Exercise-induced and nitroglycerin-induced myocardial preconditioning improves hemodynamics in patients with angina

In humans, regional myocardial dysfunction during ischemia may be improved by ischemic and pharmacological preconditioning. We assessed the possibility that exercise- and nitroglycerin-induced myocardial preconditioning may improve global cardiac performance during subsequent efforts in patients with angina. Ten patients suffering from chronic stable angina and ten healthy volunteers were studied. Through impedance cardiography we assessed hemodynamics during a maximal exercise test, which was used as a baseline (Bas test) and considered as a preconditioning exercise. The Bas test was followed by a sequence of maximal efforts performed during the first (FWOP; 30 min after the Bas test) and second (SWOP; 48 h after the Bas test) windows of protection conferred by ischemic preconditioning. Hemodynamics was further evaluated during maximal exercise performed 48 h later with pharmacologically induced SWOP (PI-SWOP) obtained by transdermal administration of 10 mg of nitroglycerin. In the angina patients, FWOP, SWOP, and PI-SWOP delayed the time to ischemia and allowed them to achieve higher workloads compared with the Bas test. Furthermore, heart rate and cardiac output at peak exercise were enhanced during all the preconditioning phases with respect to the Bas test. However, only SWOP and PI-SWOP increased myocardial contractility and stroke volume. No changes in hemodynamics were detectable in the control subjects. This study demonstrates that in patients with stable angina, although hemodynamics during exercise can be positively improved during both FWOP and SWOP, differences exist between these two phases. Furthermore, the mimicking of exercise-induced SWOP by PI-SWOP with transdermal nitroglycerin may represent an important clinical aspect.     

Comparison of Adrenergic Beta-blocking Drugs in Angina Pectoris

The symptomatic, electrocardiographic, and haemodynamic effects of two adrenergic beta-blocking drugs, oxprenolol and propranolol, have been compared in equipotent intravenous doses in six patients with uncomplicated angina pectoris during treadmill exercise. The method of comparison included double-blind assessment and analysis with placebo control and randomized serial comparison in each patient. Both drugs produced an equal amelioration in symptoms in most of the patients. This was closely correlated with improvement in the electrocardiographic changes and a significant reduction in the exercising heart rate and systemic arterial pressure. This method of double-blind combined subjective and objective assessment carries distinct advantages in the comparative assessment of drug treatments in angina pectoris.     

Exertional gastro-oesophageal reflux: a mechanism for symptoms in patients with angina pectoris and normal coronary angiograms.

During 24 hour oesophageal pH monitoring 52 patients who had angina pectoris and normal coronary angiograms underwent exercise testing, as far as their symptoms allowed, on a treadmill to determine whether gastro-oesophageal reflux occurred during exertion. In 11 patients the 24 hour oesophageal pH score was abnormally high; 10 of these showed exertional gastro-oesophageal reflux, and in nine this was associated with their usual chest pain. A further 13 patients had a normal 24 hour pH score but had exertional reflux coincident with chest pain during exercise testing. The mean lower oesophageal sphincter pressure in both of these groups of patients was appreciably lower than that in 28 patients who had a normal 24 hour pH score and no exertional reflux. These findings suggest that exertional gastro-oesophageal reflux accounts for the symptoms of a large proportion of patients who have angina pectoris and normal coronary angiograms and that oesophageal pH monitoring during exercise testing on a treadmill enables this group of patients to be identified.     

High-dosage isosorbide dinitrate therapy for angina.

