Blocker Carvedilol Research Articles

Aliskiren ameliorates sympathetic nerve sprouting and suppresses the inducibility of ventricular tachyarrhythmia in postinfarcted rat heart

Background Aliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular fibrillation after aliskiren treatment in myocardial infarction were investigated. Methods Male Sprague Dawley rats after coronary artery ligation were randomly allocated to four groups: angiotensin converting enzyme inhibitor enalapril, angiotensin receptor blocker valsartan, β adrenergic receptor blocker carvedilol and rennin inhibitor aliskiren treatment for six weeks. Electrophysiological study, histological examination and Western blotting were performed. Results The plasma norepinephrine level and sympathetic nerve innervation significantly increased in treated infarcted rats compared to untreated rats. Aliskiren treatment reduced the sympathetic nerve innervations after myocardial infarction. There is no significant difference in sympathetic nerve innervations after myocardial infarction among the enalapril, valsartan, carvediloand or aliskiren treated groups. Programmed electrical stimulation study showed that inducible ventricular arrhythmia was reduced, ventricular fibrillation threshold was increased and ventricular effective refractory period was prolonged in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats compared to untreated infarcted rats. Cardiomyocytic apoptosis in infarcted region was significantly decreased in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats. Conclusions Aliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic nerve innervations and reduced the vulnerability of ventricular arrhythmias after myocardial infarction. Enalapril, valsartan and carvedilol have similar effects as aliskiren on cardiomyocytic apoptosis, sympathetic nerve innervations and vulnerability of ventricular arrhythmias after myocardial infarction.

Simultaneous Treatment with Azelnidipine and Olmesartan Inhibits Apoptosis of Hl-1 Cardiac Myocytes Expressing E334k cMyBPC

Apoptosis appears to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM). We have previously reported 3 HCM patients carrying the E334K MYBPC3, and that heterologous expression of E334K cMyBPC in cultured cells induced apoptosis. The purpose of this study was to identify pharmacological agents that would inhibit apoptosis in HL-1 cardiomyocytes expressing E334K cMyBPC. E334K cMyBPC expression in cells increased levels of pro-apoptosis (p53, Bax and cytochrome c) and decreased levels of anti-apoptosis (Bcl-2 and Bcl-XL). While the beta blocker carvedilol (1 μM) normalized the level of p53 and Bcl-2 and the calcium channel blocker (CCB) bepridil (0.5 μM) normalized that of Bcl-2, both the CCB azelnidipine (1 μM) and the angiotensin receptor blocker (ARB) olmesartan (10 μM) normalized those of p53, Bax, cytochrome c, and Bcl-XL. Among those proteins, cytochrome c was the one which showed the highest degree of change. Both azelnidipine (0.1 μM) and olmesartan (1 μM) reduced the level of cytochrome c by 40.2 ± 4.3% and 31.3 ± 5.1%, respectively. The CCB amlodipine and the ARB valsartan reduced it only by 19.1 ± 2.1% and 20.1 ± 5.2%, respectively. Flow cytometric analysis and annexin V staining showed that treatment of cells with azelnidipine (0.1 μM) plus olmesartan (0.3 μM) or that with amlodipine (0.1 μM) plus valsartan (0.3 μM) reduced the number of apoptotic cells by 35.8 ± 10.5% and 18.4 ± 3.2%, respectively. Azelnidipine plus olmesartan or amlodipine plus valsartan inhibited apoptosis of HL-1 cells expressing E334K cMyBPC, and the former combination was more effective than the latter.

At the Source: Treating Heart Failure by Altering Muscle Motor Function

### Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure Malik et al Science . 2011;331:1439–1443. A new study in Science provides proof of the principle for directly modulating the cardiac muscle's motor, myosin, as a therapeutic target in heart failure. The human and economic tolls from heart failure (HF) are significant in both developed and undeveloped countries.1–3 Although HF can take many forms,4,5 it is most commonly associated with decreased cardiac contractility and is, therefore, referred to as systolic HF (sHF).6 Current therapeutic strategies rely on blocking neurohormonal activation by inhibiting associated pathways or by receptor blockade using either β-adrenergic or aldosterone blockers.7,8 Alternatively, some therapies are directed at increasing cardiac contractility in an effort to restore sufficient blood flow, usually by activating second messenger signaling pathways that increase cardiomyocyte calcium levels and augment sarcomere contraction.9 Both strategies suffer from a lack of specificity in that they target proteins upstream of the actual contractile events that underlie force production. Affecting important signaling pathways or receptor-ligand interactions can impact cellular function and perturb homeostasis in ways unrelated to the contractile apparatus, leading to undesirable side effects, such as hypotension, tachycardia, and even arrhythmias that can lead to sudden death.10 Recognizing the significant limitations of current therapeutic modalities, Malik and co-workers have directed their efforts at directly modulating cardiac contractility by tuning motor function at the source, the myosin heavy chain. The cardiac myosin heavy chains are encoded by two genes, MYH6 , which encodes α myosin heavy chain, and MYH7 , which encodes β myosin heavy chain, the latter being the predominant isoform in human ventricle. Although having greater than 90% amino acid homology, the two proteins differ significantly at the biochemical level. In comparison with α myosin, β myosin is relatively more efficient in force production as a function of energy consumption, with …

心筋梗塞の診断後約10年間の経過が観察できた109歳百寿者女性の1例

A 109-year-old woman was hospitalized with myocardial infarction in the geriatric long-term care ward of our hospital. Her medical history was unknown, and she was receiving only peroral 20 mg/day furosemide. Her medical records at another hospital revealed that she had been given a previous diagnosis of myocardial infarction of the anteroseptal wall of the left ventricle by a cardiovascular specialist approximately 10 years previously. Although treatment with cardiovascular drugs such as an angiotensin II receptor blocker, aspirin, and spironolactone had been started, it was discontinued because of her hospital transfer and change in her attending physician. Because of aggravation of the symptoms of cardiac failure caused by infection, treatment with the angiotensin-converting enzyme inhibitor temocapril (1 mg/day), spironolactone (12.5 mg/day), aspirin (100 mg/day), and a beta-adrenoceptor blocker carvedilol (2 mg/day) was tentatively initiated. Consequently, her B-type natriuretic peptide (BNP) level improved and her condition stabilized. She finally died of old age. Both inappropriate sharing of patient information among medical facilities and restrictions on medical care in Japanese health care system for the elderly may lead to improper and/or inadequate medical treatment for elderly patients. Although little evidence is available to support medical care for centenarians, treatment which is based on a thorough understanding of their physiological characteristics enables us to improve their quality of life.

Comparison of Effectiveness of Carvedilol Versus Bisoprolol for Prevention of Postdischarge Atrial Fibrillation After Coronary Artery Bypass Grafting in Patients With Heart Failure

Atrial fibrillation (AF) occurs frequently soon after coronary artery bypass grafting (CABG) and often results in increased mortality and morbidity, particularly in patients with heart failure. New-onset AF is also a common event in the early period after discharge from a cardiac surgery clinic. Current guidelines recommend β blockers as first-line medication for the prevention of AF after CABG. In this prospective study, we investigated the effectiveness of the highly selective β1 receptor antagonist bisoprolol compared to the less selective β blocker carvedilol in preventing postdischarge AF after CABG in patients with decreased left ventricular function. Three hundred twenty patients (231 men, 89 women, mean age 66 ± 10 years) with ejection fraction <40% who underwent CABG and were then referred to an in-hospital cardiac rehabilitation program were randomized to receive bisoprolol (n = 160) or carvedilol (n = 160) starting 4 to 5 days after surgery. Bisoprolol was started at 1.25 mg 1 time/day and carvedilol was started 3.125 mg 2 times/day. All patients underwent continuous telemetric electrocardiographic monitoring for 5 days after entry in the study and thereafter 2 times/day routinely up to hospital discharge. During follow-up, 23 patients (14.6%) in the bisoprolol group and 37 patients (23%) in the carvedilol group developed AF (relative risk 0.6, confidence interval 0.4 to 0.9, p = 0.032). Twenty-six percent of all AF episodes were asymptomatic. At the 4-week outpatient visit, those in the bisoprolol group showed a significantly greater decrease in heart rate, being in sinus rhythm or AF (-15.6 ± 3 vs -9.4 ± 3 beats/min, p = 0.021), whereas changes in systolic and diastolic blood pressures did not differ significantly. In conclusion, bisoprolol is more effective than carvedilol in decreasing the incidence of postdischarge AF after CABG in patients with decreased left ventricular function.

Adrenergic Receptor Blockade Reverses Right Heart Remodeling and Dysfunction in Pulmonary Hypertensive Rats

Most patients with pulmonary arterial hypertension (PAH) die from right heart failure. Beta-adrenergic receptor blockade reduces mortality by about 30% in patients with left-sided systolic heart failure, but is not used in PAH. To assess the effect of the adrenergic receptor blocker carvedilol on the pulmonary circulation and right heart in experimental pulmonary hypertension in rats. Angioproliferative pulmonary hypertension was induced in rats by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia. Carvedilol treatment was started after establishment of pulmonary hypertension and right heart dysfunction. Compared with vehicle-treated animals, treatment with carvedilol resulted in increased exercise endurance; improved right ventricular (RV) function (increased tricuspid annular plane systolic excursion and decreased RV dilatation); and an increased cardiac output. The morphology of the pulmonary vessels and the RV afterload were not affected by carvedilol. Carvedilol treatment was associated with enhancement of RV fetal gene reactivation, increased protein kinase G (PKG) activity, and a reduction in capillary rarefaction and fibrosis. Metoprolol had similar but less pronounced effects in the SU5416 and hypoxia model. Cardioprotective effects were noted of both carvedilol and metoprolol in the monocrotaline model. In the case of carvedilol, but not metoprolol, part of these effects resulted from a prevention of monocrotaline-induced lung remodeling. Adrenergic receptor blockade reverses RV remodeling and improves RV function in experimental pulmonary hypertension. Beta-adrenergic receptor blockers are not recommended in humans with PAH before their safety and efficacy are assessed in well-designed clinical trials.

Adrenergic receptor blockade-induced regression of pressure-overload cardiac hypertrophy is associated with inhibition of the calcineurin/NFAT3/GATA4 pathway

Calcineurin and its downstream effectors nuclear factor of activated T-cells 3 (NFAT3) and zinc finger-containing transcription factor (GATA4) have been implicated in the development of cardiac hypertrophy. The aims of the present study were to investigate alterations in the calcineurin/NFAT3/GATA4 pathway in pressure-overload hypertrophy, and to determine whether adrenergic receptor blockade affects this signaling pathway. In aorta-banded rats compared with sham-operated rats, a significant increase in the phosphorylation levels of calcineurin and GATA4 was observed (both p<0.05), while the NFAT3 phosphorylation level was markedly decreased (p<0.05). Oral administration of either the non-selective β blocker/α-1 blocker carvedilol or the selective β-1 blocker metoprolol, but not the selective α-1 blocker terazosin, significantly suppressed the activated calcineurin/NFAT3/GATA4 pathway (all p<0.05) in addition to inducing a regression of cardiac hypertrophy. Pressure overload-induced up-regulation of c-myc was markedly attenuated by treatment with either carvedilol or metoprolol (both p<0.05). The present findings may expand our understanding of the correlation between sympathetic activity and the calcineurin/NFAT3/GATA4 pathway, and highlight these signal transducers as effective targets in the management of pressure overload-induced cardiac hypertrophy.

Intracardiac defect demonstrated by cardiac CTA

A 50-year-old woman with history of multiple pulmonary arteriovenous malformation embolisations caused by hereditary haemorrhagic telangectasia (Rendu-Osler-Weber syndrome), complained of atypical chest pain and dyspnea. Electrcardiographic (ECG) findings were normal and the bicycle stress test was equivocal. ECG-gated 64-row cardiac multidetector computed tomography (MDCT) showed no significant coronary stenosis, but a membranous ventricular septal defect (VSD) (Fig. A, B). Patient responded well to a treatment with beta-adrenergic blocker (Carvedilol 3.125 mg/day), and considering the surgical risks, no attempt to close the VSD was performed.

EFFECTS OF CARVEDILOL ON MORTALITY AND INFLAMMATORY RESPONSES TO SEVERE HEMORRHAGIC SHOCK IN RATS

The nonselective beta-adrenoceptor and the selective alpha1-adrenoceptor blocker carvedilol are widely used in hypertensive and/or cardiac failure patients because of its efficacy. However, there have been few studies regarding the effects of carvedilol on severe hemorrhagic shock. The present study was performed to evaluate the effects of carvedilol on severe hemorrhagic shock in rats. Twenty-four male Sprague-Dawley rats were randomly assigned to 1 of the following 2 groups (n = 12 per group): control group, no medication; and treatment group, oral administration of carvedilol (10 mg/kg per day) for 5 days. All animals were anesthetized with i.p. pentobarbital. Severe hemorrhagic shock was induced by partial exsanguination. Eight minutes after shock, all removed blood was returned to the animal. No other treatments were administered before, during, or after shock. Hemodynamics and arterial blood gases were recorded, mortality was calculated for the 5-h observation period, and plasma cytokine concentrations were measured at 5 h after shock. The mortality rates at 5 h after cardiac arrest were 8% and 50% for control and treatment groups, respectively. The increases in base deficit and lactate concentrations were less in the control group than that in the treatment group. Moreover, the increases in TNF-alpha concentrations were less in the control group than in the treatment group. The present study indicated that oral administration of carvedilol had adverse effects on mortality and inflammatory responses to severe hemorrhagic shock in rats. These findings suggest that carvedilol may adversely affect recovery from severe hemorrhagic shock.

Real-world algorithms for the optimal use of drugs and devices in the patient post myocardial infarction and the future of post myocardial infarction management.

Patients with left ventricular dysfunction (LVD) are at increased risk for dying suddenly of cardiac causes. The most common causes of LVD are coronary artery disease (CAD) and myocardial infarction (MI). Aggressive intervention following MI is essential for minimizing the myocardial damage that leads to LVD and the subsequent risk for heart failure and sudden cardiac death. This article describes practical algorithms for managing the patient post MI to minimize such risks. The degree of LVD is a key factor for determining clinical management strategies in the patient post MI. Risk factor reduction and selective neurohormonal blockade, especially with angiotensin-converting enzyme inhibitors, are usually recommended in the presence or absence of LVD, along with early use of a beta blocker. In patients with LVD, more aggressive intervention includes extended use of a beta blocker. In cases of LVD progressed to heart failure, the mixed beta and alpha blocker carvedilol has improved outcomes significantly. In clinical trials, carvedilol has been demonstrated to have antiarrhythmic activity, a property that offers protection against sudden arrhythmic death in high-risk patients with LVD. Addition of an aldosterone antagonist is also advised in patients with heart failure. In selected patients with reduced ejection fractions, use of surgical/catheter treatment and device therapy offers further benefits.

A new possible strategy for prevention and preventive treatment of age-related macular degeneration resting on recent clinical and pathophysiological observations

The beneficial effect achieved by the treatment of endothelial dysfunction in chronic cardiovascular diseases is already an evidence belonging to the basic treatment of the disease. Given the fact that the vascular system is uniform and consubstantial both physiologically, pathophysiologically and in terms of therapy, and that it plays a key role in age-related macular degeneration (AMD)--a disease leading to tragic loss of vision with its etiology and therapy being unknown--endothelial dysfunction should be treated. The pleiotropic effects of ACE-inhibitors, AR-blockers and statins and third generation beta blockers help to restitute the balance between vasodilators and vasoconstrictors in endothelial dysfunction caused by oxidative stress, the balance of growth factors and their inhibitors, pro- and anti-inflammatory substances and prothrombotic and fibrinolytic factors, inhibit the formation of oxidative stress and its harmful effects; while aspirin with its pleiotropic effects acting as an antiaggregation substance on platelets helps to set the endothelial layer back to its normal balance regarding its vasodilating, antithrombotic, antiadhesive and anti-inflammatory functions; trimetazidine as an adjuvant agent helps to normalize, to restore the disturbed metabolism of the retinal tissue functioning insufficiently, in the end. The angiotensin II receptor blocker telmisartan with its peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist effect inhibits the development of choroidal neovascularisation (CNV) and improves it clinically favourably. The third generation beta adrenergic receptor blocker carvedilol and nebivolol as well as the peroxisome proliferator-activated receptor-gamma agonist pioglitazone elicit their antioxidant vascular protective effects mitochondrially. For the above reasons it is suggested that, as a part of long term primary and/or secondary prevention, the following groups of patients with AMD receive--taking into consideration all possible side effects--ACE-inhibitor and/or AR blocker and statin and aspirin treatment, and trimetazidine as adjuvant medicine, and third generation beta adrenergic receptor blockers: 1. those without macular degeneration but being above the age of 50 and having risk factors inducing endothelial dysfunction; 2. those, who already developed AMD in one eye as a prevention in the second, unaffected eye; and 3. those patients who developed AMD in both eyes in order to ameliorate or merely slow the progression of the disease. Besides, it is advisory and important to eliminate AMD risk factors (cardiovascular risk factors also) inducing oxidative stress with consecutive endothelial dysfunction.

Peyronie Disease in Association with Carvedilol: A Case Report

Beta blockade is associated with the onset and progression of Peyronie disease (PD). To date, there has not been a report of PD occurring with the alpha/beta blocker carvedilol. It remains unproven but likely that carvedilol was the cause of the PD in the patient described in this case. It is hypothesized that because of carvedilol's vasodilating alpha adrenergic receptor stimulation and its anti-inflammatory effect, PD occurs less frequently with carvedilol than with other beta blockers. However, in this case the protective properties of carvedilol, like vasodilation and the anti-inflammatory effect, may not be sufficient to overcome its vasoconstricting beta adrenergic receptor blockade.

Arg389Gly-β1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol

Administration of the beta-adrenergic receptor blocker carvedilol to patients with chronic heart failure leads to clinically significant benefits, including improvement in left ventricular systolic function in some, but not all, patients. We sought to determine the basis of the variable effect obtained with carvedilol in patients with heart failure. Carvedilol blocks both beta1-adrenergic and beta2-adrenergic receptors, and both receptors exist as polymorphisms. We aimed to determine whether these polymorphisms contribute to variability in response to carvedilol in patients with chronic heart failure. We retrospectively and prospectively investigated 135 patients with nonischemic cardiomyopathy and chronic stable heart failure (New York Heart Association class II, III) treated with carvedilol. Baseline echocardiography was obtained before introduction of carvedilol and repeated after stabilization of a maximally tolerated dose of carvedilol (50-100 mg/day) for at least 1 year. Polymerase chain reaction and restriction fragment length polymorphism analysis were used to genotype beta1-adrenergic and beta2-adrenergic receptor polymorphisms. When grouped according to receptor polymorphisms patients were well matched for severity of heart failure, comorbidity and treatment. No significant difference was observed in baseline left ventricular ejection fraction (LVEF) between groups (P>0.05). After 1.5 years of treatment with carvedilol patients with Arg389Arg-beta1-adrenergic receptors had a significantly greater improvement in LVEF compared with Gly389 carriers (Arg389Arg 18.8%; Arg389Gly 9.4%; Gly389Gly 6.0%; P<0.001) whereas there were no differences attributable to other beta1-adrenergic and beta2-adrenergic receptor polymorphisms (P>0.05). In patients with nonischemic dilated cardiomyopathy, carvedilol leads to a significantly greater improvement in LVEF in patients with the Arg389Arg-beta1 adrenergic receptor phenotype.

Comparison of Outcomes and Usefulness of Carvedilol Across a Spectrum of Left Ventricular Ejection Fractions in Patients With Heart Failure in Clinical Practice

Heart failure (HF) in the community differs meaningfully from that in clinical trials, particularly the higher prevalence of patients with preserved left ventricular (LV) ejection fraction (EF) typically excluded from clinical trials, thus limiting knowledge of their responsiveness to beta-blocker therapy. From a community-based registry of 4,280 patients with HF starting treatment with the beta blocker carvedilol, we compared characteristics, carvedilol titration, and outcomes of patients according to LVEF >40% or <40% (as in clinical trials) and across the spectrum of LVEF <21%, 21% to 30%, 31% to 40%, and >40%. Patients with preserved EF (LVEF >40%) were older and more often women and hypertensive. Lower LVEF was associated with worse functional class and more HF hospitalizations in the previous year. Carvedilol dose decreased with increasing LVEF. Hospitalization rates for HF related inversely to LVEF before starting carvedilol therapy and decreased from the previous year in all LVEF groups during follow-up. Although 1-year mortality rate decreased from 8% with LVEF < or =20% to 6% with LVEF >40%, adjusted hazard ratios were not significantly different across LVEF groups. Thus, characteristics of community patients with HF vary across the spectrum of LVEF. Patients with HF and preserved EF treated with carvedilol in the community improve symptomatically and experience fewer HF hospitalizations after initiating carvedilol. In conclusion, without a control group, the effect of carvedilol on outcomes is not conclusive and trials of carvedilol in patients with HF and preserved EF should be undertaken.

Endovascular repair of symptomatic abdominal aortic aneurysm complicated by postoperative acute myocardial infarction with cardiogenic shock

Dr. Reinhard Kopp, MD Chirurgische Klinik und Poliklinik LMU Munchen – Klinikum Groshadern Marchioninistr. 15 81377 Munich, Germany Sirs: Abdominal aortic aneurysms mostly occur in patients having positive cardiovascular risk factors. Its prevalence increases dramatically with age and is often associated with atherosclerosis and coronary artery disease. Thus perioperative mortality is mainly determined by cardiac events and is much higher in case of emergency. We report on the association of a symptomatic infrarenal aortic aneurysm combined with the most severe cardiac complication, a postoperative myocardial infarction based on a left main stenosis with a cardiogenic shock. A 79-year-old male patient presented with the past medical history of an abdominal aortic aneurysm, multivessel coronary artery disease, recent myocardial infarctions, congestive heart failure, terminal renal failure and diabetes mellitus type 2. His continuous medication consisted of a therapy according to the guidelines with aspirin, -blocker (Carvedilol), statin (Atorvastatin), ACE inhibitor (Ramipril) and diuretics (Furosemide). The patient was admitted in December 2004 to a regional district hospital with acute onset of flank and back pain. The treatment with different analgetics was without success. The patient was transmitted to our hospital with the suspicion of a symptomatic abdominal aortic aneurysm. The CT scan showed an acute expansion of the abdominal aortic aneurysm (max. 7.8×8.0×11.3 cm) without dissection or rupture (Fig. 1). The patient was immediately prepared for the vascular intervention and transferred to the operating room. Although the infrarenal aortic neck was short (less than 10 mm) an endovascular aneurysm repair (EVAR) with implantation of a monoiliac stent graft (Cook Zenith 32 mm diameter) occluding the contralateral common iliac artery was performed in combination with a femoro-femoral alloplastic cross-over bypass surgery (Fig. 2). The intervention was performed in general anesthesia and under continuous intravenous heparin application. Intraoperative angiography and also CT angiography 6 days after the EVAR showed complete exclusion of Abbreviations

Adrenergic blocker carvedilol attenuates the cardiovascular and aversive effects of nicotine in abstinent smokers

The cardiovascular response to nicotine is mediated mainly by noradrenergic activation. Whether noradrenergic activation mediates other effects of nicotine has not been well documented in humans. In this study, we examined the effects of an alpha and beta-adrenergic receptor blocker: carvedilol, on cardiovascular and subjective responses to nicotine lozenge and on the ability of nicotine lozenge to suppress tobacco withdrawal symptoms in overnight abstinent smokers. Fifteen smokers, nine men and six women, participated in a double-blind, placebo-controlled, crossover study. In each of the three experimental sessions, participants were treated orally with a single 25 or 50 mg dose of carvedilol or placebo. Two hours and 10 min following the medication treatment, participants received a single 4 mg nicotine lozenge. Carvedilol treatment attenuated the nicotine-induced heart rate, systolic and diastolic blood pressure increases. Carvedilol also attenuated the self-report rating of 'bad effects' in response to nicotine. Carvedilol, alone or in combination with nicotine lozenge, did not affect tobacco withdrawal symptoms. Carvedilol treatment did not affect performance on the Stroop Test. These results support the effectiveness of carvedilol for attenuating the cardiovascular effects of nicotine. Attenuation of the rating of 'bad effects' by carvedilol suggests that noradrenergic activation may also mediate the aversive effects of nicotine.

Carvedilol-induced antagonism of angiotensin II: a matter of α1-adrenoceptor blockade

To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective beta + alpha1-adrenoceptor blocker carvedilol as compared with the selective beta1-adrenoceptor blocker metoprolol. Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs. Angiotensin II and the alpha1-adrenoceptor agonist phenylephrine constricted HCMAs to maximally 63 +/- 10 and 46 +/- 15% of the contraction to 100 mmol/l K. Neither carvedilol, metoprolol, the nonselective beta-adrenoceptor antagonist propranolol, nor the alpha1-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. alpha1-adrenoreceptors and beta-adrenoceptors are thus not involved in the direct constrictor effects of angiotensin II. When added to the organ bath at a subthreshold concentration, angiotensin II greatly amplified the response to phenylephrine. Both carvedilol and the angiotensin II type 1 (AT1) receptor antagonist irbesartan inhibited this angiotensin II-induced potentiation. Furthermore, carvedilol blocked the angiotensin II-induced amplification of phenylephrine-induced inositol phosphate accumulation in cardiomyocytes. AT1-alpha1-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to alpha1-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT1 receptor blockade via its alpha1-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.

Pleiotropic Effects of the β-Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Carvedilol is a nonselective beta-adrenoceptor blocker with multiple pleiotropic actions. A recent clinical study suggested that carvedilol may be superior to other beta-adrenoceptor blockers in the treatment of heart failure. Despite numerous investigations, the underlying mechanisms of carvedilol on improving heart failure are yet to be fully established. The purpose of this study is to clarify the pleiotropic effect of carvedilol on cytosolic and mitochondrial calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes. Carvedilol (10 microM), but not metoprolol (10 microM), reduced H2O2 (100 microM)-induced apoptosis in neonatal rat cardiomyocytes. During the process, changes in cytosolic calcium concentration ([Ca2+]i) and mitochondrial calcium concentration ([Ca2+]m) and mitochondrial membrane potential (DeltaPsim) were measured by fluorescent probes [Fluo-3/acetoxymethyl ester (AM), Rhod-2/AM, and tetramethylrhodamine ethyl ester, respectively] and imaged by laser confocal microscopy. The results showed that H2O2 caused [Ca2]m overload first, followed by [Ca2+]i overload, leading to DeltaPsim dissipation and the induction of apoptosis. Carvedilol (10 microM) significantly delayed these processes and reduced apoptosis. These effects were not observed with other beta-adrenoceptor blockers (metoprolol, atenolol, and propranolol) or with a combination of the alpha (phentolamine)- and the beta-adrenoceptor blocker. The antioxidant N-acetyl-L-cysteine (NAC, 5 mM) and the combination of NAC and propranolol (10 microM) showed an effect similar to that of carvedilol. Therefore, the effect of carvedilol on H2O2-induced changes in [Ca2+]m, [Ca2+]i, and DeltaPsi(m) is independent of alpha- and beta-adrenoceptors but is probably dependent on the antioxidant effect.

Are β-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

The effect of beta blocker use on cyclosporine level in cardiac transplant recipients

Background: Beta blockers are frequently used after cardiac transplantation for their favorable effects on blood pressure control. There is no well-known interaction between beta blockers and cyclosporine (CsA). The aim of this study is to evaluate the effects of the commonly used beta blockers carvedilol and metoprolol on CsA level when initiated in cardiac transplant recipients. Methods: Using the cardiac transplant database at our center, we identified patients who were started on either carvedilol or metoprolol for blood pressure control. We then compared their CsA doses and levels before and within one to two weeks after the initiation of beta blocker therapy. Comparisons were also made between carvedilol and metoprolol groups. Results: In our transplant population, we found 20 patients on metoprolol, and 12 patients on carvedilol. With initiation of metoprolol, CsA level decreased in 12 patients and increased in 8 patients. The mean CsA level before and after metoprolol initiation was 236 and 253 ng/ml, respectively (p=0.50). In an attempt to maintain a therapeutic CsA level, the mean CsA dose was not significantly adjusted (from a mean of 293 mg/day to a mean of 294 mg/day; p=0.92). In the carvedilol group, CsA level increased in 10 of 12 patients. The mean CsA level before the initiation of carvedilol was 257 ng/ml. The mean CsA level after carvedilol initiation was 380 ng/ml (p=0.009). In an attempt to maintain a therapeutic CsA level, the mean CsA dose was reduced by 10% from a mean of 319 mg/day to a mean of 288 mg/day (p=0.004). Conclusion: Carvedilol, but not metoprolol, was associated with a significant increase in CsA levels after initiation in cardiac transplant recipients. An average reduction of 10% is necessary on the CsA dose upon initiation of carvedilol, and close follow up on the level is essential.