Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.     

The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress

BACKGROUND. Mental stress can cause angina in patients with coronary artery disease, but its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress. METHODS. We studied 26 patients who performed mental arithmetic under stressful conditions during cardiac catheterization. (An additional four patients who did not perform the mental arithmetic served as controls.) Coronary segments were classified on the basis of angiographic findings as smooth, irregular, or stenosed. In 15 of the patients without focal stenoses in the left anterior descending artery, acetylcholine (10(-8) to 10(-6) mol per liter) was infused into the artery to test endothelium-dependent vasodilation. Changes in coronary blood flow were measured with an intracoronary Doppler catheter in these 15 patients. RESULTS. The response of the coronary arteries to mental stress varied from 38 percent constriction to 29 percent dilation, whereas the change in coronary blood flow varied from a decrease of 48 percent to an increase of 42 percent. The direction and magnitude of the change in the coronary diameter were not predicted by the changes in the heart rate, blood pressure, or plasma norepinephrine level. Segments with stenoses (n = 7) were constricted by a mean (+/- SE) of 24 +/- 4 percent, and irregular segments (n = 20) by 9 +/- 3 percent, whereas smooth segments (n = 25) did not change significantly (dilation, 3 +/- 3 percent; P less than 0.0002). Coronary blood flow increased by 10 +/- 10 percent in smooth vessels, whereas the flow in irregular vessels decreased by 27 +/- 5 percent. The degree of constriction or dilation during mental stress correlated with the response to the infusions of acetylcholine (P less than 0.0003, r = 0.58). CONCLUSIONS. Atherosclerosis disturbs the normal vasomotor response (no change or dilation) of large coronary arteries to mental stress; in patients with atherosclerosis paradoxical constriction occurs during mental stress, particularly at points of stenosis. This vasomotor response correlates with the extent of atherosclerosis in the artery and with the endothelium-dependent response to an infusion of acetylcholine. These data suggest that in atherosclerosis unopposed constriction caused by a local failure of endothelium-dependent dilation causes the coronary arteries to respond abnormally to mental stress.     

Decreased rate of coronary restenosis after lowering of plasma homocysteine levels.

BACKGROUND: We have previously demonstrated an association between elevated total plasma homocysteine levels and restenosis after percutaneous coronary angioplasty. We designed this study to evaluate the effect of lowering plasma homocysteine levels on restenosis after coronary angioplasty. METHODS: A combination of folic acid (1 mg), vitamin B12 (400 microg), and pyridoxine (10 mg)--referred to as folate treatment--or placebo was administered to 205 patients (mean [+/-SD] age, 61+/-11 years) for six months after successful coronary angioplasty in a prospective, double-blind, randomized trial. The primary end point was restenosis within six months as assessed by quantitative coronary angiography. The secondary end point was a composite of major adverse cardiac events. RESULTS: Base-tine characteristics and initial angiographic results after coronary angioplasty were similar in the two study groups. Folate treatment significantly lowered plasma homocysteine levels from 11.1+/-4.3 to 7.2+/-2.4 micromol per liter (P<0.001). At follow-up, the minimal luminal diameter was significantly larger in the group assigned to folate treatment (1.72+/-0.76 vs. 1.45+/-0.88 mm, P=0.02), and the degree of stenosis was less severe (39.9+/-20.3 vs. 48.2+/-28.3 percent, P=0.01). The rate of restenosis was significantly lower in patients assigned to folate treatment (19.6 vs. 37.6 percent, P=0.01), as was the need for revascularization of the target lesion (10.8 vs. 22.3 percent, P=0.047). CONCLUSIONS: Treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduces homocysteine levels and decreases the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. This inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty.     

