dihydropyridines and Coronary-Vasospasm

Coronary artery spasm is one of the causes of angina pectoris,acute myocardial infarction and ventricular fibrillation-related sudden death. It has been established that Ca channel blockers are protective against vasospastic angina (VSA) and treatment with Ca channel blockers provides a better prognosis of VSA. However, it is not still clarified what kinds of Ca channel blockers shows the best prognosis of VSA. We performed a meta-analysis in which 4Ca channel blockers amlodipine, nifedipine, benidipine and diltiazem were used for the treatment of VSA patients and found that among 4 Ca channel blockers, benidipine showed a statistically significant better prognostic effect on MACE than amlodipine, nifedipine or diltiazem.

Topics: Angina Pectoris; Calcium Channel Blockers; Coronary Vasospasm; Dihydropyridines; Humans; Prognosis; Risk Factors

Although calcium channel blockers (CCB) are highly effective for suppression of vasospastic angina (VSA) attacks, their prognostic effects in VSA patients remain to be examined in a large number of patients.. Databases for related papers were searched and then a meta-analysis regarding the effects of CCB on major adverse cardiovascular events (MACE) in Japanese VSA patients with the 4 previous studies was performed. A total of 1,997 patients with positive coronary spasm provocation tests were evaluated. They were treated with either alone or combination of benidipine (n=320), amlodipine (n=308), nifedipine (n=182) or diltiazem (n=960). MACE were observed in 143 patients (cardiac death: 36, myocardial infarction: 51, heart failure: 26, stroke: 65, and aortic aneurysm: 11). The hazard ratio for the occurrence of MACE was significantly lower in patients treated with benidipine than in those with diltiazem. There was no significant difference in the clinical characteristics affecting the occurrence of MACE among the 4 CCB groups. Furthermore, the hazard ratio for the occurrence of MACE was significantly lower in those treated with benidipine, even after correction for patient characteristics that could have affected the occurrence of MACE (hazard ratio 0.41, P=0.016).. These results suggest that among the 4 major CCB that effectively suppress VSA attacks in general, benidipine showed significantly more beneficial prognostic effects than others.

Topics: Amlodipine; Angina Pectoris; Asian People; Calcium Channel Blockers; Coronary Vasospasm; Dihydropyridines; Diltiazem; Humans; Nifedipine; Prognosis; Treatment Outcome

We compared the efficacy of once-daily treatment with nifedipine CR 40 mg (NR) and twice-daily treatment with benidipine 4 mg (BD) in patients with coronary spastic angina (CSA) registered in 3 cardiovascular institutes in Tokyo.. CSA was diagnosed by an ischemic ST change during Holter ECG monitoring or drug-induced test. Thirty patients were randomly allocated to either NR or BD group. The number of symptomatic attacks and the total frequency of short-acting nitrates were examined based on the data in diaries written by patients. There were no significant differences in the baseline characteristics between the two groups. The median number (25-75% quartile) of attacks per week was significantly decreased in NR group, i.e., 1.0 (0.8-2.0) at baseline, 0.0 (0.0-1.0) after 4 weeks of treatment, and 0.0 (0.0-0.0) after 8 weeks of treatment (P=0.0093, P=0.0002, Wilcoxon's rank-sum test). No significant decrease was observed in BD, i.e. 1.0 (0.5-2.0) at baseline, 1.3 (0.0-3.0) after 4 weeks, and 0.0 (0.0-1.0) after 8 weeks. The number of attacks was fewer in NR than in BD group (P=0.074, P=0.015, U-test for difference).. Once-daily treatment with NR 40 mg was more effective than twice-daily treatment with BD in the prevention of CSA attacks.