We investigated the possibility that high dosages (480 mg/d) of isosorbide dinitrate might reduce the frequency of angina attacks in selected patients who had not responded to low dosages of the drug (40 mg/d), and that the patients could tolerate the high levels of medication and maintain their responsiveness over the long term. In the single-blind phases of this trial 24 patients with grade 3 stable angina pectoris were given a placebo for 4 weeks and then increasing doses of isosorbide dinitrate for a further 6 weeks. The 19 patients who both responded to and tolerated high doses of the drug kept taking 480 mg/d for an average of 1 year. The average weekly rate of angina attacks fell by 74%, from 6.05 in the placebo phase to 1.6 during long-term active treatment (p less than 0.01). Nitroglycerin consumption decreased accordingly. The patients'' assessments of their levels of activity and well-being and their angina thresholds showed improvement among most of them. The trend of angina frequency was stable in 12 cases, downward in 6 and upward in only 1 case. Exercise performance as evaluated by a graded treadmill test showed a small but nonsignificant improvement of 18%. It was concluded that some patients who do not respond to the antianginal action of low-dosage isosorbide dinitrate and cannot be given beta-blockers may respond to high dosages and tolerate them for over a year. Isosorbide dinitrate may be clinically useful in patients with coronary heart disease even though their exercise performance is not significantly improved.     

Additive antianginal effect of verapamil in patients receiving propranolol

Ten men with stable angina pectoris not fully relieved by optimal doses of propranolol (mean 218 mg daily) were given a single oral dose of 120 mg verapamil or a placebo on alternate mornings; the order of treatment was double blind. Patients had trained in a protocol that precipitated angina after three to six minutes of exercise on a bicycle ergometer. On test days, and with continued propranolol treatment, bicycle exercise was performed just before the administration of verapamil or placebo and hourly thereafter for eight hours. Mean exercise tolerance was 118 seconds greater one hour after verapamil than one hour after placebo (p <0·001), and a significant though somewhat diminished difference of 66 seconds was still present at six hours (p <0·01). Verapamil lowered resting systolic blood pressure by 12 mm Hg (p <0·01) without changing heart rate. None of the 10 patients showed adverse effects from the verapamil-propranolol combination.The results of this study suggest that verapamil is a highly effective antianginal supplement to propranolol.     

Nifedipine does not impair the hormonal responses to graded exercise in healthy subjects

The aim of this study was to assess whether the potent calcium antagonist nifedipine was capable of modifying the hormonal response to graded exercise in 7 healthy young men. After fasting overnight, each subject came to the laboratory on 2 consecutive mornings. On one day he was given 10 mg of nifedipine sublingually and on the other an identical placebo capsule; the order was randomised in a double-blind fashion over the 2 days. Thereafter each subject performed 2 successive short treadmill runs, equivalent to 60 and 100%, respectively, of maximal aerobic power. While significantly blunting the rise in mean systolic blood pressure and inducing a greater fall in diastolic blood pressure during and after exercise compared with the placebo, nifedipine did not impair the brisk response to pituitary-adrenal hormones (ACTH, cortisol and total catecholamines). Nifedipine also did not modify the effects of short-term exercise in raising mean plasma glucose levels, stimulating pancreatic glucagon secretion and producing a delayed increase in plasma insulin concentrations. Nor did the drug blunt the significant rise of growth hormone and prolactin levels occurring during and after the treadmill run. It was concluded that, apart from inducing significant changes in blood pressure, a single dose of nifedipine does not appear to suppress the counterregulatory hormonal responses to short-term physical activity in healthy men.     

Effects of naloxone on exercise performance

This study was designed to investigate the effects of naloxone on athletic performance in humans. Two groups of elite middle-distance runners performed a maximal or a submaximal exercise protocol following the double-blind intravenous injection of either naloxone (0.15 mg X kg body wt-1) or saline. The maximal test (group M) was comprised of a short-duration treadmill run to maximal intensity; the submaximal test (group S), a prolonged submaximal treadmill run to exhaustion. O2 uptake, heart rate, ventilation, and perceived exertion were determined during each test. Perception of pain was assessed after exercise by use of a modified McGill pain questionnaire. No significant differences between placebo and naloxone treatments were found in any of the measured variables at the usually accepted 5% (P = 0.05) confidence level; however, evidence suggesting differences (i.e., P = 0.1 to 0.05) in these important respects was observed. In group M, maximal exercise performance measured by maximal O2 consumption was not different between placebo and naloxone; results suggest that VE was increased (P = 0.08) following naloxone, but only at the final work stage. In group S, exercise performance time was reduced following naloxone (P = 0.09), whereas the affective component of pain was increased (P = 0.06); no differences in the measured physiological variables were observed. These results suggest the following: 1) the opiate receptor-endorphin system may alter the perception of pain associated with prolonged high-intensity submaximal exercise with a resultant significant effect on performance; and 2) it may play a role in the control of ventilation during maximal exercise.     

