Denopamine,a selective beta1-receptor agonist and a new coronary vasodilator

Up until now, it has been suggested that nitrate and/or calcium channel blockers were effective against variant angina pectoris. On the other hand, it is known that about 20% of variant angina pectoris was refractory to both nitrate and calcium channel blockers. In Japan, it has been reported that denopamine, which is an oral beta1-adrenoceptor selective agonist developed by the Japanese pharmaceutical industry (Tanabe Seiyaku), is effective in those refractory cases. To date, in Japan nine cases have been recognized of patients with vasospastic angina pectoris whose symptoms were relieved by taking denopamine, including one case in which the author has had personal experience. Eight of these nine cases were refractory, and were not relieved by combined therapy using both nitrate and a calcium channel blocker. It was also documented that denopamine was effective in cases where attacks were not relieved by prazosin or magnesium, which have been documented as effective in other refractory cases. In a study of canine coronary arteries, localization of beta-adrenoceptor subtypes was documented, with the beta1-adrenoceptor predominantly found in the conduit coronary artery. In recent years it has been emphasized that the principal role of sympathetic nerves was not associated with the constrictive action of alpha-adrenoceptors, but with the coronary dilative action of beta-adrenoceptors. It would therefore be worthwhile to determine whether denopamine is able to relieve vasospastic angina pectoris in many more cases.     

Clinical efficacy of benidipine for vasospastic angina pectoris

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This study suggests that benidipine may be helpful in Japanese patients with vasospastic or variant angina pectoris, if diltiazem was not successful.     

Effects of benidipine and some other calcium channel blockers on the prognosis of patients with vasospastic angina. Cohort study with evaluation of the ergonovine coronary spasm induction test

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.     

Transient electrocardiographic recording of acute myocardial ischemia with ST-segment elevation of the diaphragmal location accompanied by a total atrioventricular block as an initial manifestation of Prinzmetal’s angina — A case report

Prinzmetal’s angina, also known as Prinzmetal’s variant or Prinzmetal’s vasospastic angina is characterized by angina attacks caused by spasm of the great epicardial coronary arteries. Coronary artery endothelial dysfunction plays a crucial role in the development of this vasospastic angina. The attacks of vasospastic angina can be prevented with calcium antagonists and nitrates, whereas in refractory variant angina, coronary angioplasty with stenting may help prevent further coronary spasm. In this case report, we present a 52-year-old male patient with a transient electrocardiographic recording of acute myocardial ischemia with ST-segment elevation of the diaphragmal location accompanied by a total atrioventricular block immediately after exercise testing and as a first manifestation of Prinzmetal’s angina. After regression of the symptoms and electrocardiographic changes, significant pathomorphologic changes of coronary arteries were excluded by coronary angiography. Following discharge, the patient was treated with calcium antagonists and did not show symptoms during a 4-year follow-up period.     

Advances in the treatment of unstable angina pectoris.

The pathogenesis, clinical manifestations and diagnosis, and drug and nondrug therapies of unstable angina pectoris are reviewed. Coronary-artery plaque fissure and rupture, with subsequent platelet aggregation and thrombosis, are the primary underlying stimuli for unstable angina. Unstable angina has been defined as consisting of new-onset angina; angina that is increasing in frequency, intensity, or duration (crescendo angina); or angina at rest. The diagnosis of unstable angina is based on the clinical presentation, electrocardiographic findings, the lack of evidence of myocardial infarction (MI), exercise testing, and coronary angiography. I.V. nitroglycerin is the cornerstone of medical therapy for unstable angina, it relieves chest pain and has a short onset of action. I.V. nitroglycerin, however, has not been shown to reduce the occurrence of MI or death, and its beneficial effects may decrease over time. Aspirin reduces the occurrence of MI and death in patients with unstable angina, but the ideal dosage has not been established. Heparin may reduce the frequency of angina and MI, but its effect on mortality is unknown. Nifedipine has produced beneficial effects in small trials, whereas larger trials have suggested that the drug has deleterious effects when used in the treatment of unstable angina. Verapamil and diltiazem may be effective in relieving chest pain. Calcium-channel blockers have generally not been proved to reduce the risk of MI and death. Data evaluating the efficacy of beta-adrenergic blockers as monotherapy for unstable angina are lacking; these drugs should not be used in patients with vasospastic or Prinzmetal's angina. Thrombolytic therapy has produced mixed results when used in the treatment of unstable angina. Nondrug therapies for unstable angina include intra-aortic balloon counterpulsation, percutaneous transluminal coronary angioplasty, and coronary-artery bypass surgery. Numerous drug and nondrug therapies may be employed in the treatment of unstable angina pectoris.     

Impact of Ranolazine on Clinical Outcomes and Healthcare Resource Utilization in Patients with Refractory Angina Pectoris

Background

Ranolazine is a novel antianginal medication approved for the treatment of chronic angina. There are only limited data concerning the efficacy of ranolazine in reducing healthcare resource utilization in patients with refractory angina pectoris.

Objective

The primary objective of this analysis was to evaluate the efficacy and safety of ranolazine in refractory angina pectoris. In addition, the impact of ranolazine on healthcare resource utilization was assessed.

Methods

Consecutive patients with refractory angina pectoris treated with ranolazine at two cardiology practices in the state of Nebraska were included in this analysis. The Canadian Cardiovascular Society (CCS) angina class and frequency and type of healthcare resource consumption were determined during the 12 months prior to and the 12 months after initiation of ranolazine.

Results

A total of 150 pts (64 % men) with a mean age of 66 ± 12 years were included in this analysis. All patients had previously undergone coronary revascularization. Nitrates, β-adrenoceptor antagonists (β-blockers), and calcium antagonists (calcium channel blockers) were being used in 83, 97, and 75 % of patients, respectively. During ranolazine treatment, a significant improvement in CCS angina class was observed, with 23 patients improving by one class and no patient experiencing a deterioration in functional class (p = 0.025). A total of 53 side effects occurred in 28 (19 %) patients receiving ranolazine. Of those patients with side effects, four required dose reduction and seven required drug discontinuation. The frequency of clinic visits and emergency room visits was lower during ranolazine treatment, but the differences in frequency were not significant. The number of patients hospitalized and the number of hospitalizations were significantly lower during ranolazine therapy than in the pre-ranolazine study period (p = 0.002).

Conclusion

Ranolazine improved the CCS angina class and reduced hospitalizations over a 12-month follow-up period in a group of patients with difficult-to-treat refractory angina pectoris.     

Characterization of the adrenoceptors in coronary arteries of pigs

The effects of phenylephrine and norepinephrine and the influence of adrenoceptor blockers on them were investigated on isolated strips of pig coronary arteries of different diameter. Phenylephrine contracted large coronary arteries, an effect inhibited by phentolamine, but was ineffective on small coronary arteries. Norepinephrine either relaxed large coronary arteries or occasionally contracted them. Phentolamine potentiated the relaxing effect of norepinephrine and propranolol inhibited or even reversed it into a contraction.Small coronary arteries were without exception relaxed by norepinephrine. This effect was not influenced by phentolamine but was inhibited by propranolol. These findings prove the presence of α-adrenoceptors in pig coronary arteries with a large diameter although β-adrenoceptors predominate; α-adrenoceptors are not found in coronary arteries with a small diameter.The classification of β-adrenoceptors in the coronary musculature into one of the two β-types was determined by comparing the affinities of propranolol, practolol and H 35/25 on the β-adrenoceptors of isolated atrial preparation of guinea pigs and of strips of pig coronary arteries. While the affinities of propranolol were the same to both organs the affinity of practolol to the myocardium was 100 times higher than to the coronary arteries. On the other hand the affinity of H 35/25 to the coronary arteries was three times higher than to the myocardium.The selective effects of the β₁-adrenoceptor blocker practolol on the myocardium and the β₂-adrenoceptor blocker H 35/25 on the coronary arteries indicate that the β-adrenoceptors of the coronary arteries should be classified as β₂-adrenoceptors.     