Topics: Acetylcholine; Angina Pectoris; Blood Pressure; Coronary Vasospasm; Dihydropyridines; Electrocardiography, Ambulatory; Ergonovine; Female; Heart Rate; Humans; Male; Middle Aged; Nifedipine; Nitrates; Vasodilator Agents

The effects of the 3 classes of L-type calcium-channel blockers (CCBs) on vascular endothelial function have not been clarified in patients with coronary vasospasm.. Twenty-five normotensive patients (age 64.0+/-1.4 years) with coronary vasospasm were randomly treated for 3 months with benidipine, diltiazem, and verapamil, which belong to the dihydropyridine, benzothiazepine, and phenylalkylamine classes of CCBs, respectively. Endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent nitroglycerin-induced dilatation in the brachial arteries, and plasma cyclic guanosine 3',5'-monophosphate (cGMP), a nitric-oxide-related product, were assessed before and after treatment. At baseline, the patients with vasospasm had significantly lower FMD as compared with normal subjects (n=8). Blood pressure did not differ among the 3 groups before and after treatment. Benidipine significantly increased FMD (from 4.7+/-0.6 to 7.4+/-1.1%, P<0.05) and plasma cGMP levels. In contrast, neither diltiazem nor verapamil affected FMD and cGMP levels. None of the treatments affected nitroglycerin-induced dilatation.. Benidipine, but not diltiazem or verapamil, improves endothelial dysfunction beyond blood pressure lowering effects in patients with coronary vasospasm. Upregulation of the nitric oxide - cGMP system by benidipine may partly contribute to the improvement. The dihydropyridine class may be more beneficial for vascular endothelial function than the non-dihydropyridine classes of CCBs.

Topics: Aged; Blood Pressure; Calcium Channel Blockers; Coronary Vasospasm; Dihydropyridines; Diltiazem; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Vasodilation; Verapamil

Exercise-induced vasospastic angina (VSA) is an uncommon entity of coronary artery disease. Here, we report a case of exercise-induced VSA, which was detected by exercise stress myocardial perfusion imaging.

Topics: Angina Pectoris; Computed Tomography Angiography; Coronary Angiography; Coronary Circulation; Coronary Vasospasm; Dihydropyridines; Exercise Test; Humans; Male; Middle Aged; Myocardial Perfusion Imaging; Physical Exertion; Predictive Value of Tests; Vasoconstriction; Vasodilator Agents

We assessed the anti-anginal effects of cilnidipine in comparison with those of nicardipine and nifedipine (1 and 10 µg/kg, n = 6 for each drug) or vehicle (n = 6) by using the vasopressin-induced angina model of rats. The administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram reflecting the presence of subendocardial ischemia, whereas it significantly increased the mean blood pressure, resulting in the decrease of the heart rate and the prolongation of the PR interval possibly through a reflex-mediated increase in vagal tone. Cilnidipine suppressed the vasopressin-induced depression of the S-wave level in a dose-related manner, which was not observed by nicardipine or nifedipine. In addition, the low dose of cilnidipine hardly affected the vasopressin-induced pressor response, but it attenuated the negative dromotropic effect, suggesting N-type Ca

Topics: Angina Pectoris; Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Coronary Vasospasm; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Male; Nicardipine; Nifedipine; Rats; Time Factors; Vasoconstriction; Vasodilator Agents; Vasopressins

Topics: Angiocardiography; Cardiopulmonary Resuscitation; Coronary Angiography; Coronary Vasospasm; Dihydropyridines; Electrophysiologic Techniques, Cardiac; Heart Arrest; Humans; Isosorbide Dinitrate; Male; Middle Aged; Treatment Outcome; Vasodilator Agents

Combined therapy with a statin and a calcium channel blocker, which can improve lipid metabolism and reduce oxidative stress, may attenuate coronary vasoconstriction in patients with coronary spastic angina (CSA). After 6 months of therapy with benidipine and pravastatin, an acetylcholine provocation test was performed a second time in 25 patients with CSA. The patients were divided into 2 groups according to whether the result of this second test was positive (n = 13) or negative (n = 12). The test was designated as positive when the intracoronary injection of acetylcholine induced angiographically demonstrable total or subtotal occlusion (positive-test group). In the negative-test group, significant decrease in the plasma levels of low-density lipoprotein (LDL) cholesterol (-20.7 +/- 11.1%, P < 0.01 versus baseline) were observed along with a dramatic increase in the serum level of high-density lipoprotein (HDL) cholesterol (26.8 +/- 13.2%, P < 0.01 versus baseline). Furthermore, a significant decrease of the malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a marker of oxidative stress, was also observed (-22.6 +/- 14.1%, P < 0.01 versus baseline) in this group. In the positive-test group, however, no significant changes were found in any of the aforementioned parameters. The results showed that improvement of lipid metabolism, especially an increase of HDL cholesterol level and a reduction of MDA-LDL, may inhibit vascular contractility.