Effects of continuous vs interval exercise training on oxygen uptake efficiency slope in patients with coronary artery disease

The oxygen uptake efficiency slope (OUES) is a submaximal index incorporating cardiovascular, peripheral, and pulmonary factors that determine the ventilatory response to exercise. The purpose of this study was to evaluate the effects of continuous exercise training and interval exercise training on the OUES in patients with coronary artery disease. Thirty-five patients (59.3±1.8 years old; 28 men, 7 women) with coronary artery disease were randomly divided into two groups: continuous exercise training (n=18) and interval exercise training (n=17). All patients performed graded exercise tests with respiratory gas analysis before and 3 months after the exercise-training program to determine ventilatory anaerobic threshold (VAT), respiratory compensation point, and peak oxygen consumption (peak VO₂). The OUES was assessed based on data from the second minute of exercise until exhaustion by calculating the slope of the linear relation between oxygen uptake and the logarithm of total ventilation. After the interventions, both groups showed increased aerobic fitness (P<0.05). In addition, both the continuous exercise and interval exercise training groups demonstrated an increase in OUES (P<0.05). Significant associations were observed in both groups: 1) continuous exercise training (OUES and peak VO₂ r=0.57; OUES and VO₂ VAT r=0.57); 2) interval exercise training (OUES and peak VO₂ r=0.80; OUES and VO₂ VAT r=0.67). Continuous and interval exercise training resulted in a similar increase in OUES among patients with coronary artery disease. These findings suggest that improvements in OUES among CAD patients after aerobic exercise training may be dependent on peripheral and central mechanisms.     

Myocardial ischemia caused by distal coronary-artery constriction in stable angina pectoris

BACKGROUND. In patients with stable coronary artery disease, the ischemic threshold for the production of effort-related angina is often quite variable. Although this feature is commonly attributed to changes in the caliber of coronary arteries at the site of stenosis, it could also be caused by the constriction of distal vessels, collateral vessels, or both. METHODS. In order to test this hypothesis, we studied 11 patients with stable angina, total occlusion of a single coronary artery that was supplied by collateral vessels, normal ventricular function, no evidence of coronary-artery spasm, and no other coronary stenoses. These conditions precluded the modulation of coronary flow by vasomotion at the site of the coronary stenosis. RESULTS. The ischemic threshold--assessed by multiplying the heart rate by the systolic blood pressure at a 1-mm depression of the ST segment during exercise testing--increased by 19 percent after the administration of nitroglycerin (P less than 0.05) and decreased by 18 percent after the administration of ergonovine (P less than 0.01). Ambulatory electrocardiographic monitoring of the patients when not receiving treatment detected 73 ischemic episodes that, in keeping with the history, showed variations of 25 to 52 beats per minute in the heart rate at a 1-mm depression of the ST segment; 12 episodes of sinus tachycardia exceeded the lowest ischemic heart rate by a mean (+/- SD) of 22 +/- 13 beats per minute without ST-segment depression. Furthermore, 21 ischemic episodes occurred at a heart rate more than 25 beats per minute below that at a 1-mm depression of the ST segment during exercise testing. Delayed and reduced filling of collateral and collateralized vessels associated with depression of the ST segment similar to that observed during ambulatory monitoring was detected on angiographic evaluation after the intracoronary administration of ergonovine in three patients. CONCLUSIONS. We propose that the constriction of distal coronary arteries, collateral vessels, or both may cause myocardial ischemia in patients with chronic stable angina.     

Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina

BACKGROUND. Serotonin, a major product of platelet activation, has potent vasoactive effects in animal models, but its role in human coronary artery disease remains largely speculative. METHODS. Using quantitative coronary angiography, we compared the effects of the intracoronary infusion of graded concentrations of serotonin (10(-7) to 10(-4) mol per liter) on coronary vessels in two groups of patients with different clinical presentations of coronary disease (nine with stable angina and five with variant angina), with the effects in a control group of eight subjects with normal vessels on angiography. RESULTS. Normal coronary vessels had a biphasic response to intracoronary serotonin: dilation at concentrations up to 10(-5) mol per liter, but constriction at 10(-4) mol per liter. Vessels in patients with stable angina constricted at all concentrations, with mean (+/- SEM) maximal decreases in diameter of 23.9 +/- 3.6, 33.1 +/- 3.9, and 41.7 +/- 3.1 percent from base line in proximal, middle, and distal segments at a serotonin concentration of 10(-4) mol per liter. Smooth segments constricted more than irregular segments (42.0 +/- 4.6 vs. 21.1 +/- 1.6 percent). Four patients with stable angina had a marked reduction in collateral filling. All the patients with stable angina had angina during the intracoronary infusion of serotonin, and electrocardiographic changes were noted in six. All the patients with variant angina had angina, electrocardiographic changes, and localized occlusive epicardial coronary-artery spasm at concentrations of 10(-6) (n = 2) or 10(-5) (n = 3) mol per liter. CONCLUSIONS. Patients with stable coronary disease do not have the normal vasodilator response to intracoronary serotonin, but rather have progressive constriction, which is particularly intense in small distal and collateral vessels. Patients with variant angina have occlusive coronary-artery spasm at a dose that dilates normal vessels and causes only slight constriction in vessels from patients with stable angina. These findings suggest that serotonin, released after the intracoronary activation of platelets, may contribute to or cause myocardial ischemia in patients with coronary artery disease.     

A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty

Patients presenting within four hours of the onset of acute myocardial infarction were randomly assigned to receive 80 to 100 mg of recombinant human-tissue plasminogen activator (t-PA) intravenously over a period of three hours (n = 72) or placebo (n = 66). Administration of the study drug was followed by coronary arteriography, and candidates for percutaneous transluminal coronary angioplasty were randomly assigned either to undergo angioplasty on the third hospital day (n = 42) or not to undergo angioplasty during the 10-day study period (n = 43). The patency rates of the infarct-related arteries were 66 percent in the t-PA group and 24 percent in the placebo group. No fatal or intracerebral hemorrhages occurred, and episodes of bleeding requiring transfusion were observed in 7.6 percent of the placebo group and 9.8 percent of the t-PA group. As compared with the use of placebo, administration of t-PA was associated with a higher mean (+/- SEM) ejection fraction on the 10th hospital day (53.2 +/- 2.0 vs. 46.4 +/- 2.0 percent, P less than 0.02), an improved ejection fraction during the study period (+3.6 +/- 1.3 vs. -4.7 +/- 1.3 percentage points, P less than 0.0001), and a reduction in the prevalence of congestive heart failure from 33 to 14 percent (P less than 0.01). Angioplasty improved the response of the ejection fraction to exercise (+8.1 +/- 1.4 vs. +1.2 +/- 2.2 percentage points, P less than 0.02) and reduced the incidence of postinfarction angina from 19 to 5 percent (P less than 0.05), but did not influence the ejection fraction at rest. These data support an approach to the treatment of acute myocardial infarction that includes early intravenous administration of t-PA and deferred cardiac catheterization and coronary angioplasty.     

Improvement in exercise performance by inhalation of methoxamine in patients with impaired left ventricular function.

BACKGROUND. Bronchial hyperresponsiveness to cholinergic stimuli such as the inhalation of methacholine is common in patients with impaired left ventricular function. Such hyperresponsiveness is best explained by cholinergic vasodilation of blood vessels in the small airways, with extravasation of plasma due to high left ventricular filling pressure. Because this vasodilation may be prevented by the inhalation of the vasoconstrictor agent methoxamine, we studied the effect of methoxamine on exercise performance in patients with chronic left ventricular dysfunction. METHODS. We studied 19 patients with a mean left ventricular ejection fraction of 22 +/- 4 percent and moderate exertional dyspnea. In the first part of the study, we performed treadmill exercise tests in 10 patients (group 1) at a constant maximal workload to assess the effects of 10 mg of inhaled methoxamine on the duration of exercise (a measure of endurance). In the second part of the study, we used a graded exercise protocol in nine additional patients (group 2) to assess the effects of inhaled methoxamine on maximal exercise capacity and oxygen consumption. Both studies were carried out after the patients inhaled methoxamine or placebo given according to a randomized, double-blind, crossover design. RESULTS. In group 1, the mean (+/- SD) duration of exercise increased from 293 +/- 136 seconds after the inhalation of placebo to 612 +/- 257 seconds after the inhalation of methoxamine (P = 0.001). In group 2, exercise time (a measure of maximal exercise capacity) increased from 526 +/- 236 seconds after placebo administration to 578 +/- 255 seconds after methoxamine (P = 0.006), and peak oxygen consumption increased from 18.5 +/- 6.0 to 20.0 +/- 6.0 ml per minute per kilogram of body weight (P = 0.03). CONCLUSIONS. The inhalation of methoxamine enhanced exercise performance in patients with chronic left ventricular dysfunction. However, the improvement in the duration of exercise at a constant workload (endurance) was much more than the improvement in maximal exercise capacity assessed with a progressive workload. These data suggest that exercise-induced vasodilation of airway vessels may contribute to exertional dyspnea in such patients. Whether or not inhaled methoxamine can provide long-term benefit in patients with heart failure will require further study.     

Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease

BACKGROUND. The maintenance of cellular levels of high-energy phosphates is required for myocardial function and preservation. In animals, severe myocardial ischemia is characterized by the rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP. METHODS. To determine whether ischemic metabolic changes are detectable in humans, we recorded spatially localized phosphorus-31 nuclear-magnetic-resonance (31P NMR) spectra from the anterior myocardium before, during, and after isometric hand-grip exercise. RESULTS. The mean (+/- SD) ratio of phosphocreatine to ATP in the left ventricular wall when subjects were at rest was 1.72 +/- 0.15 in normal subjects (n = 11) and 1.59 +/- 0.31 in patients with nonischemic heart disease (n = 9), and the ratio did not change during hand-grip exercise in either group. However, in patients with coronary heart disease and ischemia due to severe stenosis (greater than or equal to 70 percent) of the left anterior descending or left main coronary arteries (n = 16), the ratio decreased from 1.45 +/- 0.31 at rest to 0.91 +/- 0.24 during exercise (P less than 0.001) and recovered to 1.27 +/- 0.38 two minutes after exercise. Only three patients with coronary heart disease had clinical symptoms of ischemia during exercise. Repeat exercise testing in five patients after revascularization yielded values of 1.60 +/- 0.20 at rest and 1.62 +/- 0.18 during exercise (P not significant), as compared with 1.51 +/- 0.19 at rest and 1.02 +/- 0.26 during exercise before revascularization (P less than 0.02). CONCLUSIONS. The decrease in the ratio of phosphocreatine to ATP during hand-grip exercise in patients with myocardial ischemia reflects a transient imbalance between oxygen supply and demand in myocardium with compromised blood flow. Exercise testing with 31P NMR is a useful method of assessing the effect of ischemia on myocardial metabolism of high-energy phosphates and of monitoring the response to treatment.     

The effects of isometric exercise training on resting blood pressure and orthostatic tolerance in humans