Effect of partial agonist activity in beta blockers in severe angina pectoris: a double blind comparison of pindolol and atenolol.

The use of beta adrenoceptor blockade in the treatment of rest angina is controversial, and the effects on severe angina of partial agonist activity in beta blockers are unknown. Eight patients with effort angina and seven with effort and nocturnal angina and severe coronary artery disease were studied initially when they were not taking any antianginal drugs. Pindolol 5 mg thrice daily (with partial agonist activity) and atenolol 100 mg daily (without partial agonist activity) were given for five days each in a double blind randomised manner. Diaries of angina were kept and treadmill exercise testing and ambulatory ST monitoring performed during the last 48 hours of each period of treatment. Daytime and nocturnal resting heart rates and the frequency of angina were significantly reduced by atenolol compared with pindolol (p less than 0.01). The duration of exercise was significantly increased and the frequency, duration, and magnitude of daytime and nocturnal episodes of ST segment depression on ambulatory monitoring were reduced by atenolol. Reduction in resting heart rate is important in the treatment of both effort and nocturnal angina. Partial agonist activity in beta adrenoceptor antagonists may be deleterious in patients with severe angina pectoris.     

心可舒胶囊联合氯吡格雷对冠心病心绞痛患者血管内皮功能、血液流变学及炎症因子的影响

摘要 目的：观察心可舒胶囊联合氯吡格雷对冠心病心绞痛患者血管内皮功能、血液流变学及炎症因子的影响。方法：选取2020年3月~2021年10月期间中国人民解放军东部战区总医院收治的92例冠心病心绞痛患者。按照信封抽签法分为对照组（46例）和观察组（46例）。对照组患者接受氯吡格雷治疗,观察组接受心可舒胶囊联合氯吡格雷治疗,对比两组疗效、血管内皮功能、血液流变学、炎症因子、心绞痛发作频率、硝酸甘油用量、心绞痛发作持续时间及不良反应。结果：与对照组相比,观察组治疗1个月后的临床总有效率更高（P<0.05）。与对照组相比,观察组治疗1个月后全血黏度、血浆比黏度、红细胞聚集指数更低（P<0.05）。与对照组相比,观察组治疗1个月后内皮素-1（ET-1）更低,一氧化氮（NO）更高（P<0.05）。与对照组相比,观察组治疗1个月后白介素-6（IL-6）、超敏C反应蛋白（hs-CRP）、单核细胞趋化蛋白-1（MCP-1）更低（P<0.05）。与对照组相比,观察组治疗1个月后心绞痛发作频率、硝酸甘油用量更少,心绞痛发作持续时间更短（P<0.05）。两组不良反应发生率组间对比无统计学差异（P>0.05）。结论：心可舒胶囊联合氯吡格雷可改善冠心病心绞痛患者临床症状,改善血管内皮功能和血液流变学,降低炎症因子水平,效果显著。     

尼可地尔对冠心病合并2型糖尿病不完全血运重建术后的疗效观察

目的:比较尼可地尔与单硝酸异山梨酯对冠心病合并2型糖尿病患者不完全血运重建术后的疗效。方法:入选112例经皮冠状动脉介入治疗(PCI)部分血运重建的冠心病合并2型糖尿病患者。随机分为2组:尼可地尔组(5 mg,3次/d,口服)60例,单硝酸异山梨酯组(50 mg,1次/d,口服)52例,两组患者均给予常规冠心病及糖尿病药物治疗。术后4周末行运动负荷试验,观察总运动时间,从开始运动到出现ST段压低1.0 mv和出现心绞痛的时间(s),以及最大ST段压低幅度,同时记录每周心绞痛发作次数及硝酸甘油用量。结果:4周后两组患者同服药前比较,从开始运动到出现ST段压低1.0 mv的时间延长,总运动时间延长,从开始运动到出现心绞痛的时间延长,最大ST段压低幅度降低(P0.01),但尼可地尔组与单硝酸异山梨酯组比较无明显统计学差异(P0.05);尼可地尔组每周心绞痛发作次数及硝酸甘油用量明显少于单硝酸异山梨酯组(P0.05)。结论:尼可地尔可增加冠心病合并糖尿病患者行不完全血运重建术后患者运动耐量,在减少心绞痛方面作用优于单硝酸异山梨酯。     

Animal pharmacology of nitroglycerin

Nitroglycerin, first introduced over a hundred years ago, is now finding wider clinical applications. To a large degree, the renewed interest in the clinical pharmacologic usage of nitroglycerin is due to the availability of new formulations and drug delivery systems. The current review focuses on the physiological and pharmacological actions of nitroglycerin in mammals. Routes of nitroglycerin metabolism, biochemistry and absorption are discussed. The phenomenon of nitroglycerin tolerance is illustrated and related to specific quantitative alterations occurring at the cellular level. The cardiovascular effects of nitroglycerin are discussed in terms of its effects on coronary flow, the myocardium itself, and on the peripheral vasculature. The early speculation of Murrell (3) that nitroglycerin “would probably prove of service in the treatment of angina pectoris…and other vascular disorders…” has now been realized.     

Comparison of Adrenergic Beta-receptor Antagonists in Angina Pectoris

The symptomatic, electrocardiographic, and circulatory effects of intravenous and oral preparations of propranolol, oxprenolol, and practolol were compared in 16 patients with uncomplicated angina pectoris precipitated by exertion. The method of study included treadmill exercise, double-blind assessment, single-blind analysis, with placebo control and randomized serial comparison of each drug in each patient. The doses used were selected to give the same near-maximum suppression of the heart rate response to exercise. The symptomatic, electrocardiographic, and circulatory response of each patient to both preparations of each of the three drugs was similar. Exercise tolerance was increased in two-thirds, unchanged in one-sixth, and significantly worsened in one-sixth of the studies. Electrocardiographic evidence of myocardial ischaemia was conspicuously reduced by all three drugs in most studies irrespective of their symptomatic effects. Though the exclusive choice of patients, the single dose design of the trial, and the treadmill method of assessment limit the general application of these results, they do clearly indicate that in doses that induce equal suppression of the exercise heart rate these three drugs have similar distinct anti-anginal activity. Their ancillary pharmacological properties are probably of little importance in this respect. Equally, the similarity in the symptomatic, circulatory, and electrocardiographic response to the intravenous and oral preparations suggests that metabolic breakdown products are probably of therapeutic importance only in so far as they antagonize beta-receptor activity.     

Effect of naloxone on exercise-induced angina pectoris: a randomized double blind crossover trial

To determine whether endogenous opioids play a role in modulating the appreciation of chest pain in angina pectoris, the specific opioid antagonist, Naloxone, was used. The hypothesis was that the appearance time of ischemic myocardial pain should decrease after Naloxone if centrally mediated pain perception is significantly influenced by the endorphin system in angina pectoris. A randomized double blind clinical trial was conducted in 5 men with effort-induced angina pectoris associated with ST segment changes. Three multi-stage exercise tests, using the Bruce protocol were performed on the same day and time, on three successive weeks. Chest pain was reported 4.3 +/- 0.3 (SEM) minutes after starting exercise on the first or baseline test. On subsequent tests patients received either Naloxone 2 mg IV or a similar volume of saline placebo. Angina pectoris occurred significantly (p. less than 0.05) earlier (1.6 +/- 0.2 minutes) after Naloxone compared to placebo. There were no significant differences in myocardial ischemia indicated by ST segment changes and no significant differences in resting or exercise blood pressure and heart rate between Naloxone and placebo. Thus, these data focus attention on a neglected area of myocardial ischemic pain and suggest that endogenous opioids play a significant role in the recognition of the pain of effort-related angina pectoris.     