Topics: Angina Pectoris, Variant; Calcium Channel Blockers; Cholesterol, HDL; Cholesterol, LDL; Coronary Vasospasm; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipoproteins, LDL; Male; Malondialdehyde; Middle Aged; Pilot Projects; Pravastatin

We experienced a case of vasospastic angina showing resolution of vasospasm in the acetylcholine provocation test corresponding to regression of coronary atherosclerotic plaque following treatment with a combination of benidipine and pravastatin.

Topics: Acetylcholine; Angina Pectoris; Angina Pectoris, Variant; Anticholesteremic Agents; Cholinergic Agents; Coronary Artery Disease; Coronary Vasospasm; Dihydropyridines; Humans; Hypercholesterolemia; Male; Middle Aged; Pravastatin; Ultrasonography; Vasodilator Agents

We have previously reported the changing clinical characteristics of patients with vasospastic angina (VSA) before and after the introduction of new calcium channel blockers (benidipine and amlodipine) in 1990. In this subanalysis study, we compared the prognostic effects of 3 calcium channel blockers (benidipine, diltiazem, and amlodipine) on the incidence of cardiovascular events in patients with VSA in our cohort study, where 527 patients (318 men and 209 women) enrolled after 1990 (from January 1990 to December 2002) were followed-up for a mean period of 5.2 years. There was no significant difference in the clinical characteristics among the 3 calcium channel blocker groups. Multivariate analysis demonstrated that 4 factors, including smoking, hypertension, diabetes mellitus and reduced left ventricular ejection fraction, were significant risk factors for cardiovascular events. Among the 3 calcium channel blockers examined, benidipine (n = 148) tended to be associated with a lower incidence of total events, cardiovascular events, and cerebral infarction, compared with diltiazem (n = 313) and amlodipine (n = 111). Furthermore, benidipine significantly reduced the incidence of vascular infarction events, a possible indicator of atherosclerosis, as compared with diltiazem. These results suggest that benidipine may be more useful for the treatment of VSA as compared with diltiazem and amlodipine.

Topics: Adult; Aged; Aged, 80 and over; Amlodipine; Angina Pectoris; Calcium Channel Blockers; Cardiovascular Diseases; Cohort Studies; Coronary Vasospasm; Dihydropyridines; Diltiazem; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Prognosis; Retrospective Studies; Risk Factors

Most patients with vasospastic angina who have no significant organic coronary arterial stenosis are well controlled by medical therapy and the prognosis is almost satisfactory. Calcium channel (Ca) blockers are used as the first choice and effective agents for vasospastic angina pectoris. However, they do not always work well. Some uncontrolled coronary vasospasms would happen to cause prolonged occlusion of coronary artery resulting in myocardial infarction, life-threatening arrhythmias and sudden death. Therefore, it is very important to pay attention to such a refractory coronary spasm and choose the most effective agent out of Ca blockers for the treatment of each patient with vasospastic angina attacks. This study was designed to evaluate the anti-vasospastic efficacy of benidipine, a long acting dihydropyridine (DHP) Ca blocker, in patients with other Ca blockers-resistant angina.. Patients treated with diltiazem but not enough to control angina attacks were enrolled in the present study. Treatment with diltiazem (CAS 33286-22-5, 42399-41-7) was changed to treatment with benidipine (CAS 91599-74-5) and the parameters such as angina frequency, duration, blood pressure, heart rate, electrocardiogram and hematological parameters (serum NO(x), plasma cGMP) were measured and compared.. Fifteen patients with vasospastic angina were enrolled. After switching from diltiazem to benidipine, angina attacks were completely disappeared in six patients. Although the frequency was not decreased, the average duration of attacks was shorter than before in three patients. Four patients did not improve and two patients obviously worsened. In the improved nine patients, serum nitrite/nitrate (NO(x)) levels showed a significant increase from 37.6 +/- 15.3 to 54.5 +/- 26.7 pmol/L (p < 0.05) and cGMP levels subsequently elevated from 2.2 +/- 0.8 to 2.5 +/- 0.6 micromol/L (p = 0.05) after benidipine therapy started. Adverse effects such as hypotension and bradycardia were not observed.. This study suggests that benidipine may be helpful in Japanese patients with vasospastic or variant angina pectoris, if diltiazem was not successful.

