usually resolves spontaneously within 2 to 3 minutes and allows further studies; spasms resolved spontaneously without use of nitroglycerin in all patients with coronary spastic angina in this study. Details of the method of injecting ACh were reported previously.3 4 5 6
Ten minutes after completion of the intracoronary injection of ACh, when the systemic hemodynamic parameters and the coronary arterial diameter on angiograms had returned to the baseline level, diltiazem (2.5 mg for 2 minutes) was infused into the left coronary artery, and measurement of systemic hemodynamics and coronary angiography were performed 2 minutes thereafter in 11 patients with coronary spastic angina and in 11 control patients. This dose of diltiazem dilates coronary arteries without causing significant systemic hemodynamic changes.26
After an additional 10 minutes, an intravenous bolus injection of nitroglycerin (250 µg) was given, and 3 minutes thereafter, coronary angiography was performed in all study patients in multiple projections.
Protocol 2
This protocol was designed to examine NO release stimulated by ACh. Nine patients with coronary spastic angina (mean age, 62 years; 4 men and 5 women) and 12 control patients (mean age, 61 years; 6 men and 6 women) were included in protocol 2. After baseline measurements of heart rate and blood pressure were obtained, angiography of the left and right coronary arteries was performed. Thereafter, incremental doses of ACh were injected into the left coronary artery (50 and 100 µg) and subsequently into the RCA (20 and 50 µg) in the same manner as in protocol 1. Coronary spasm resolved spontaneously without use of nitroglycerin in all patients with coronary spastic angina in this study. Fifteen minutes after completion of the intracoronary injection of ACh, when the systemic hemodynamic parameters and the coronary arterial diameter on angiograms had returned to baseline levels, L-NMMA (50 µmol/min) was infused for 5 minutes into the left coronary artery in the same manner as in protocol 1. At the last 1 minute of the L-NMMA infusion, 50 µg of ACh was simultaneously injected into the left coronary artery in the same manner as performed before L-NMMA infusion, and measurement of systemic hemodynamics and coronary angiography were performed at the end of the combined infusion of L-NMMA and ACh. After an additional 15 minutes, coronary angiography was performed after nitroglycerin in all study patients in the same manner as in protocol 1.
Drugs
L-NMMA was obtained from Wako Chemicals and was dissolved in physiological saline and then filtered in a sterile manner before use. L-arginine solution was obtained from Morishita Pharmaceutical.
Statistical Analysis
Data are expressed as mean±SD unless otherwise indicated. For comparison of the dose-response relation of the coronary luminal diameters to L-NMMA between spasm arteries and control arteries, two-way ANOVA for repeated measures followed by Bonferroni's multiple comparison test was used. Serial changes in coronary diameter in response to L-NMMA were compared by use of one-way ANOVA. Differences between two means were compared by paired or unpaired Student's t test. The correlation of percent changes in coronary diameters between responses to L-NMMA and nitroglycerin was examined by use of linear regression analysis. A value of P<.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Protocol 1
Baseline Parameters and Response to Saline
As shown in the Table
, baseline values of heart rate and mean blood pressure in patients with coronary spastic angina were not significantly different from those in control patients. Baseline diameters of the spasm arteries in patients with coronary spastic angina were significantly smaller compared with the respective diameters of arteries in the control patients (2.5±0.4 mm versus 3.1±0.5 mm, P<.01 at the proximal segment, and 1.3±0.4 mm versus 1.8±0.5 mm, P<.01 at the distal segment, respectively, in the LAD). Thus, basal tone was increased in the spasm arteries compared with the control arteries. Intracoronary infusion of 0.9% saline did not affect systemic hemodynamic parameters or the coronary diameters of the spasm or control arteries, as shown in the Table and Fig 2, respectively.
|
|
) and control (
) arteries from baseline values at the proximal and distal segments after intracoronary infusion of saline and L-NMMA in patients with coronary spastic angina and in control patients (protocol 1). The probability value refers to the comparison of the two curves by two-way ANOVA for repeated measures. *P<.05 and **P<.01 compared with the respective saline values.