Assessment of dermal glyceryl trinitrate and isosorbide dinitrate for patients with angina pectoris.

Dermal nitrate preparations are claimed to be useful in the treatment of angina, as their slow absorption by-passing the liver leads to a sustained action. Ten patients with angina were exercised on a treadmill after dermal application of 16.64 mg glyceryl trinitrate or 100 mg isosorbide dinitrate or placebo. Exercise duration was significantly increased at one and three hours for both nitrate preparations but not at six hours after application. The calculated workload achieved was significantly increased (p less than 0.01) at one and three hours for both preparations and at six hours (p less than 0.05) for isosorbide dinitrate. Headaches were common with glyceryl trinitrate cream. The dermal nitrate preparations studied had a duration of antianginal action similar to that of oral nitrate tablets. Aside from their value when the oral route cannot be used or absorption may be delayed, dermal nitrate preparations have no advantage over oral preparations for angina pectoris.     

Objective assessment of antianginal treatment: a double-blind comparison of propranolol,nifedipine, and their combination.

In a double-blind clinical trial the antianginal effects of nifedipine (30 and 60 mg/day) and propranolol 240 and 480 mg/day) and a combination of both drugs were compared with those of placebo in 16 patients with severe exertional angina pectoris. Response to treatment was assessed by the objective criteria of 16-point precordial exercise mapping and 48-hour ambulatory electrocardiographic monitoring and subjectively by analysis of patients'' daily diaries of episodes of angina and consumption of glyceryl trintrate. The incidence of pain and consumption of glyceryl trinitrate were significantly decreased by each drug compared with placebo, and the combination produced a further significant improvement. Objectively the total area and amount of ST depression on the precordial exercise map and the total number of episodes of ST depression detected on ambulatory monitoring confirmed the efficacy of each treatment regimen; the combination was significantly better than either drug alone (p <0.005). The objective methods permitted greater separation of treatment efficacy and showed reliably that the combination of propranolol and nifedipine was significantly better than either drug alone. Thus this combination is a safe and effective form of treatment for angina.     

Supine lower body negative pressure exercise during bed rest maintains upright exercise capacity.

Bed rest and spaceflight reduce exercise fitness. Supine lower body negative pressure (LBNP) treadmill exercise provides integrated cardiovascular and musculoskeletal stimulation similar to that imposed by upright exercise in Earth gravity. We hypothesized that 40 min of supine exercise per day in a LBNP chamber at 1.0-1.2 body wt (58 +/- 2 mmHg LBNP) maintains aerobic fitness and sprint speed during 15 days of 6 degrees head-down bed rest (simulated microgravity). Seven male subjects underwent two such bed-rest studies in random order: one as a control study (no exercise) and one with daily supine LBNP treadmill exercise. After controlled bed-rest, time to exhaustion during an upright treadmill exercise test decreased 10%, peak oxygen consumption during the test decreased 14%, and sprint speed decreased 16% (all P < 0.05). Supine LBNP exercise during bed rest maintained all the above variables at pre-bed-rest levels. Our findings support further evaluation of LBNP exercise as a countermeasure against long-term microgravity-induced deconditioning.     

Double-blind comparison of tolamolol,propranolol, practolol,and placebo in the treatment of angina pectoris.

Forty-two patients with angina pectoris have completed a randomized, double-blind trial comparing tolamolol 100 mg and 200 mg with propranolol 80 mg, practolol 100 mg, and placebo, all given three times a day. Tolamolol 200 mg thrice daily was found to be equivalent to propranolol 80 mg thrice daily in anti-anginal efficacy. Anginal attack rates and trinitrin consumption were significantly reduced by all active treatments as compared with the placebo but tolamolol and propranolol were the most effective. Tolamolol 200 mg thrice daily was most effective in reducing blood pressure, while propranolol was most effective in reducing the resting heart rate. All treatments except the placebo significantly increased the amount of exercise which could be performed before angina appeared (exercise work), while tolamolol 200 mg thrice daily significantly reduced Robinson''s index when compared with all other active agents. The degree of S-T segment depression induced by exercise was significantly lessened by both tolamolol and propranolol but not by practolol or placebo. There was no difference in patient preference between tolamolol and propranolol but tolamolol at both dose levels was preferred to practolol. Both tolamolol and propranolol are potent adrenergic beta-receptor antagonists and equal in anti-anginal efficacy but tolamolol has the advantage of being cardioselective. It is superior to practolol.     

