Antianginal Effects Research Articles

Comparison of trimetazidine with nifedipine in effort angina: A double-blind, crossover study

Trimetazidine has been shown to have an antianginal effect, increasing exercise capability without producing any significant change of heart rate or systolic blood pressure. The aim of this study was to compare trimetazidine efficiency to that of another classical antianginal drug. A double-blind crossover trimetazidine versus nifedipine trial was carried out in 39 male patients, mean age 58 years, with effort angina for 5 years on average, and a mean number of weekly attacks of 2.4. Thirteen patients had previous myocardial infarction. Nineteen patients received nifedipine (40 mg per day) then trimetazidine (60 mg per day), and 20 patients received the drugs in the opposite order. Each therapeutic period of 6 weeks was preceded by 1 week of washout with placebo. Drug efficacy was assessed by a bicycle exercise tolerance test, performed at the beginning and at the end of each therapeutic period, and by clinical symptoms observed with placebo or with treatment. The statistical analysis was performed according to a crossover design, with repeated measurements. The decrease of the number of weekly attacks was not significantly different with trimetazidine and nifedipine. Results on the exercise test showed no significant differences for maximum workload, the duration of exercise, ST-segment depression at peak exercise, and the time to 1-mm ST-segment depression. Heart rate and systolic blood pressure were not significantly different at rest and at peak exercise. However, the change in the rate-pressure product at the same workload differed significantly between the drugs: It decreased with nifedipine and remained unchanged with trimetazidine, indicating the difference to be in the mode of action of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology and therapeutic effects of nicorandil

Nicorandil, a nicotinamide derivative, is an orally efficacious antianginal drug possessing a nitrate moiety in its chemical structure. This drug is an effective and well-tolerated treatment for various types of angina pectoris. Its general efficacy is similar to that of nitrates, with several unique effects on the cardiovascular system. Nicorandil causes sustained dilation of both the arterial resistance and conductive vessels, thus markedly dilating the coronary artery and increasing coronary blood flow. In addition, nicorandil, unlike nitroglycerin or isosorbide dinitrate, possesses little hemodynamic effect on heart rate, blood pressure, or cardiac contractility with clinical doses yielding antianginal effects. The mechanism causing coronary vasodilation has not been completely clarified but appears to be associated partly with increases in c-GMP, as well as the hyperpolarization of the smooth muscle membrane. Nicorandil, in single oral doses of 10-30 mg, has been shown to be effective in chronic stable angina, as assessed objectively by increases in exercise duration and/or the time to onset of ST-segment depression during treadmill exercise. In open studies and controlled efficacy evaluations, nicorandil in daily oral doses of 15-40 mg demonstrated significant effectiveness in the treatment of various types of angina pectoris. Headaches due to vasodilation may occur, and some side effects occurred in 5.1-34% of patients receiving nicorandil, but were generally minor in nature. There was no depressant effect on atrioventricular conduction, which occurs frequently in patients treated with calcium antagonists of the verapamil and diltiazem type. Nicorandil may be effective even in patients with rest and effort angina who do not respond to combination therapy with calcium antagonists and oral nitrates. Thus, nicorandil appears to be a valuable addition to the arsenal of antianginal drugs due to its low incidence of serious side effects.

Antianginal, hemodynamic and coronary vascular effects of captopril in stable angina pectoris

A pilot study was performed to assess the short-term effects of intravenous captopril on anginal threshold and systemic and coronary hemodynamics in patients with stable angina pectoris. Twelve patients with documented coronary artery disease, stable angina pectoris and normal left ventricular function were studied by an incremental atrial pacing stress test before and after intravenous captopril (n = 8) or placebo (n = 4). There were no significant differences in the extent of coronary disease or left ventricular function between the 2 groups and resting plasma-renin levels were normal. Captopril increased the time to angina (14 ± 4 to 19 ± 5 minutes, p <0.05), increased heart rate at development of angina (126 ± 7 to 142 ±7 beats/min, p <0.05) and tended to increase coronary blood flow (229 ± 154 to 296 ± 259 ml/min, p = 0.11) and decrease coronary vascular resistance (53 ± 10 to 47 ± 3 dynes s cm −5/1,000, p = 0.11) at peak stress without alteration in systemic hemodynamics. No significant changes were seen after placebo administration. Therefore, intravenous captopril appears to cause a short-term increase of coronary vascular reserve, and anginal threshold in patients with chronic stable angina. This effect appears to be independent of inhibition of the systemic renin-angiotensin system or systemic hemodynamic changes.

Does N-acetylcysteine modify haemodinamic and antianginal effects of nitroglycerin?

Does N-acetylcysteine modify haemodinamic and antianginal effects of nitroglycerin?

Randomized double-blind comparison of isosorbide dinitrate and nifedipine in variant angina pectoris

The antianginal and anti-ischemic effect of isosorbide dinitrate (ISDN), 120 mg once daily, and nifedipine, 20 mg twice daily, both in slow-release formulations, were compared in 17 patients with variant angina pectoris in a randomized, double-blind trial. The design included a placebo run-in period and two 6-week crossover periods of active treatment. Mean frequency of angina decreased significantly from 43 attacks per week during the placebo period to 4 per week with ISDN and 8 with nifedipine (p < 0.001). Sublingual nitroglycerin consumption decreased significantly from 37 tablets per week with placebo to 3 tablets per week with ISDN and 7 with nifedipine (p < 0.001). Both drugs reduced the silent and symptomatic ST-segment deviations on ambulatory electrocardiographic recording and increased maximal exercise tolerance. Episodes of coronary spasm could be provoked, by hyperventilation, in all patients during the placebo phase but in no patient during therapy with either active drug. Thus, both ISDN and nifedipine, in their slow-release formulations, are effective in the treatment of variant angina pectoris.

Evaluation of the efficacy and duration of action of isosorbide mononitrate in angina pectoris

The magnitude and duration of the antianginal and anti-ischemic effects of isosorbide mononitrate (IS-5-MN), 20 mg, were determined in 10 patients with chronic stable angina pectoris. An exercise test (treadmill, Brace protocol) was performed before and at 1, 6,8 and 10 hours after oral administration of the drug. The patients were randomly assigned to receive IS-5-MN or placebo, and after 1 week of therapy were crossed over to the other formulations. The drag increased the exercise duration from 321 to 455 seconds at 1 hour (p < 0.001). Time to moderate angina increased from 237 to 324 seconds (p < 0.05) and time to ST depression ≥1 mm increased from 150 to 307 seconds (p < 0.01) at 1 hour. Placebo had no effect on any of the exercise parameters. Although partially attenuated at 6 hours, the effect of IS-5-MN remained statistically significant even at 8 hours, but not at 10 hours. It is concluded that the duration of action of a single tablet of IS-5-MN, given orally, is 8 hours.

Comparison of the effects of a controlled-release formulation of isosorbide-5-mononitratt and conventional isosorbide dinitrate on exercise performance in men with stable angina pectoris

Thirty-three men with stable exercise-induced angina pectoris entered a randomized, doubleblind, crossover study in which controlled-release isosorbide-5-mononitrate 60 mg once daily was compared with conventional isosorbide dinitrate 20 mg 3 times daily. Each drug was given for 2 weeks. Twenty-eight patients completed the study and data on exercise variables are available in 23 patients. Treatment with either drug resulted in significant antianginal effects, when measured 6 hours after a single dose and after 2 weeks of therapy compared with baseline placebo; however, there were significantly fewer signs of myocardial ischemia during treatment with Isosorbide-5-mononitrate. There was no evidence of tolerance to either drug treatment but a significant attenuation of resting blood pressure (but not of exercise blood pressure) was observed with both drugs. Headache was the only clinically significant adverse event during therapy and it occurred more frequently in the isosorbide dinitrate treatment group (p <0.05 vs placebo); 3 such patients had to withdraw from the study because of headache. Thus, once-daily, controlled-release Isosorbide-5-mononitrate appears as effective as conventional Isosorbide dinitrate 3 times daily in patients with stable angina pectoris. The once-daily administration is convenient and improves patient compliance.

Development of tolerance to nifedipine in patients with stable angina pectoris.

1. The possibility of development of tolerance to the anti-ischaemic and anti-anginal effects of nifedipine during sustained administration for 2 months was studied in 15 patients with stable angina pectoris by means of repeated exercise tests on a treadmill. 2. After acute administration of nifedipine (20-30 mg) substantial anti-ischaemic and anti-anginal effects lasted for at least 4 h in all patients. 3. During sustained nifedipine treatment with a dose schedule which provided continuous anti-ischaemic effect during a day (mean daily dose 82.7 +/- 6.0 mg, range 60-120 mg) a substantial attenuation of this effect was registered. The duration of the anti-ischaemic effect was 5.4 +/- 0.3 h after acute administration, decreasing significantly to 3.6 +/- 0.4 h during sustained administration. 4. The attenuation of the nifedipine effect was not associated with worsening of the patients' condition. 5. Plasma concentrations of nifedipine and its metabolite were similar after acute administration and during sustained treatment. Protein binding of nifedipine also remained constant during the study. 6. There was marked interindividual variation in the degree of attenuation of the nifedipine effect during sustained administration. In five patients nearly complete loss of nifedipine efficacy was registered. Eight to ten days after stopping regular administration of nifedipine only partial restoration of nifedipine effect was observed. 7. We conclude that during sustained nifedipine administration tolerance to its anti-ischaemic, anti-anginal and circulatory effects develops in a substantial number of patients with stable angina pectoris.

Hemodynamic profile of carvedilol

Several so-called multiple-action compounds have been developed, such as medroxalol (alpha and beta blockade, and beta-2 stimulation), celiprolol (alpha-2 and beta-1 blockade, and beta-2 stimulation) and carvedilol (beta blockade and vasodilatation) for the treatment of patients with arterial hypertension and with coronary heart disease. Carvedilol exerts relatively uniform peripheral effects, i.e. a reduction of both systolic and diastolic blood pressure at rest and during exercise, and a decrease in the resting and exercise heart rate. Blood pressure fall due to carvedilol may be induced by its vasodilating effect, as documented by measurements of forearm blood flow and peripheral vascular resistance. Moreover, renal hemodynamics does not seem to be significantly altered by carvedilol. Carvedilol may also produce an improvement of the LV contractile status in patients with CHD and impaired LV function, mainly due to afterload reduction, in addition to its antianginal effect, which is due mainly to the beta-blocking properties of this substance. From the studies mentioned it may be concluded that carvedilol is a useful and promising drug for treating patients with both arterial hypertension and with coronary artery disease.

Acute antianginal hemodynamic effects of nicardipine in coronary artery disease

To define the short-term effects of intravenous nicardipine on exercise- and pacing-induced myocardial ischemia, 15 men with coronary artery disease were studied. Nicardipine was administered as a 2 mg bolus followed by an infusion, titrated to maintain a 10 to 20 mm Hg decrease in systolic arterial pressure. At rest, nicardipine significantly decreased systemic and coronary vascular resistances and left ventricular end-diastolic pressure but increased coronary blood flow, heart rate, and myocardial oxygen consumption. With bicycle exercise performed to evoke myocardial ischemia, nicardipine prolonged exercise duration, time to of 1 mm ST segment depression, and increased cardiac work to onset of angina in most patients. These changes in cardiac performance were not associated with alteration in the product of systolic pressure and heart rate or with increased left ventricular end-diastolic pressure. During increased heart rate induced by atrial pacing to cause ischemia, the heart rate threshold for myocardial ischemia was not changed by nicardipine. This occurred despite decreased myocardial oxygen consumption, unchanged coronary blood flow, and otherwise similar hemodynamic changes as those observed during exercise. However, left ventricular end-diastolic pressure remained lower and stroke volume increased more after nicardipine with pacing stress when compared with observations before nicardipine with the same heart rate stress. These findings support beneficial antiischemic actions of nicardipine with possible prevention of ischemia-related left ventricular dysfunction.

Verification of a canine model of transient exercise induced myocardial dysfunction: antianginal effects of flestolol, an ultra short acting adrenoceptor antagonist

STUDY OBJECTIVE - The aim of the study was to verify the reproducibility of a canine model of treadmill exercise induced regional myocardial dysfunction designed to mimic exertional angina pectoris in man. DESIGN - Dogs trained to run on a treadmill were chronically instrumented with a microtip manometer in the left ventricle, a hydraulic occluder around the circumflex branch of the left coronary artery, two pairs of crystals for sonomicrometry, and arterial and venous catheters. Experiments were started 10 d after surgery, when the animals were submitted to seven treadmill exercise cycles, each of 3 min, with a 7 min recovery period. Ischaemia was adjusted so as not to impair regional function at rest but to produce progressive dysfunction with increasing work load. Flestolol (1 microgram.kg-1.min-1) was infused intravenously during the third and fourth exercise cycle. SUBJECTS - Six mongrel dogs, 13.5-29.5 kg, were used. MEASUREMENTS and RESULTS - Flestolol caused a marked reduction in the exercise induced increase in left ventricular positive dP/dtmax, and minor reductions in heart rate and systolic blood pressure, resulting in a decrease in myocardial oxygen demand and an improvement in regional function in the circumflex area of the left coronary artery. The functional improvement was transient and disappeared entirely after termination of flestolol infusion. CONCLUSIONS - The results show that flestolol is beneficial in conditions of limited coronary reserve and exercise induced myocardial dysfunction. The fact that the extent of regional myocardial dysfunction was comparable before and after flestolol infusion confirms the stability and usefulness of this experimental model in the evaluation of antianginal drugs.

Potential role of coronary vasoconstriction in ischaemic heart disease: effect of exercise

Coronary vasomotion plays an important role in the regulation of coronary perfusion at rest and during exercise. Normal coronary arteries show coronary vasodilation of the proximal (+20%) and distal (+40%) vessel segments during supine bicycle exercise. However, patients with coronary artery disease show exercise-induced vasoconstriction of the stenotic vessel segments. The exact mechanism of exercise-induced stenosis narrowing is not clear but might be related to a passive collapse of the disease-free vessel wall (Venturi mechanism), elevated plasma levels of circulating catecholamines, an insufficient production of the endothelium-derived vasorelaxing factor or increased platelet aggregation due to turbulent blood flow with release of thromboxane A2 and serotonin. Various vasoactive drugs, such as nitroglycerin and calcium antagonists, prevent exercise-induced stenosis vasoconstriction. An additive effect on coronary vasodilation of the stenotic vessel segment was observed after combination of nitroglycerin with diltiazem. Thus, exercise-induced stenosis narrowing plays an important role in the pathophysiology of myocardial ischaemia during dynamic exercise. The antianginal effect of vasoactive substances can be explained--besides the effect on pre- and afterload--by a direct action on coronary stenosis vasomotion.

Clinical experience with Imdur in angina pectoris

Imdur contains isosorbide-5-mononitrate (IS-5-MN) in a controlled-release (Durules) formulation. It has a significant anti-anginal effect when taken once daily at a dose of 60 mg. This anti-anginal effect persists during long-term treatment without the development of tolerance; once-daily treatment produces a plasma nitrate profile that is high enough to give anti-anginal protection during the daytime, but low enough during the latter part of the dosage interval to avoid the development of tolerance. Evidence shows that once-daily Imdur is equivalent in efficacy to plain tablets of IS-5-MN and isosorbide dinitrate taken three times daily at the same total daily dosage (60 mg), and to the calcium antagonist diltiazem (60 mg three times daily). In addition, the anti-anginal protection provided by Imdur in combination with beta-blocker treatment is superior to that achieved with beta-blocker treatment alone. In long-term studies Imdur has been shown to be well tolerated.

Nitrate patches: Duration of action and loss of efficacy

Nitroglycerin patches deliver 0.003 mg nitroglycerin per minute through the skin. This small dose led to an antianginal effect in the short term and when applied with a nitrate pause at night also during sustained use. Minimal doses of i.v. nitroglycerin (0.025 mg) do have antianginal activity. This dose has no effect on pre- and afterload, but increases the diameter at the point of the stenosis. These findings are in accordance with newly won insights into the mode of action of nitrate in coronary heart disease. In the area of the stenosis EDRF cannot be produced by the intima because of damage resulting from arteriosclerotic plaques. EDRF is identical with NO. Thus, the administration of low doses of nitrates that act by means of the NO radical can increase the diameter in the stenosis, since the physiological dilator (EDRF) is no longer present. The increased flow caused by dilatation is the main factor in the antianginal activity of nitrates.

P-069 - Antianginal and antiarrhytlimic effects of AJ-2615, a novel Ca2+ entry blocker, in anesthetized experimental animals

P-069 - Antianginal and antiarrhytlimic effects of AJ-2615, a novel Ca2+ entry blocker, in anesthetized experimental animals

Evaluation of a new vasodilating .BETA.-blocking agent, carvedilol, in exertional angina using holter monitoring.

Antianginal and antiischemic effects and clinical pharmacologic actions of carvedilol, a novel beta-blocking agent with a vasodilator action, were determined by Holter electrocardiographic monitoring in 13 patients with exertional angina. The patients were observed for 1 week prior to entry into the study, followed by 1 to 2 weeks of treatment with carvedilol. During the observation period the patients received one placebo tablet daily, and during the treatment period one 20 mg tablet of carvedilol daily. Before and after the treatment 24-hour Holter electrocardiographic tracings were obtained. The mean interval of Holter monitoring was 11.2 +/- 4.5 days for the observation and treatment periods, and the mean time of drug administration was 8:25 a.m. (+/- 30 min). The Holter electrocardiographic tracings which were obtained twice in 9 patients during the observation period showed a high degree of reproducibility with respect to the frequency, magnitude and duration of ST-segment depression. The total frequency of ST depression per patient was 4.5 +/- 3.4 events/day pre-drug and 2.1 +/- 2.1 events/day post-drug. There was a significant reduction in total frequency of ST depression post-drug (p less than 0.01). The frequency of asymptomatic ST depression was similarly decreased post-drug (p less than 0.01), and the total magnitude and duration of ST depression were significantly improved post-drug (p less than 0.01 and p less than 0.05, respectively). These effects of carvedilol lasted for 24 hours after administration. Considering that the heart rate was not excessively reduced during the night, and nocturnal myocardial ischemic episodes were not exacerbated, the mode of action of this drug seems to be based on not only a beta-blocking action but also on a vasodilator action. Carvedilol benefits exertional angina when used in a 20 mg s.i.d. regimen.

P-080 - Antianginal effect of KRN2391, a novel vasodilator, on the experimental model of angina pectoris induced by vasopressin treatment in anesthetized rats

P-080 - Antianginal effect of KRN2391, a novel vasodilator, on the experimental model of angina pectoris induced by vasopressin treatment in anesthetized rats

O-318 - Antianginal effect of NKY-722, a new water soluble dihydropyrldine Ca2+-antagonist

O-318 - Antianginal effect of NKY-722, a new water soluble dihydropyrldine Ca2+-antagonist

Angiographic response to a vasodilating drug, nicorandil, in patients with coronary artery disease.

To investigate the usefulness of nicorandil as an antianginal drug, we compared the coronary vasodilatory response in nonstenotic coronary artery segments and the hemodynamic response in 26 coronary artery disease patients. Both responses were studied prior to sublingual administration of 10 mg of this drug and 10, 30 and 60 min afterward. The plasma nicorandil concentration was determined up to 120 min after administration. The mean coronary dilating ratio of nicorandil was 117% 30 min after administration (p less than 0.01) and showed a good correlation to the plasma nicorandil concentration. The mean maximum dilating ratio of each patient was 125%. There was no difference between individual coronary arteries or between proximal and distal segments in terms of the coronary artery dilating ratio. The plasma nicorandil concentration required for 120% dilation of the coronary arteries was 26 ng/ml, 89 ng/ml and 142 ng/ml for those cases with variant angina, exertional angina and postinfarction angina, respectively. Hemodynamic changes due to administration of this drug included a decrease in blood pressure, and a reduction in total peripheral resistance, rate-pressure product, pulmonary capillary pressure and stroke-work index. These results indicate that the antianginal effects of nicorandil are derived from its coronary vasodilatory action and an inhibitory effect on myocardial oxygen consumption.

Nitrate tolerance

The organic nitrates are effective agents in the management of patients with angina pectoris. They are the agents of choice in the treatment of acute episodes of angina pectoris and are useful in angina prophylaxis. While the organic nitrates are extremely effective in angina prophylaxis during acute therapy, there is increasing evidence that with many dosing regimens for oral and transdermal therapy, substantial attenuation of the antianginal effects develops. Thus, during acute therapy the organic nitrates improve exercise tolerance for many hours, but during sustained therapy designed to provide antianginal efficacy throughout the 24-h period there is significant attenuation of the beneficial effects. It has been documented that treatment regimens designed to provide a period of nitrate washout prevent or reverse nitrate tolerance, and such changes in dosing regimens have been shown to provide continued antianginal protection. It is clear that the objective of providing 24-h antianginal protection with the organic nitrates cannot be achieved. With appropriate dosing schedules, however, it is possible to improve exercise tolerance throughout the major portion of the 24-h dosing period.