Response to ACh and Provocation of Coronary Spasm
In all patients with coronary spastic angina, spasm occurred in the coronary artery into which ACh was injected, in association with ischemic ST-segment changes (ST-segment elevation in 10 patients, ST-segment depression in 10 patients) on the ECG leads that corresponded to the area of myocardium perfused by the artery. Coronary spasm was documented in 31 coronary arteries, including 20 LADs, 4 LCxs, and 7 RCAs. Spasm was induced by injection of ACh at a dose of 50 µg in 14 coronary arteries and 100 µg in 17 coronary arteries. Total occlusion occurred at the proximal segment of 3 coronary arteries, and subtotal occlusion occurred diffusely from the proximal to the distal segments in the remaining 28 coronary arteries. Of these spasm arteries, the artery diameter was measured in 24 coronary arteries, including 20 LADs and 4 LCxs, to demonstrate the vasomotor responses to various drugs. On the other hand, intracoronary injection of ACh did not induce coronary spasm associated with myocardial ischemia in any of the control patients. With regard to the LAD and LCx in control patients, ACh dilated 9 control arteries at 6 proximal and 9 distal segments at a dose of 50 µg, but it constricted most of the remaining control arteries diffusely at both the proximal and the distal segments. Thus, the control coronary arteries as a whole showed a slight but statistically significant constrictor response to ACh. As shown in Fig 3, the constrictor response to ACh was markedly augmented in the spasm arteries compared with the control coronary arteries (percent coronary diameter change after 50 µg ACh injection, -50±39% versus -12±12%, P<.001 at the proximal segment, and -44±36% versus -8.5±14%, P<.001 at the distal segment, respectively). There was no significant difference between the constrictor response to ACh after L-NMMA and that after L-arginine (percent coronary diameter change after 50 µg ACh injection at the distal segment, spasm artery -47±32% versus -41±34%, P=NS, and control artery -9.2±12% versus -8.1±10%, P=NS).
|
Response of Baseline Coronary Diameter to L-NMMA
The effects of L-NMMA infusion on coronary luminal diameter were analyzed at 25 spasm sites in 13 proximal (11 LADs and 2 LCxs) and 12 distal segments (10 LADs and 2 LCxs) of the 13 spasm arteries in 12 patients with coronary spastic angina and at 32 proximal (16 LADs and 16 LCxs) and 32 distal segments (16 LADs and 16 LCxs) of the 32 control arteries in 16 control patients. As shown in Fig 2
, the infusion of L-NMMA dose-dependently decreased the coronary luminal diameter in both the proximal and distal segments of coronary arteries in the control patients. In contrast, L-NMMA infusion showed little effect on the coronary diameter of the spasm arteries either at the proximal or distal segment in patients with coronary spastic angina. Intracoronary infusion of L-NMMA showed no appreciable effects on heart rate or mean blood pressure, either in patients with coronary spastic angina or in control patients.
Response to L-Arginine
Infusion of L-arginine did not significantly affect heart rate or mean blood pressure in either group of patients, as shown in the Table. The effects of L-arginine infusion on coronary diameters were evaluated at the proximal and distal segments of 11 spasm arteries in 8 patients with coronary spastic angina and at the proximal and distal segments of 18 control arteries in 9 control patients. Coronary luminal diameter did not differ during L-arginine infusion compared with during saline infusion in the spasm arteries (2.6±0.6 mm versus 2.5±0.4 mm, P=NS at the proximal segment, and 1.4±0.6 mm versus 1.4±0.5 mm, P=NS at the distal segment, respectively, in LADs) or in the arteries of the control patients (3.1±0.7 mm versus 3.0±0.6 mm at the proximal segment and 2.0±0.7 mm versus 1.9±0.5 mm at the distal segment, P=NS in both, in LADs), as shown in Fig 4.
|
Response to Diltiazem
Intracoronary infusion of diltiazem tended to decrease heart rate and blood pressure in both the control patients and those with coronary spastic angina. The effect of diltiazem was analyzed at the proximal and distal segments of 13 spasm arteries in 11 patients with coronary spastic angina and of 22 control arteries in 11 control patients. Diltiazem infusion increased the arterial diameter of the spasm arteries as well as of the control arteries at both the proximal and distal segments, and there was no significant difference in the response to diltiazem between spasm and control arteries at either the proximal or the distal segment, as shown in Fig 5.
|
Response to Nitroglycerin
Nitroglycerin increased the coronary diameter of all segments of the coronary arteries in both groups of patients. The percent increase in coronary diameter after nitroglycerin was significantly greater in spasm than in control arteries at either the proximal or the distal segment, as shown in Fig 5. Coronary diameters of the spasm arteries after nitroglycerin administration were not different from those of the control arteries at either the proximal segment or the distal segment (3.5±0.6 mm versus 3.7±0.8 mm at the proximal segment, and 1.9±0.7 mm versus 2.1±0.7 mm at the distal segment, P=NS, respectively, in LADs).
Correlation Between Percent Change of Coronary Luminal Diameter in Response to Nitroglycerin and That in Response to L-NMMA
As shown in Fig 6, there was a significant correlation between the percent change of the coronary diameters from baseline in response to nitroglycerin and that of the baseline diameter to L-NMMA. This indicates that the response of the coronary artery to nitroglycerin is related to the endogenous release of NO from the artery.
|
Protocol 2
Response to ACh and Provocation of Coronary Spasm
Spasm occurred in the coronary artery into which ACh was injected, in association with ischemic ST-segment changes, in all patients with coronary spastic angina. Coronary spasm was documented in 17 coronary arteries, including 8 LADs, 5 LCxs, and 4 RCAs. Spasm was induced by injection of ACh at a dose of 100 µg but not at 50 µg in LADs and LCxs and at 50 µg in RCAs. On the other hand, intracoronary injection of ACh did not induce coronary spasm associated with myocardial ischemia in any of the control patients. The artery diameter was analyzed for its vasomotor responses to various drugs at 21 spasm sites in 10 proximal (5 LADs and 5 LCxs) and 11 distal segments (7 LADs and 4 LCxs) of the 13 spasm arteries in 9 patients with coronary spastic angina and in 24 proximal (12 LADs and 12 LCxs) and 24 distal segments (12 LADs and 12 LCxs) of the 24 control arteries in 12 control patients. With regard to LADs and LCxs in control patients, ACh dilated 9 control arteries at 4 proximal and 9 distal segments at the dose of 50 µg, but it constricted most of the remaining control arteries at both the proximal and distal segments. Thus, the control coronary arteries as a whole showed a slight but statistically significant constrictor response to ACh at baseline. The constrictor response to ACh at baseline was markedly augmented in the spasm arteries compared with the control coronary arteries (percent coronary diameter change after 50 µg ACh injection, -46±31% versus -10±10%, P<.001 at the proximal segment, and -41±32% versus -7.8±12%, P<.001 at the distal segment, respectively), as shown in Fig 7. The magnitude of the response of the coronary artery diameter to ACh injection in protocol 2 was not significantly different from that to ACh, which was given 15 minutes after L-NMMA and L-arginine, in protocol 1.
|
Effect of L-NMMA on Response to ACh
Simultaneous infusion of L-NMMA converted the dilator response to 50 µg of ACh to constriction in all 9 control coronary arteries and enhanced the constrictor response to ACh in the remaining control coronary arteries at both the proximal and distal segments in control patients, as shown in Fig 7. In contrast, simultaneous infusion of L-NMMA had no significant effect on the constrictor response to 50 µg of ACh in the spasm arteries at either the proximal or distal segments. However, the constrictor response to the combined infusion of ACh and L-NMMA was still much greater in the spasm arteries than in the control arteries (percent coronary diameter change after ACh and L-NMMA, -52±30% versus -26±12%, P<.01 at the proximal segment; -48±31% versus -21±13%, P<.01 at the distal segment), as shown in Fig 7. The combined infusion of L-NMMA with ACh showed no appreciable effects on heart rate or mean blood pressure compared with ACh alone either in patients with coronary spastic angina or in control patients.
Response to Nitroglycerin
The dilator responses of the spasm and control arteries to nitroglycerin were comparable to those in protocol 1. The response in the spasm arteries was significantly greater than that in the control arteries (P<.01 at both the proximal and the distal segments). Coronary diameters of the spasm arteries after nitroglycerin were not different from those of the control arteries at either the proximal or the distal segment (3.4±0.5 mm versus 3.7±0.6 mm at the proximal segment and 1.9±0.5 mm versus 2.2±0.5 mm at the distal segment, respectively, P=NS, in LADs). There was no significant difference in the magnitude of the coronary dilator response to nitroglycerin between protocol 1 and protocol 2 in either the control or the spasm arteries, respectively (percent change from the baseline at the distal segment: control arteries, 21±16% in protocol 1 versus 22±17% in protocol 2, P=NS; spasm arteries: 43±18% in protocol 1 versus 40±20% in protocol 2, P=NS). Thus, the characteristic response to nitroglycerin in the spasm arteries was not affected by the prior infusion of L-NMMA and L-arginine in protocol 1.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study showed that coronary arteries constricted in response to L-NMMA in control patients, whereas spasm arteries had little or no response to intracoronary infusion of L-NMMA in patients with coronary spastic angina. The results indicate that there is a basal release of NO that maintains a basal tone in coronary arteries in humans, which is in agreement with results of previous studies,16 17 and also reveal that the basal release of NO is deficient in the spasm arteries of patients with coronary spastic angina.
The present study also demonstrated that the vasodilator response to nitroglycerin was increased markedly in spasm arteries compared with control arteries, whereas there was no difference between spasm arteries and control arteries in the vasodilator response to diltiazem, a calcium antagonist. Thus, the increased vasodilator response of spasm arteries to nitroglycerin is not common to all vasodilators but may be specific for nitroglycerin or a nitrovasodilator.
The present study also showed that there was a significant positive correlation between the percent change in basal coronary artery diameter in response to L-NMMA and that to nitroglycerin in the study patients. It has been shown recently22 that nitrovasodilators including nitroglycerin cause vasodilation by way of their conversion to NO. It is thus quite possible that the spasm arteries are hyperresponsive to nitroglycerin because endogenous release of NO is deficient in the arteries. These results are in agreement with those of previous experimental studies10 27 28 that demonstrated that the removal of basal NO-mediated vasodilation in the vascular system leads to supersensitivity to an exogenous nitrovasodilator. The present and our previous1 18 studies demonstrated that the diameters of spasm arteries are smaller at baseline but comparable after nitroglycerin compared with those of control arteries, which indicates that basal tone in the spasm arteries is increased. Thus, deficiency in basal NO production may cause increased basal tone in the spasm arteries of patients with coronary spastic angina.
The precise mechanism for deficient basal NO release in spasm arteries remains undetermined in the present study. NO is synthesized from L-arginine by various isoforms of NOS,11 and endothelial NOS is a constitutive, calcium/calmodulin-dependent isoform.12 13 The present study shows that decreased availability of the substrate or of L-arginine for NO synthesis is not involved in the deficient production of NO because the infusion of a sufficient amount of L-arginine had no effect on coronary diameter either in spasm arteries or in control arteries. This indicates that basal endothelial NOS activity in the spasm artery is deficient, although the possibility of increased breakdown of NO by the increased superoxide anions, as reported previously,29 cannot be excluded.
ACh causes vasodilation by release of NO when the endothelium is intact, whereas it causes vasoconstriction by its direct effect on vascular smooth muscle when the endothelium is removed or damaged.7 8 9 10 11 The present study showed that simultaneous infusion of L-NMMA abolished the dilator response to ACh and augmented the constrictor response to ACh in control arteries, whereas it had no effect on the constrictor response to ACh in spasm arteries. The present results thus indicate that NO regulates coronary tone in response to ACh in humans, which is in agreement with the results of Quyyumi and coworkers,17 and that NO release in response to ACh is also deficient in the spasm arteries of patients with coronary spastic angina. Coronary spasm can also be induced by other endothelium-dependent agonists, such as serotonin, ergonovine, and histamine.5 19 20 21 30 It is thus probable that endothelial NO release in response to these agonists also may be deficient in the coronary arteries of patients with coronary spastic angina. Although there are studies31 that have demonstrated vasodilation of spasm arteries in response to substance P and reported therefore that endothelial function was preserved in patients with coronary spastic angina, substance P is now shown to cause dilation in animal and human vessels even in the presence of NOS inhibition.32 33
Deficient NO release, however, may not be the sole cause of coronary spasm because atherosclerosis also impairs endothelial NO release,6 34 35 but coronary atherosclerosis is not necessarily associated with coronary spasm.4 In addition to NO, the endothelium produces vasodilators such as prostacyclin36 or hyperpolarizing factor37 and vasoconstrictors such as endothelins38 or endothelium-dependent constricting factors,39 and it is possible that a decrease of these vasodilators or an increase of these vasoconstrictors may also be involved in the pathogenesis of coronary spasm. The probability of hyperreactivity of coronary vascular smooth muscle to the vasoconstrictor stimuli also must be considered in the pathogenesis of coronary spasm.40 41 In fact, as shown in the present study, the magnitude of the constrictor response to ACh was still greater in spasm arteries compared with control arteries after NO inhibition by L-NMMA, which indicates that not only NO but also the hyperreactivity of smooth muscle and endothelium-derived factors other than NO may participate in the genesis of coronary spasm. In this regard, the present study suggests that dysfunction of the calcium channel42 in the vascular smooth muscle does not play an important role in the pathogenesis of coronary spasm because there was no difference in the response to diltiazem between spasm and control arteries.
In summary, the present study shows that (1) the spasm coronary artery does not respond, whereas the control coronary artery constricts to intracoronary infusion of L-NMMA in the basal state, (2) L-NMMA abolishes the dilator response and enhances the constrictor response to ACh in control arteries, whereas it has minimal effect on the constrictor response to ACh in spasm arteries, (3) intracoronary infusion of L-arginine does not affect the tone of either spasm arteries or control arteries, (4) there is an increased vasodilator response to nitroglycerin in spasm arteries compared with control arteries, whereas there is no significant difference between them in the vasodilator response to diltiazem, (5) the increased vasodilator response to nitroglycerin is significantly correlated with the decreased vasoconstrictor response to L-NMMA, and (6) the spasm arteries are supersensitive to the vasoconstrictor effect of ACh, which results in spasm.
From these results, we conclude that there is a deficiency of both basal and stimulated NO activity in the spasm arteries of patients with coronary spastic angina and that this deficient NO release plays an important role in the pathogenesis of coronary spasm.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported in part by a grant-in-aid for scientific research (No. C05670622) from the Ministry of Education, Science, and Culture in Japan and by a Smoking Research Foundation grant for biochemical research, Tokyo, Japan. We thank Dr Yusuke Moriyama, Department of Pharmacy at Kumamoto University Hospital, for preparing L-NMMA.
Received September 25, 1995; revision received November 10, 1995; accepted December 5, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Yasue H, Omote S, Takizawa A, Nagano M. Coronary arterial spasm in ischemic heart disease and its pathogenesis. Circ Res. 1983;52(suppl I):147-152.
2. Maseri A, Severi S, De Nes DM, L'Abbate A, Chierchia S, Marzilli M, Ballestra AM, Parodi O, Biagini A, Distante A. `Variant' angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardiol. 1978;42:1019-1035.[Medline] [Order article via Infotrieve]
3.
Yasue H, Horio Y, Nakamura N, Fujii H, Imoto N, Sonoda R, Kugiyama K, Obata K, Morikami Y, Kimura T. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation. 1986;74:955-963.
4.
Okumura K, Yasue H, Horio Y, Takaoka K, Matsuyama K, Kugiyama K, Fujii H, Morikami Y. Multivessel coronary spasm in patients with variant angina: a study with intracoronary injection of acetylcholine. Circulation. 1988;77:535-542.
5. Okumura K, Yasue H, Matsuyama K, Matsuyama K, Morikami Y, Ogawa H, Obata K. Effect of H1 receptor stimulation on coronary artery diameter in patients with variant angina: comparison with effect of acetylcholine. J Am Coll Cardiol. 1991;17:338-345.[Abstract]
6.
Yasue H, Matsuyama K, Matsuyama K, Okumura K, Morikami Y, Ogawa H. Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment: possible role of early coronary atherosclerosis. Circulation. 1990;81:482-490.
7.
Furchgott RF. Role of endothelium in response of vascular smooth muscle. Circ Res. 1983;53:557-573.
8.
Ignarro LJ. Biological action and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ Res. 1989;65:1-21.
9. Vanhoutte PM. The endothelium: modulator of vascular smooth muscle tone. N Engl J Med. 1988;319:512-513.[Medline] [Order article via Infotrieve]
10. Bassenge E. Coronary vasomotor responses: role of endothelium and nitrovasodilators. Cardiovasc Drugs Ther. 1994;8:600-612.
11. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109-142.[Medline] [Order article via Infotrieve]
12. Nishida K, Harrison DG, Navas JP, Fisher AA, Dockery SP, Uematsu M, Nerem RM, Alexander RW, Murphy TJ. Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest. 1992;90:2092-2096.
13.
Lamas S, Marsden PA, Li GK, Tempst P, Michel T. Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci U S A. 1992;89:6348-6352.
14. Chu A, Chambers DE, Lin C, Kuehl WD, Palmer RMJ, Moncada S, Cobb FR. Effects of inhibition of nitric oxide formation on basal vasomotion and endothelium-dependent responses of the coronary arteries in awake dogs. J Clin Invest. 1991;87:1964-1968.
15. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997-1000.[Medline] [Order article via Infotrieve]
16.
Lefroy DC, Crake T, Uren NG, Davies GJ, Maseri A. Effect of inhibition of nitric oxide synthesis on epicardial coronary artery caliber and coronary blood flow in humans. Circulation. 1993;88:43-54.
17. Quyyumi AA, Dakak N, Andrews NP, Husain S, Arora S, Gilligan DM, Panza JA, Cannon RO III, Johnson G, Mincemoyer R. Nitric oxide activity in the human coronary circulation: impact of risk factors for coronary atherosclerosis. J Clin Invest. 1995;95:1747-1755.
18.
Yasue H, Omote S, Takizawa A, Nagao M, Miwa K, Tanaka S. Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exercise-induced coronary arterial spasm. Circulation. 1979;59:938-948.
19.
Hackett D, Larkin S, Chierchia S, Davies G, Kaski JC, Maseri A. Induction of coronary artery spasm by a direct local action of ergonovine. Circulation. 1987;75:577-582.
20. Kuga T, Egashira K, Inou T, Takeshita A. Correlation of basal coronary artery tone with constrictive response to ergonovine in patients with variant angina. J Am Coll Cardiol. 1993;22:144-150.[Abstract]
21. Hoshio A, Kotake H, Mashiba H. Significance of coronary artery tone in patients with vasospastic angina. J Am Coll Cardiol. 1989;14:604-609.[Abstract]
22. Feelisch M. The biochemical pathways of nitric oxide formation from nitrovasodilators: appropriate choice of exogenous NO donors and aspects of preparation and handling of aqueous NO solutions. J Cardiovasc Pharmacol. 1991;17(suppl 3):S25-S33.
23.
Nichols AB, Gabrieli CFO, Fenoglio JJ, Esser PD. Quantification of relative coronary arterial stenosis by videodensitometric analysis of the coronary angiograms. Circulation. 1984;69:512-522.
24. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991;338:1546-1550.[Medline] [Order article via Infotrieve]
25. Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992;90:1248-1253.
26. Bertrand ME, Dupuis BA, Lablanche JM, Tilmant PY, Thieuleux FA. Coronary hemodynamics following intravenous or intracoronary injection of diltiazem in man. J Cardiovasc Pharmacol. 1982;4:695-699.[Medline] [Order article via Infotrieve]
27.
Moncada S, Rees DD, Schulz R, Palmer RMJ. Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci U S A. 1991;88:2166-2170.
28.
Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993;329:2002-2012.
29. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993;91:2546-2551.
30. McFadden EP, Clarke JG, Davies GJ, Kaski JC, Haider AW, Maseri A. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med. 1991;324:648-654.[Abstract]
31. Egashira K, Inou T, Yamada A, Hirooka Y, Takeshita A. Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina. J Clin Invest. 1992;89:1047-1052.
32. Shiramoto M, Imaizumi T, Namba T, Endo T, Takeshita A. Are vasodilator effects of substance P and ATP mediated by nitric oxide in human forearm vessels? Circulation. 1994;90(suppl I):I-321. Abstract.
33. Kilpatrick EV, Cock TM. Evidence for differential roles of nitric oxide (NO) and hyperpolarization in endothelium-dependent relaxation of a pig isolated coronary artery. Br J Pharmacol. 1994;112:557-565.[Medline] [Order article via Infotrieve]
34. Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest. 1987;79:170-174.
35.
Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor response to acetylcholine relates to risk factor for coronary artery disease. Circulation. 1990;81:491-497.
36. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev. 1979;30:293-331.[Medline] [Order article via Infotrieve]
37. Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol. 1988;93:515-524.[Medline] [Order article via Infotrieve]
38. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415.[Medline] [Order article via Infotrieve]
39.
Luscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986;8:344-348.
40.
Maseri A, Davies G, Hackett D, Kaski JC. Coronary artery spasm and vasoconstriction: the case for a distinction. Circulation. 1990;81:1983-1991.
41. Ganz P, Alexander RW. New insights into the cellular mechanisms of vasospasm. Am J Cardiol. 1985;56:11E-15E.[Medline] [Order article via Infotrieve]
42.
Ito A, Shimokawa H, Nakaike R, Fukai T, Sakata M, Takayanagi T, Egashira K, Takeshita A. Role of protein kinase C–mediated pathway in the pathogenesis of coronary artery spasm in a swine model. Circulation. 1994;90:2425-2431.
This article has been cited by other articles:
 |
|
 |
|
  H. Nakagawa, Y. Morikawa, Y. Mizuno, E. Harada, T. Ito, K. Matsui, Y. Saito, and H. Yasue Coronary Spasm Preferentially Occurs at Branch Points: An Angiographic Comparison With Atherosclerotic Plaque Circ Cardiovasc Interv, April 1, 2009; 2(2): 97 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. B. Goldsmith, N. Roistacher, and M. S. Baum Capecitabine-Induced Coronary Vasospasm J. Clin. Oncol., August 1, 2008; 26(22): 3802 - 3804. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yasue, Y. Mizuno, E. Harada, T. Itoh, H. Nakagawa, M. Nakayama, H. Ogawa, S. Tayama, T. Honda, S. Hokimoto, et al. Effects of a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Fluvastatin, on Coronary Spasm After Withdrawal of Calcium-Channel Blockers J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1742 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Singh, R. Arora, A. Khraisat, K. Handa, A. Bahekar, A. Trivedi, and S. Khosla Increased Incidence of In-Stent Thrombosis Related to Cocaine Use: Case Series and Review of Literature Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2007; 12(4): 298 - 303. [Abstract] [PDF]
|
|
|
|
|
|
J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Takano, Y. Kodama, Y. Kitta, T. Nakamura, J.-e. Obata, A. Mende, K.-i. Kawabata, Y. Saitoh, D. Fujioka, T. Kobayashi, et al. Transcardiac adiponectin gradient is independently related to endothelial vasomotor function in large and resistance coronary arteries in humans Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2641 - H2646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Mishra Variations in presentation and various options in management of variant angina. Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 748 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Neishi, S. Mochizuki, T. Miyasaka, T. Kawamoto, T. Kume, R. Sukmawan, M. Tsukiji, Y. Ogasawara, F. Kajiya, T. Akasaka, et al. Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration PNAS, August 9, 2005; 102(32): 11456 - 11461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Koga, S. Sugiyama, K. Kugiyama, K. Watanabe, H. Fukushima, T. Tanaka, T. Sakamoto, M. Yoshimura, H. Jinnouchi, and H. Ogawa Elevated Levels of VE-Cadherin-Positive Endothelial Microparticles in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1622 - 1630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ichigi, H. Takano, K. Umetani, K. Kawabata, J.-e. Obata, Y. Kitta, Y. Kodama, A. Mende, T. Nakamura, D. Fujioka, et al. Increased Ambulatory Pulse Pressure Is a Strong Risk Factor for Coronary Endothelial Vasomotor Dysfunction J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1461 - 1466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Raja and S. H. Nayak Sildenafil: Emerging Cardiovascular Indications Ann. Thorac. Surg., October 1, 2004; 78(4): 1496 - 1506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Vilahur, E. Segales, E. Salas, and L. Badimon Effects of a Novel Platelet Nitric Oxide Donor (LA816), Aspirin, Clopidogrel, and Combined Therapy in Inhibiting Flow- and Lesion-Dependent Thrombosis in the Porcine Ex Vivo Model Circulation, September 21, 2004; 110(12): 1686 - 1693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Reffelmann and R. A. Kloner Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease Circulation, July 15, 2003; 108(2): 239 - 244. [Full Text] [PDF]
|
|
|
|
|
|
H. Soejima, A. Irie, S. Miyamoto, I. Kajiwara, S. Kojima, J. Hokamaki, T. Sakamoto, T. Tanaka, M. Yoshimura, Y. Nishimura, et al. Preference Toward a T-Helper Type 1 Response in Patients With Coronary Spastic Angina Circulation, May 6, 2003; 107(17): 2196 - 2200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kawano, T. Motoyama, N. Hirai, K. Kugiyama, H. Ogawa, and H. Yasue Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina J. Am. Coll. Cardiol., March 1, 2001; 37(3): 735 - 740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ogawa, H. Soejima, K. Takazoe, S. Miyamoto, I. Kajiwara, H. Shimomura, T. Sakamoto, M. Yoshimura, K. Kugiyama, M. Kimura, et al. Increased Autoantibodies Against Oxidized Low-Density Lipoprotein in Coronary Circulation in Patients with Coronary Spastic Angina Angiology, March 1, 2001; 52(3): 167 - 174. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Teragawa, M. Kato, T. Yamagata, H. Matsuura, and G. Kajiyama The Preventive Effect of Magnesium on Coronary Spasm in Patients With Vasospastic Angina Chest, December 1, 2000; 118(6): 1690 - 1695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Suzuki, T. Yoshii, T. Ohtsuka, O. Sasaki, Y. Hara, T. Okura, Y. Shigematsu, M. Hamada, and K. Hiwada Coronary Spastic Angina Induced by Anticholinesterase Medication for Myasthenia Gravis: A Case Report Angiology, December 1, 2000; 51(12): 1031 - 1034. [Abstract] [PDF]
|
|
|
|
 |
|
 Y. Miyamoto, Y. Saito, M. Nakayama, Y. Shimasaki, T. Yoshimura, M. Yoshimura, M. Harada, N. Kajiyama, I. Kishimoto, K. Kuwahara, et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T->C mutation associated with coronary spastic angina Hum. Mol. Genet., November 1, 2000; 9(18): 2629 - 2637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Braunwald, E. M. Antman, J. W. Beasley, R. M. Califf, M. D. Cheitlin, J. S. Hochman, R. H. Jones, D. Kereiakes, J. Kupersmith, T. N. Levin, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: A report of the american college of cardiology/ american heart association task force on practice guidelines (committee on the management of patients with unstable angina) J. Am. Coll. Cardiol., September 1, 2000; 36(3): 970 - 1062. [Full Text] [PDF]
|
|
|
|
|
|
Y. Miyao, K. Kugiyama, H. Kawano, T. Motoyama, H. Ogawa, M. Yoshimura, T. Sakamoto, and H. Yasue Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina J. Am. Coll. Cardiol., August 1, 2000; 36(2): 432 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Elbaz, O. Poirier, T. Moulin, F. Chedru, F. Cambien, and P. Amarenco Association Between the Glu298Asp Polymorphism in the Endothelial Constitutive Nitric Oxide Synthase Gene and Brain Infarction Stroke, July 1, 2000; 31(7): 1634 - 1639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kugiyama, Y. Ota, H. Kawano, H. Soejima, H. Ogawa, S. Sugiyama, H. Doi, and H. Yasue Increase in plasma levels of secretory type II phospholipase A2 in patients with coronary spastic angina Cardiovasc Res, July 1, 2000; 47(1): 159 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Hirashima, H. Kawano, T. Motoyama, N. Hirai, M. Ohgushi, K. Kugiyama, H. Ogawa, and H. Yasue Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: Possible role of reactive oxygen species J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1860 - 1866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sztajzel, F. Mach, and A. Righetti Current concepts in medicine: Role of the vascular endothelium in patients with angina pectoris or acute myocardial infarction with normal coronary arteries Postgrad. Med. J., January 1, 2000; 76(891): 16 - 21. [Abstract] [Full Text]
|
|
|
|
|
|
K. Miyata, H. Shimokawa, T. Yamawaki, I. Kunihiro, X. Zhou, T. Higo, E. Tanaka, N. Katsumata, K. Egashira, and A. Takeshita Endothelial Vasodilator Function Is Preserved at the Spastic/Inflammatory Coronary Lesions in Pigs Circulation, September 28, 1999; 100(13): 1432 - 1437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nakayama, H. Yasue, M. Yoshimura, Y. Shimasaki, K. Kugiyama, H. Ogawa, T. Motoyama, Y. Saito, Y. Ogawa, Y. Miyamoto, et al. T-786->C Mutation in the 5'-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated With Coronary Spasm Circulation, June 8, 1999; 99(22): 2864 - 2870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Beltrame, S. Sasayama, and A. Maseri Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and caucasian patients J. Am. Coll. Cardiol., May 1, 1999; 33(6): 1442 - 1452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V. Lewis, A. M. Dart, and J. P. F. Chin-Dusting Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol J. Am. Coll. Cardiol., March 1, 1999; 33(3): 805 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Bonin, K. Madden, K. Shera, J. Ihle, C. Matthews, S. Aziz, N. Perez-Reyes, J. K. McDougall, and S. C. Conroy Generation and Characterization of Human Smooth Muscle Cell Lines Derived From Atherosclerotic Plaque Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 575 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Ostos, J. Lopez-Miranda, J. M. Ordovas, C. Marin, A. Blanco, P. Castro, F. Lopez-Segura, J. Jimenez-Pereperez, and F. Perez-Jimenez Dietary fat clearance is modulated by genetic variation in apolipoprotein A-IV gene locus J. Lipid Res., December 1, 1998; 39(12): 2493 - 2500. [Abstract] [Full Text]
|
|
|
|
|
|
T. Motoyama, H. Kawano, K. Kugiyama, O. Hirashima, M. Ohgushi, R. Tsunoda, Y. Moriyama, Y. Miyao, M. Yoshimura, H. Ogawa, et al. Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spastic angina J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1672 - 1679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hibi, T. Ishigami, K. Tamura, S. Mizushima, N. Nyui, T. Fujita, H. Ochiai, M. Kosuge, Y. Watanabe, Y. Yoshii, et al. Endothelial Nitric Oxide Synthase Gene Polymorphism and Acute Myocardial Infarction Hypertension, September 1, 1998; 32(3): 521 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kugiyama, T. Motoyama, O. Hirashima, M. Ohgushi, H. Soejima, K. Misumi, H. Kawano, Y. Miyao, M. Yoshimura, H. Ogawa, et al. Vitamin C attenuates abnormal vasomotor reactivity in spasm coronary arteries in patients with coronary spastic angina J. Am. Coll. Cardiol., July 1, 1998; 32(1): 103 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Niemeyer, H. A. J. Kleinjans, R. de Ree, A. H. Zwinderman, T. J. M. Cleophas, E. E. van der Wall, A.J.M. Cleophas, and Dutch Mononitrate Quality of Life Study Group Comparison of Multiple-Dose and Once-Daily Nitrate Therapy in 1212 Patients with Stable Angina Pectoris: Effects on Quality of Life Indices Angiology, October 1, 1997; 48(10): 855 - 862. [Abstract] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||