Isometric exercise training has been shown to reduce resting blood pressure, but the effect that this might have on orthostatic tolerance is poorly understood. Changes in orthostatic tolerance may also be dependent on whether the upper or lower limbs of the body are trained using isometric exercise. Twenty-seven subjects were allocated to either a training or control group. A training group first undertook 5 weeks of isometric exercise training of the legs, and after an 8 week intervening period, a second training group containing six subjects from the initial training group, undertook 5 weeks of isometric arm-training. The control group were asked to continue their normal daily activities throughout the 18 weeks of the study. In all subjects orthostatic tolerance, assessed using lower body negative pressure (LBNP), and resting blood pressure were measured before and after each of the 5 week training or control periods. Estimated lean leg volume was determined before and after leg-training. During all LBNP tests, heart rate and blood pressure were recorded each minute, and the time taken to reach the highest heart rate was derived (time to peak HR). Resting systolic blood pressure (mean +/- S.D.), when measured during the last week of training, was significantly reduced after both leg (-10 +/- 8.7 mmHg) and arm (-12.4 +/- 9.3 mmHg; P < 0.05) isometric exercise training, compared to controls. This reduction disappeared when blood pressure was measured immediately before the LBNP tests, which followed training. Orthostatic tolerance only increased after leg-training (20.8 +/- 16.4 LTI; P < 0.05) and was accompanied by an increased time to peak HR (119.8 +/- 106.3 beats min(-1); P < 0.05) in this group. Blood pressure responses to LBNP did not change after arm-training, leg-training or in controls (P > 0.05). There was a small but significant increase in estimated lean leg volume after leg-training (0.1 +/- 0.1 1; P < 0.05). These results suggest that lower resting blood pressure is probably not responsible for the increased orthostatic tolerance after isometric exercise training of the legs. Rather, it is possible that the training altered some other aspect of cardiovascular control during orthostatic stress that was apparent in the changes in heart rate. Leg-training was accompanied by increases in estimated lean leg volume. The effects of isometric training on orthostatic tolerance appear to be specific to limbs that are directly involved in LBNP testing.     

Ameroid constriction of the proximal left circumflex coronary artery in swine. A model of limited coronary collateral circulation

Gradual narrowing and occlusion of a coronary artery in patients with atherosclerotic heart disease frequently causes enlargement of the collateral circulation. Although these vessels may protect from development of myocardial infarction, they frequently do not supply sufficient blood flow to prevent ischemia during periods of augmented myocardial oxygen demand. The purpose of this study was to develop a model of the collateral circulation in pigs, a species that previously has been shown to develop sparse collateral vessels. Eighteen pigs were instrumented with an Ameroid constrictor around the proximal left circumflex artery and left atrial and aortic catheters. In four animals the constrictor was placed just distal to a large proximal obtuse marginal vessel. Seven of the pigs were treated daily with oral aspirin (325 mg) and disopyramide (200 mg) throughout the study; the other 11 served as controls. After an average of 24 days postoperatively, radioactive microspheres were injected at rest, during exercise (mean heart rate = 245 beats/min), and during intravenous infusion of dypridamole (700 micrograms/kg). At autopsy the extent of necrosis was assessed by a point counting technique in the bed at risk. We found that 75-83% of the bed at risk remained viable. Although aspirin and disopyramide did not significantly alter the extent of infarction (37 +/- 36% untreated vs 17 +/- 6% treated), there was less variability of infarction in the treated group, and subendocardial blood flow during exercise was higher in the treated group compared to controls. The majority of infarction occurred in the subendocardial region. Animals with a large obtuse marginal branch developed significantly smaller infarcts (8 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Rehabilitation training improves exercise tolerance after percutaneous coronary intervention

The aim of this present study was to investigate the effects of training on exercise tolerance of patients with coronary heart disease after percutaneous coronary intervention.Fifty-seven cases of coronary heart disease after percutaneous coronary intervention were divided randomly into the rehabilitation training group(26 cases) and control group(31 cases).Patients in the rehabilitation training group received rehabilitation training at different stages and exercise intensities 3 d after percutaneous coronary intervention for 3 months.The heart rate,blood pressure,ECG changes in treadmill exercise test,and the frequency of anginal episodes were observed.The results showed that NST and ΣST of ECG and the frequency of anginal episodes were significantly reduced in the rehabilitation training group.In addition,exercise tolerance was improved and the total exercise time was lengthened in these patients.Moreover,ST segment depression time and emergence time of angina with exercise were also lengthened compared with controls(P < 0.05,or 0.01).However,the heart rate and blood pressure before and after exercise of the two groups were similar.The study indicated that rehabilitation training could significantly relieve angina,amend ischemic features of ECG,and improve exercise tolerance of coronary heart disease patients after percutaneous coronary intervention.     

Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension

BACKGROUND. Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic arteries in humans and animals and in animal models of hypertension. METHODS. To determine whether patients with essential hypertension have an endothelium-dependent abnormality in vascular relaxation, we studied the response of the forearm vasculature to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct dilator of smooth muscle) in 18 hypertensive patients (mean age [+/- SD], 50.7 +/- 10 years; 10 men and 8 women) two weeks after the withdrawal of antihypertensive medications and in 18 normal controls (mean age, 49.9 +/- 9; 9 men and 9 women). The drugs were infused at increasing concentrations into the brachial artery, and the response in forearm blood flow was measured by strain-gauge plethysmography. RESULTS. The basal forearm blood flow was similar in the patients and controls (mean +/- SD, 3.4 +/- 1.3 and 3.7 +/- 0.8 ml per minute per 100 ml of forearm tissue, respectively; P not significant). The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P less than 0.0001); maximal forearm flow was 9.1 +/- 5 ml per minute per 100 ml in the patients and 20.0 +/- 8 ml per minute per 100 ml in the controls (P less than 0.0002). However, there were no significant differences between groups in the responses of blood flow and vascular resistance to sodium nitroprusside. Because the vasodilator effect of acetylcholine might also be due to presynaptic inhibition of the release of norepinephrine by adrenergic nerve terminals, the effect of acetylcholine was assessed during phentolamine-induced alpha-adrenergic blockade. Under these conditions, it was also evident that the responses to acetylcholine were significantly blunted in the hypertensive patients (P less than 0.03). CONCLUSIONS. Endothelium-mediated vasodilation is impaired in patients with essential hypertension. This defect may play an important part in the functional abnormalities of resistance vessels that are observed in hypertensive patients.     

Volume overload left ventricular hypertrophy: effects on coronary microvascular reactivity in rabbits

The mechanisms controlling the coronary vascular responses of vessels perfusing the left ventricular (LV) myocardium that is hypertrophied from chronic volume overload are unclear. We hypothesised that endothelial function is compromised, and receptor-mediated contraction is exacerbated, in coronary resistance vessels from rabbits with LV hypertrophy compared to controls. The mitral valve of 10 rabbits was damaged surgically to cause mitral regurgitation and chronic volume overload, resulting in LV hypertrophy (LV hypertrophy rabbits). Echocardiographic assessment at 12 weeks verified that mitral regurgitation was present in LV hypertrophy but not sham-operated, weight- and age-matched animals (control rabbits; n = 17). Percentage increases from weeks 0 to 12 in LV cross-sectional area (47 +/- 7 % vs. 2 +/- 8 %), LV volume (47 +/- 14 % vs. 7 +/- 10 %) and LV mass (27 +/- 4 % vs. 3 +/- 6 %), were greater (all P < 0.05) in LV hypertrophy vs. control rabbits, respectively. At 12 weeks, coronary resistance vessel (approximately 130 microm, internal diameter) reactivity was evaluated using wire myography. Endothelium-dependent (i.e. acetylcholine, 10(-8)-10(-5) M) and -independent (i.e. sodium nitroprusside, 10(-9)-10(-4) M) relaxation, and receptor-mediated vasocontraction (i.e. endothelin-1, 10(-11)-10(-7) M) were similar between groups. However, tension development in response to nitric oxide synthase inhibition (10(-6) M N (G)-monomethyl-L-arginine) was greater (P < 0.05) in LV hypertrophy compared to control rabbits. These results indicate that while coronary resistance vessel function is similar between groups, our estimate of basal nitric oxide production is greater in vessels from LV hypertrophy than control rabbits.     