Nicorandil for angina--an update

Around 2 million people in the UK have angina pectoris and are therefore at high risk of severe coronary events such as myocardial infarction (MI) or sudden death. Conventional management of patients with stable angina includes glyceryl trinitrate, a beta-blocker, aspirin and a statin, with the aim of controlling symptoms and reducing the risk of a coronary event. For patients unable to tolerate a beta-blocker, the choice is less clear but calcium channel blockers and long-acting nitrates provide effective symptom control. Another option is nicorandil (Ikorel--Rh?ne-Poulenc Rorer), a potassium channel activator licensed for the "prevention and long term treatment of chronic stable angina pectoris". In our review of nicorandil 8 years ago, we concluded that it provided symptom control that was as good as, but no better than, other less expensive anti-anginal drugs. Since then, new data have suggested that nicorandil might reduce the frequency of coronary events in patients with stable angina. Here, we consider these findings and reassess the place of nicorandil for patients with angina.     

Diltiazem. A review of its pharmacological properties and therapeutic efficacy

Diltiazem is an orally and intravenously active calcium channel blocking agent shown to be an effective and well-tolerated treatment for stable angina and angina due to coronary artery spasm. Its efficacy in these diseases has generally been similar to that of nifedipine or verapamil - alternative calcium channel blockers with which diltiazem has many electrophysiological, haemodynamic, and antiarrhythmic similarities. The antianginal mechanism of diltiazem cannot be precisely described; however, it appears to increase myocardial oxygen supply and decrease myocardial oxygen demand, mainly by coronary artery dilatation and/or via both direct and indirect haemodynamic alterations. Diltiazem has also shown substantial efficacy in the treatment of unstable angina, hypertension, and supraventricular tachyarrhythmias, but further study is necessary before its place in the treatment of these diseases may be clearly established. Although headache due to peripheral vasodilatation and depression of atrioventricular nodal conduction may be troublesome, side effects occur in only 2 to 10% of patients receiving diltiazem and are generally minor in nature. Thus, diltiazem offers a worthwhile alternative to other agents currently available for the treatment of angina pectoris. Although the infrequency of serious side effects may offer an advantage, its relative place in therapy compared with that of other calcium channel blockers remains to be clarified.     

Effectiveness of Diltiazem for Chronic Stable Angina Pectoris

Abstract: Diltiazem can be effective monotherapy for most patients with chronic stable angina pectoris. The exact mechanism(s) of action of diltiazem for producing a salutary effect in patients with angina pectoris is unknown, but probably involves a reduction in myocardial oxygen demand and an increase in supply via coronary artery dilatation. Administration of ≤240 mg/day in divided doses uncommonly produces any side effects. Doses of 360 mg/day may be required in some patients. The major adverse effect of high dose therapy is mild pedal oedema. Caution concerning orthostatic hypotension is advised when high dose diltiazem is combined with nitrate therapy or used in patients with poor left ventricular function. Also, diltiazem may potentiate bradycardia or atrio-ventricular block, especially when combined with digitalis preparations or β-blockers. However, in patients with severe angina, diltiazem may be additive to nitrate and/or β-blocker therapy.     

尼可地尔联合替格瑞洛治疗PCI术后难治性心绞痛的效果

目的探讨尼可地尔联合替格瑞洛治疗经皮冠状动脉介入治疗(PCI)术后难治性心绞痛的效果。方法 300例PCI术后出现难治性心绞痛的患者,随机分为研究组和对比组,每组150例。对比组患者实施标准抗心绞痛治疗,研究组患者在对比组的基础上进行尼可地尔联合替格瑞洛治疗。比较两组患者的治疗效果。结果治疗后,研究组患者的总有效率为86%,高于对比组的56%,差异具有统计学意义(P<0.05)。结论尼可地尔联合替格瑞洛治疗PCI术后难治性心绞痛效果较好,对患者心肌供血的改善情况具有显著的效果。     

Nisoldipine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of angina pectoris, hypertension and related cardiovascular disorders

Nisoldipine is an orally administered calcium entry blocking drug structurally related to nifedipine. In limited clinical trials it has been shown to be effective and relatively well tolerated in the treatment of patients with chronic stable angina pectoris and mild to moderate essential hypertension. As for all dihydropyridine-calcium antagonists, its major properties include potent peripheral and coronary vasodilation and improvement in myocardial oxygen supply relative to demand. These actions occur without depression of cardiac conduction or left ventricular function. Short term clinical trials have shown nisoldipine to produce both symptomatic and objective improvements in patients with chronic angina of effort and have suggested a benefit in vasospastic angina. A small number of comparative trials indicate that nisoldipine is equally as effective as nifedipine. In addition, in combination with beta-adrenoceptor blockade nisoldipine appears to offer additional benefit compared with beta-blockade alone and is well tolerated. In patients with mild to moderate essential hypertension nisoldipine monotherapy, in 1 or 2 daily doses, has maintained blood pressure control and has also been a useful addition to diuretics and beta-adrenoceptor blocking drugs in patients with poorly controlled disease. Side effects appear to be dose related, generally mild and transient, and are primarily those resulting from potent peripheral vasodilation - headache, flushing and pretibial or ankle oedema. Although studies to date are promising, there are no published long term studies (greater than 1 year) of nisoldipine in comparison with other calcium entry blockers and other drugs currently in clinical use for the treatment of angina pectoris or hypertension. Until such studies are completed the exact place of nisoldipine in the treatment of these diseases remains to be established.     

复方雪莲胶囊联合玻璃酸钠治疗膝骨关节炎的临床研究

目的观察心通口服液治疗冠心病心绞痛患者的临床疗效。方法选取2019年10月-2020年10月内蒙古自治区人民医院治疗的78例冠心病心绞痛患者为研究对象,根据治疗方案将患者分为对照组和观察组,各39例。对照组患者均给予冠心病心绞痛二级预防治疗,观察组在对照组基础上口服心通口服液,10 mL/次,3次/d。两组均治疗4周。比较两组患者的临床疗效、心绞痛的发作次数和持续时间及服用硝酸异山梨酯片的剂量。结果治疗后,观察组总有效率为89.7%,显著高于对照组的69.2%（P<0.05）。治疗后,两组心绞痛发作次数、每次发作持续时间、含服硝酸异山梨酯片剂量均显著降低（P<0.05）;观察组心绞痛发作次数、每次发作持续时间、含服硝酸异山梨酯片剂量显著低于对照组（P<0.05）。结论心通口服液治疗冠心病心绞痛患者可提高治疗有效率,减少心绞痛发作次数、持续时间及硝酸异山梨酯含服剂量,效果优于单纯西药治疗,且相对安全,值得临床应用。     

ATP-sensitive K+ channel openers: old drugs with new clinical benefits for the heart