Increased exercise tolerance with nitrates in beta-blockaded patients with angina.

In 14 beta-blockaded anginal subjects, 10 of whom had poor left ventricular function, sublingual isosorbide dinitrate significantly increased maximal exercise capacity on a standardized multistage treadmill test. This was associated with changes in heart rate and blood pressure suggestive of a fall in left ventricular work. The effect of isosorbide lasts for at least two hours and when taken before exercise may be a useful addition to beta-blockade in patients with angina.     

Influence of acetaminophen consumption and exercise on Achilles tendon structural properties in male Wistar rats

Chronic consumption of acetaminophen (APAP) during exercise training leads to a reduction in tendon stiffness and modulus compared with a placebo. We explored whether this effect could be due to a reduction in tendon collagen content or cross-linking. Ten-week-old male Wistar rats (n = 50) were divided into placebo or APAP groups and into sedentary or treadmill-exercised groups. APAP (200 mg/kg) or saline was administered once daily by oral gavage. Rats in the exercise groups ran on a treadmill 5 days per week for 8 wk with progression to 60 min per day, 20 m/min, and 8° incline. After 8 wk, lyophilized Achilles tendon samples were assayed for the collagen-specific amino acid hydroxyproline and cross-linking [hydroxylyslpyridinoline (HP)] content by high-performance liquid chromatrography. Collagen content was not influenced by exercise or APAP (P > 0.05). Compared with placebo, tendon water content was 7% (P = 0.006, main effect) lower in animals consuming APAP (placebo: 54.79 ± 0.8%, APAP: 50.89 ± 1.2%). HP in the Achilles tendon was 36% greater (sedentary: 141 ± 15, exercise: 204 ± 26 mmol/mol collagen) in the exercise-trained rats independent of drug treatment (P = 0.020, main effect). Independent of exercise, HP content was 33% lower (P = 0.032, main effect) in the animals consuming APAP (placebo: 195 ± 21, APAP: 140 ± 19 mmol/mol collagen). Our data suggests that chronic consumption of APAP results in a reduction in collagen cross-linking and a loss of tissue water independent of chronic exercise. This reduction in cross-linking and water content could contribute to the decrease in tendon stiffness noted in humans chronically consuming APAP.     

Antioxidant supplementation influences the neutrophil tocopherol associated protein expression, but not the inflammatory response to exercise

Intense exercise induces inflammatory-like changes and oxidative stress in immune cells. Our aim was to study the effects of antioxidant diet supplementation on the neutrophil inflammatory response and on the tocopherol associated protein (TAP) expression after exhaustive exercise. Fourteen male-trained amateur runners were randomly divided in two placebo and supplemented groups. Vitamins C (152 mg/d) and E (50 mg/d) supplementation were administrated to the athletes for a month, using an almond based isotonic and energetic beverage. Non-enriched beverage was given to the placebo group. After one month, the subjects participated in a half-marathon race (21 km-run). Neutrophil TAP mRNA expression and markers of the inflammatory response were determined before, immediately after, and 3 h after finishing the half-marathon race. TAP expression increased after exercise mainly in the neutrophils of the placebo group. Exercise induced an inflammatory response in both placebo and supplemented groups, manifested with neutrophilia, increased creatine kinase and lactate dehydrogenase serum activities, neutrophil luminol chemiluminescence and myeloperoxidase release. Plasma malondialdehyde only increased in the placebo group after exercise. Diet supplementation with moderate levels of antioxidant vitamins avoids plasma damage in response to exhaustive exercise without the effects on the inflammatory process. Neutrophil degranulation and increased tocopherol associated protein could contribute to the neutrophil protection from the oxidative stress.