The effect of exercise on atherosclerosis in the coronary artery and abdominal aorta of mature female swine

Summary This study investigated the effects of chronic exercise on atherosclerosis in the aorta and coronary artery in mature female swine. Preceding and during the exercise training period these animals were fed high fat, (soybean or corn oil) cholesterol-free diets. Sixteen swine were paired according to breed, body weight, and diet. Eight swine were a non-exercise control group while the remaining eight were an experimental group and exercised 4 days per week for 4 months. The exercise training program initially consisted of running at 5.6 km·h⁻¹, zero gradient, for 15 min with increments of 1 min of running time every 2 weeks. The amount of atherosclerosis in the coronary artery and abdominal aorta was determined directly. Plasma lipids, body weight, body potassium, and percent fat were recorded at three intervals during the training program. Four months of exercise had no significant effect on plasma cholesterol, phospholipids, total lipids or triglycerides, although there was a significant effect of test periods on cholesterol. Diet was found to have no influence on plasma lipids. The exercise group did not have larger heart weights, ratio of heart weight to body weight or ratio of heart weight to fat-free body weight. The percent lipid in the lesion area and the lesion surface area of the abdominal aorta was not significantly different between the two groups. The amount of lipid obtained from the intima-media of the coronary artery and the lesion area involvement was not significantly different between the exercise group and the non-exercise group. It is concluded that 4 months of exercise had no effect on plasma lipids, body potassium, body weight, or coronary and aortic atherosclerosis.     

Effect of exercise on the bone strength, bone mineral density, and metal content in rat femurs

We have investigated the effect of exercise on the bone strength, bone mineral density (BMD), and metal content in rat femurs. Five Wister rats acting as an exercised group (E group) were exercised at intervals on a treadmill every day for four weeks. Another five rats were fed in a cage, acting as a control group (C group), without any exercise. After four weeks, the bend strength, Young's modulus, BMD value, and metal content of the femurs were measured using a three-point bend test, Dual-Energy X-ray Absorptiometry (DEXA), and chemical analysis. The bend strength of the E group was 101+/-5 MPa, and that of the C group was 86+/-7 MPa. The Young's modulus was 1.16+/-0.03 GPa for the E group, and 0.98+/-0.06 GPa for the C group. The BMD values were 0.179+/-0.002 g/cm(2) for the E group, and 0.166+/-0.002 g/cm(2) for the C group. The Ca concentration was 230600 +/- 1500 microg/g for the E group, and 223000 +/- 2700 microg/g for the C group. The Zn concentration was 160 +/- 7 microg/g for the E group, and 188 +/- 8 microg/g for the C group.     

Exercise stress testing in angina patients with positive response to hyperventilation testing: influence of the coronary artery tone

We studied the exercise stress test and the coronary artery tone in two groups of angina patients with comparable coronary atherosclerosis. Group I (20 males and 5 females, mean age 53.5 years) with a positive, and group II (22 males and 3 females, mean age 52.5 years) with a negative response to the hyperventilation test (HVT). A positive exercise stress test (ST depression greater than or equal to 1 mm) was found in 24 patients in group I vs. 15 in group II (p less than 0.01), despite a lower maximal rate pressure product (198 +/- 11.2 vs. 236 +/- 10.1, p less than 0.05) and maximal work load (110 W +/- 7.1 vs. 136 +/- 7.4 W, p less than 0.02) in group I. A high coronary artery tone (dilatation (DIL%) of the coronary arteries after nitroglycerin greater than or equal to 10%) was found in 18 patients in group I and in 4 in group II (p less than 0.01). DIL% was 22.6 +/- 3.8 vs. 5.8 +/- 1.4 in groups I and II, respectively (p less than 0.005). DIL% was significantly related to persistence of ST depression after exercise (r = 0.36, p less than 0.05), and 21 of 22 patients with high tone had a positive exercise stress test vs. 18 of 28 with low tone (p less than 0.05). These findings suggest that the coronary artery tone influences the response to exercise in some patients with angina. Since the patients in group I were identified by HVT, our results underline the clinical relevance of this test.     