Different types of ATP-sensitive K+ (K(ATP)) channels have been identified in cardiomyocytes, vascular smooth muscle cells, pancreatic beta-cells, neurons and mitochondria. Years before the discovery of the K(ATP) channel in cardiomyocytes, pharmacological openers of this channel had been developed for the treatment of angina pectoris and hypertension. The K(ATP) channel plays an important role not only in coronary blood flow regulation but also in protection of cardiovascular cells from ischemia/reperfusion injury. In animal models of myocardial ischemia/reperfusion, activation of the mitochondrial K(ATP) channels by their pharmacological openers has been shown to attenuate endothelial dysfunction and to reduce myocardial necrosis. Conversely, blockade of the K(ATP) channel aggravates microvascular necrosis and the no-reflow phenomenon after ischemia/reperfusion, resulting in augmentation of post-infarct ventricular dysfunction. Recent clinical studies have shown that a combination of coronary reperfusion therapy and infusion of nicorandil, a hybrid of K(ATP) channel opener and nitrate, improved left ventricular function in patients with acute myocardial infarction. Furthermore, chronic treatment with nicorandil has been shown to significantly improve prognosis of patients with high-risk stable angina pectoris. Both of these clinical benefits cannot be attributed to the nitrate property of nicorandil. However, a recent basic investigation has suggested that the protective function of K(ATP) channel openers is compromised by concurrent hypercholesterolemia and administration of sulfonylureas for diabetes mellitus. These interferences in the beneficial action of K(ATP) channel openers by concurrent illness and pharmacological agents need to be further investigated to allow a more effective use of K(ATP) channel openers in patients with coronary artery diseases.     

Nitrate tolerance A problem during continuous nitrate administration

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.     

Modulation of human cardiac function through 4 β-adrenoceptor populations

In human heart there is now evidence for the involvement of four β-adrenoceptor populations, three identical to the recombinant β₁-, b₂- and β₃-adrenoceptors, and a fourth as yet uncloned putative β-adrenoceptor population, which we designate provisionally as the cardiac putative β₄-adrenoceptor. This review described novel features of β-adrenoceptors as modulators of cardiac systolic and diastolic function. We also discuss evidence for modulation by unoccupied β₁- and β₂-adrenoceptors. Human cardiac and recombinant β₁- and β₂-adrenoceptors are both mainly coupled to adenylyl cyclase through Gs protein, the latter more tightly than the former. Activation of both human β₁- and β₂-adrenoceptors not only increases cardiac force during systole but also hastens relaxation through cyclic AMP-dependent phosphorylation of phospholamban and troponin I, thereby facilitating diastolic function. Furthermore, both β₁ and β₂-adrenoceptors can mediate experimental arrhythmias in human cardiac preparations elicited by noradrenaline and adrenaline. Human ventricular β₃-adrenoceptors appear to be coupled to a pertussis toxin-sensitive protein (Gi?). β₃-Adrenoceptor-selective agonists shorten the action potential and cause cardiodepression, suggesting direct coupling of a Gi protein to a K⁺ channel. In a variety of species, including man, cardiac putative β₄-adrenoceptors mediate cardiostimulant effects of non-conventional partial agonists, i.e. high affinity β₁- and β₂-adrenoceptor blockers that cause agonist effects at concentrations considerably higher than those that block these receptors. Putative β₄-adrenoceptors appear to be coupled positively to a cyclic AMP-dependent cascade and can undergo some desensitisation.     

Rate Control with Ivabradine

The importance of heart rate in human health and disease has been well known to clinicians for quite some time. Recent epidemiologic studies have further strengthened this concept. Modulation of heart rate by pharmacologic as well as non-pharmacologic means has affected cardiovascular mortality and morbidity in various trials and observational studies. Conventional rate-control agents, such as β-adrenoceptor antagonists (β-blockers), calcium channel blockers, and digoxin, have contributed greatly to the management of various diseases where heart-rate reduction is required; however, these agents have effects beyond rate control that may be unacceptable. Ivabradine has recently been recognized as a pure heart-rate-reducing agent and is being extensively studied. It is the latest addition to the class of drugs used to control angina. It is indicated in cases of β-blocker intolerance or when β-blockers fail to achieve a heart rate of <60 beats/min. The pure heart-rate-reducing effect of ivabradine has also been reported in smaller studies and anecdotal case reports. The theoretical possibilities of the utility of ivabradine are many and have opened up a whole new field of research for the future. The BEAUTIFUL trial enrolled approximately 10 000 patients with coronary artery disease (CAD) and left ventricular dysfunction, with the aim of assessing the effect of ivabradine versus atenolol on various cardiovascular outcomes. Although ivabradine failed to achieve favorable results for primary endpoints, it appeared effective in achieving a favorable secondary endpoint in a subgroup of patients who had a heart rate of >70 beats/min. Other large trials are also underway to assess the effects of ivabradine on heart failure, acute coronary syndromes, CAD, and other cardiovascular disorders. In this review, we discuss the pharmacologic basis of the action of ivabradine and its role in angina control, as well as in other conditions being actively studied or in which a role for ivabradine has been hypothesized.     

Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker

Benidipine is a dihydropyridine-derived calcium channel blocker developed in Japan, with several unique mechanisms of action, that is, triple calcium channels (L, N, and T) blocking action with a membrane approach. Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases. In fact, benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina. In addition, benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate anti-hypertensive effects are not achieved by ARBs alone, indicating that benidipine is an useful calcium channel blocker in combination therapy for hypertension. Benidipine was launched on the Japanese market 14 years ago, but few severe side effects have been reported, suggesting that this is a drug with established safety and long-acting pharmacological effects.     

The protein kinase inhibitor fasudil protects against ischemic myocardial injury induced by endothelin-1 in the rabbit

Endothelin-1 (ET-1) induces severe pathologic conditions such as coronary spasm followed by vasospastic angina pectoris and acute myocardial infarction. The related pathophysiologic mechanisms have remained obscure. Endothelin-1 receptor (ET(A) and ET(B)) is reported to couple with several types of G protein-involved pathways that participate in phospholipase C activation and atrial myofibrils organization into sarcomeric units. Here we demonstrate that ET-1 induces histologic and pathologic dysfunction in the rabbit myocardium and that such pathologic events are prevented by the Rho-kinase inhibitor fasudil. Although the bolus injection of ET-1 (1.4 nmol/kg) via the auricular vein of the rabbit induced only transient T-wave elevation, irreversible, severe histologic changes were observed in papillary muscles of the ventricle, and multifocal myocardial necrosis with infiltration of neutrophils and macrophages in the left ventricle occurred. Oral administration of fasudil (10 mg/kg) significantly reduced the occurrence of myocardial injury determinants, whereas conventional Ca2+ channel blockers (nifedipine, diltiazem) and a K+ channel opener (nicorandil; 10 mg/kg, p.o. each) showed a lesser or no effect on such determinants. These results suggest that ET-1 induces severe myocardial dysfunction based not only on the occurrence of vasospastic ischemia but also on its direct effects on the myocardium.     

N-acetylcysteine modifies the acute effects of isosorbide-5-mononitrate in angina pectoris patients evaluated by exercise testing

Nitrates are well established in the treatment of angina pectoris and the presence of sulfhydryl groups seems to be fundamental to nitrate-induced vasodilatation. The present study was performed to elucidate if large oral doses of N-acetylcysteine (NAC, 2,400 mg X 2), a donor of sulfhydryl groups, given together with a single oral dose of the long-acting nitrate, isosorbide-5-mononitrate (5-ISMN, 60 mg), would modify the nitrate effect evaluated by exercise testing before and after additional sublingual doses of nitroglycerin (NTG). Ten patients with angina pectoris and angiographically proven significant coronary artery disease were included. All patients received a baseline therapy with beta blockers. None of the patients had developed nitrate tolerance at inclusion. NAC/5-ISMN treatment significantly prolonged the total exercise time as compared with placebo/5-ISMN (7.7 +/- 2.1 min vs. 6.8 +/- 1.7 min, p less than 0.05). This increase was of such magnitude that no further effect was obtained after additional NTG doses. This study demonstrated that increased availability of sulfhydryl groups can increase the exercise capacity in angina pectoris patients treated with 5-ISMN without nitrate tolerance.