Topics: Aged; Angina Pectoris; Blood Pressure; Calcium Channel Blockers; Coronary Vasospasm; Cyclic GMP; Dihydropyridines; Diltiazem; Female; Heart Rate; Humans; Male; Middle Aged; Nitric Oxide; Treatment Failure; Treatment Outcome; Vasodilator Agents

It has been reported that the morbidity rate of vasospastic angina is higher in Japan compared to western countries, and its prognosis has already been reported. However, the prognosis of vasospastic angina in relation to coronary angiographic findings, prognostic risk factors and treatment has not yet been fully investigated.. From January 2000 to October 2005, 1047 patients with vasospastic angina diagnosed by coronary angiography at Gifu University Hospital and related hospitals were registered in a cohort study (follow-up rate: 91.4%, median follow-up duration: 3.8 years). The presence of coronary artery stenosis, diabetes mellitus, total spasm, and age of more than 65 years had a negative prognostic impact on cardiovascular events. Patients were treated with calcium channel blockers such as diltiazem (CAS 33286-22-5, CAS 42399-41-7), amlodipine (CAS 111470-99-6), nifedipine (CAS 21829-25-4), and benidipine (CAS 91599-74-5). Among these calcium channel blockers, when patient background was matched by the propensity score in patients treated with calcium channel blockers only, the cardiovascular event rate was significantly lower in the benidipine group than in the diltiazem group.. The study demonstrated for the first time that total spasm is a risk factor, independent of other factors, for cardiovascular events in patients with vasospastic angina. Treatment with benidipine showed a better prognosis than that with diltiazem.

Topics: Adult; Aged; Aging; Amlodipine; Angina Pectoris; Calcium Channel Blockers; Cohort Studies; Coronary Angiography; Coronary Stenosis; Coronary Vasospasm; Diabetes Complications; Dihydropyridines; Diltiazem; Ergonovine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nifedipine; Oxytocics; Prognosis; Risk Factors

The antianginal effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in various experimental angina models and compared with those of nifedipine and propranolol. In anesthetized dogs, YM-16151-4 (0.3 and 1 mg/kg intravenously, i.v.) increased coronary blood flow and reduced myocardial oxygen consumption (MVO2). In isolated dog coronary arteries, YM-16151-4 concentration-dependently inhibited 3,4-diaminopyridine-induced rhythmic contractions with an IC50 value of 91 nM. In anesthetized rats, YM-16151-4 also inhibited the ST-segment depression induced by vasopressin (0.5 U/kg i.v.) with an ED50 value of 29 mg/kg orally, (p.o.). Nifedipine was also effective in these models, but propranolol was not. In addition, YM-16151-4 (0.3 mg/kg i.v.) inhibited the ST-segment elevation in the epicardial ECG induced by coronary artery occlusion in anesthetized dogs. Propranolol (1 mg/kg i.v.) also inhibited this elevation, but nifedipine (0.003 mg/kg i.v.) did not. In anesthetized dogs, furthermore, the prolongation of PQ-interval induced by YM-16151-4 was almost the same as that induced by propranolol. These results demonstrate that YM-16151-4, in contrast to nifedipine and propranolol, is fully effective in these various types of angina models. Thus, YM-16151-4 is expected to prove a valuable antianginal agent in treatment of various types of angina pectoris, with these antianginal effects resulting from the sum of its calcium entry blocking and beta 1-adrenoceptor blocking activities.

Topics: 4-Aminopyridine; Amifampridine; Angina Pectoris; Animals; Arginine Vasopressin; Atrioventricular Node; Calcium Channel Blockers; Coronary Circulation; Coronary Vasospasm; Dihydropyridines; Dogs; Electrocardiography; Female; Heart Conduction System; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nifedipine; Nitrophenols; Oxygen Consumption; Potassium Channels; Propranolol