In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries

The mechanism by which tolerance to the clinical effects of organic nitrates develops has not been elucidated. This study was done to determine whether an intravenous infusion of nitroglycerin induces tolerance in the coronary vascular bed and whether such tolerance is reversed by the sulfhydryl-group donor N-acetylcysteine. We studied 19 subjects--17 with coronary artery disease and 2 without it--who had a mean age (+/- SD) of 54 +/- 9 years. Coronary sinus blood flow, which approximates blood flow to the left ventricle, was measured before and during intracoronary injections of nitroglycerin (10, 25, 50, and 100 micrograms). The patients then received a 24-hour intravenous infusion of saline (n = 7) or of nitroglycerin, 45 +/- 13 micrograms per minute (n = 12), after which the responses of coronary sinus flow to the same doses of intracoronary nitroglycerin used earlier were measured. In the seven patients given saline, the four doses of intracoronary nitroglycerin caused similar percentage increases in coronary sinus flow before and after the saline infusion. In the 12 patients given intravenous nitroglycerin, the four intracoronary doses caused percentage increases in coronary flow before the infusion of 30 +/- 9, 35 +/- 14, 41 +/- 12, and 52 +/- 15, respectively. After the infusion, the same doses of nitroglycerin caused smaller (P less than 0.05) percentage increases (16 +/- 6, 21 +/- 11, 23 +/- 12, and 27 +/- 11, respectively), indicating the development of partial tolerance. Subsequently, 7 of the 12 patients received N-acetylcysteine, after which intracoronary nitroglycerin caused percentage increases in coronary sinus flow similar to the values measured before the intravenous nitroglycerin was given (34 +/- 13, 32 +/- 8, 38 +/- 11, and 44 +/- 16, respectively). We conclude that the coronary vasodilator effect of nitroglycerin is attenuated by an intravenous infusion of nitroglycerin (that is, partial tolerance develops) and that tolerance to the agent can be reversed by administration of the sulfhydryl-group donor N-acetylcysteine. The mechanism by which N-acetylcysteine reverses tolerance will require further investigation.     

Exercise training enhances relaxation of the isolated guinea-pig saphenous artery in response to acetylcholine

The effects of exercise training were investigated on the vascular responses in the isolated guinea-pig saphenous artery. Exercising animals swam 5 days week-1 for 6 weeks (60 min day-1 for weeks 1 and 2; 75 min day-1 for weeks 3 and 4; 90 min day-1 for weeks 5 and 6), while control animals were placed into shallow water for the same duration. Trained animals had significantly higher ventricular:body weight ratios, increased citrate synthase activity in the latissimus dorsi, and enhanced Na+ pump concentrations in the latissimus dorsi and gastrocnemius muscles (P < 0.05). In vitro isometric techniques were used to measure constriction and relaxation responses of saphenous artery rings from trained and control animals. There were no significant differences in the constriction responses to KCl (50 mm) and phenylephrine (0.3-100 microM) in arterial rings from control versus trained animals. Relaxation responses to acetylcholine (10 microM; ACh-relaxation), following preconstriction with phenylephrine (10 microM), were significantly enhanced in rings from trained animals (P < 0.05). Acetylcholine relaxed the vessels to 47 +/- 6% (control) and 18 +/- 3% (trained) of the preconstriction responses to phenylephrine. The nitric oxide synthase inhibitor N G-nitro-L-arginine (L-NA; 50 microM) significantly attenuated the ACh-relaxation in control and trained animals (P < 0.05). The effect of L-NA on the ACh-relaxation was significantly larger in trained (change in ACh-relaxation with L-NA = 29 +/- 9%) than control (14 +/- 3%) animals (P < 0.05). In conclusion, exercise training enhanced the ACh-relaxation of the isolated guinea-pig saphenous artery. Inhibition of nitric oxide synthase attenuated the ACh-relaxation of rings from control and trained animals, but this effect was significantly larger in the vessels from trained animals. These results are consistent with the idea that nitric oxide could contribute to the enhanced ACh-relaxation of the saphenous artery with exercise training.     

Secondary coronary artery vasospasm promotes cardiomyopathy progression

Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of gamma-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of gamma-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated gamma-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, gamma-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 +/- 13.3% treated versus 37.4 +/- 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 +/- 27.9 cm/second versus 92.8 +/- 22.7 cm/second), and cardiac index (1.06 +/- 0.30 ml/minute/g versus 0.67 +/- 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression.