Influence of beta-blockers on the myocardial mRNA expressions of circadian clock- and metabolism-related genes

Daily rhythms are regulated by a master clock-system in the suprachiasmatic nucleus and by a peripheral clock-system in each organ. Because norepinephrine is one of the timekeepers for the myocardial circadian clock that influences cardiac metabolism, it is speculated that a beta-blocker may affect the circadian clock and metabolism in heart tissue. In this study, thirty mg/kg/day of propranolol (a lipophilic beta-blocker) or atenolol (a hydrophilic beta-blocker) was given orally to Wistar rats for 4 weeks. The mRNA expressions of Bmal1 and E4BP4 in heart tissue were suppressed by the beta-blockers. However, the mRNA expressions of these clock genes in the suprachiasmatic nucleus were unchanged. Myocardial mRNA expressions of lactate dehydrogenase a and pyruvate dehydrogenase kinase 4 were also suppressed by the beta-blockers. In addition, ATP content in heart tissue was significantly elevated by the beta-blockers throughout 24 hours. The effects of propranolol and atenolol did not differ significantly. This study showed for the first time that a beta-blocker affects myocardial clock gene expression. Propranolol and atenolol increased ATP content in heart tissue throughout 24 hours. The influences of beta-blockers may be negligible on the SCN, and may be independent of lipid solubility on heart tissue. It is well known that these drugs exert a protective effect against myocardial ischemia, which may be mediated by an increase in the preservation of myocardial ATP.     

The antifibrillatory effect of fentanyl, sufentanil and carfentanil in the acute phase of local myocardial ischaemia in the dog

To determine the effect of strong analgesics on electrical instability (vulnerability to ventricular fibrillation), we examined the action of fentanyl (60 micrograms/kg), sufentanil (10 micrograms/kg) and carfentanil (3 micrograms/kg) on the ventricular fibrillation threshold (VFT) in a dog model of coronary artery occlusion. The effect of strong analgesics was compared with that of the first-generation beta-blocker propranolol (1.2 mg/kg) and the third-generation beta-blocker celiprolol (3 mg/kg). In the 5th minute of ischaemia, VFT declines in all groups of dogs. VFT values rise significantly from the 23rd to the 60th minute of ischaemia after opiate analgesic administration. The mean increase in VFT after opiate analgesics is less pronounced than after beta-blockers. Administration of opioid analgesics is followed by strong prevalence of vagal drive to the heart. Sympathetic drive to the heart after propranolol administration disappears and is depressed after the administration of celiprolol only. Blockers of the beta-receptors apparently intervene directly in the ischaemic focus and affect the "substrate" of electrical instability. The opioid analgesics probably exert their effect through a change in "substrate" modulation. There is an ongoing search for drugs that would stabilize the heart electrically in acute myocardial infarction, thus preventing sudden death. Our experimental results favour a combination of strong analgesics with other electrostabilizing drugs.     

Effects of propranolol on the QT dispersion in congestive heart failure

OBJECTIVE - Studies have shown that therapy with beta-blockers reduces mortality in patients with heart failure. However, there are no studies describing the effects of propranolol on the QT dispersion in this population. The objective of this study was to assess the electrophysiological profile, mainly QT dispersion, of patients with heart failure regularly using propranolol. METHODS - Fifteen patients with heart failure and using propranolol were assessed over a period of 12 months. Twelve-lead electrocardiograms (ECG) were recorded prior to the onset of beta-blocker therapy and after 3 months of drug use. RESULTS - A significant reduction in heart rate, in QT dispersion and in QTc dispersion was observed, as was also an increase in the PR interval and in the QT interval, after the use of propranolol in an average dosage of 100 mg/day. CONCLUSION - Reduction in QT dispersion in patients with heart failure using propranolol may explain the reduction in the risk of sudden cardiac death with beta-blocker therapy, in this specific group of patients.     

T3 plus high doses of beta-blockers: effects on energy intake, body composition, bat and heart in rats

The effects of a combined treatment with supraphysiological doses of the thyroid hormone T3 (15 micrograms/kg BW/day, s.c.) and high doses of a predominant beta 1-blocker (atenolol, 12.5 and 25 mg/kg BW, 3X/day, s.c.) or a non-specific beta-blocker (propranolol, 5 mg/kg BW s.c. and 33 mg/kg BW p.o., each 3X/day) on energy intake, body composition and the heart were studied in overfed rats with an increased body fat content. The goal of the study was to investigate whether the above treatment constitutes a therapy for obesity in that T3 causes weight and fat loss and the beta-blockers prevent the unwanted T3-effects on the heart (tachycardia and increased heart weight). T3 did not increase energy intake above the level seen in overfed animals. It caused loss of body weight due to loss of fat but not protein, an increase in interscapular brown adipose tissue (IBAT) weight and fat, tachycardia and an increase in heart weight. Atenolol and propranolol blocked T3-induced tachycardia. With the exception of the highest propranolol dose which abolished the T3-induced increase in IBAT fat content, the beta-blockers did not modify the other T3 effects. Thus, in spite of the weight and fat loss and the lack of significant protein loss and tachycardia observed under T3/high dose beta-blockers treatment, the T3-induced increase in heart weight makes this treatment unsuitable as a therapy for obesity.     

Effects of intrinsic sympathetic activity of beta-blockers on SA and AV nodes in man

The authors compare the effects of beta-blockers without intrinsic sympathetic activity (ISA) (propranolol, 160 mg/day), moderate ISA (acebutolol, 800 mg/day) and high ISA (pindolol, 20 mg/day). The sinus rate decreases more with propranolol than with acebutolol, during the day (P less than 0.01) and during the night (P less than 0.001), whereas pindolol does not change the daylight rate and increases the nighttime rate (P less than 0.001). The ventricular rate during atrial fibrillation (AV nodal transmission) is modified as is sinus rate. There is no significant difference between propranolol and acebutolol, and a highly significant difference between pindolol and propranolol (P less than 0.001) or acebutolol (P less than 0.01). Moreover, the eurythmic effect of beta-blockers, making RR intervals more regular, is maximal with propranolol and minimal with pindolol, as judged on RR interval histograms. The ISA of the beta-blockers is of major importance for the clinical use of these drugs, and in the case of SA or AV node dysfunction ISA can be useful, but it can obscure the beneficial effects of beta-blocking therapy.     

Preservation of membrane phospholipids by propranolol, pindolol, and metoprolol: a novel mechanism of action of beta-blockers.

In this study, we examined the effects of three different beta-blockers, propranolol, pindolol, and metoprolol, on membrane phospholipid preservation in the ischemic and reperfused rat heart. Isolated rat hearts were perfused with Krebs-Henseleit bicarbonate buffer by the Langdendorff technique in the presence or absence of propranolol, pindolol, or metroprolol (20 microM each) for 15 mins at 37 degrees C. Hearts where then either made ischemic alone at 37 degrees C for 30 mins, or followed by 30 mins of reperfusion. Coronary flow and perfusate creatine kinase content were monitored during both pre- and post-ischemic periods. At the end of the experiment, hearts were frozen by freeze-clamping at liquid nitrogen temperature. Membrane phospholipids, fatty acid composition of these phospholipids, non-esterified free fatty acids, and myocardial thiobabituric acid (TBA) reactive product were examined in these hearts. The beta-blocker-treated hearts exhibited significantly less lipid peroxidation than the control hearts (P less than 0.05), as indicated by decreased formation of TBA reactive product and the higher percentage of unsaturated fatty acids in the phosphatidylcholine (PC) in heart. In addition, compared to the control group, less accumulation of free fatty acids was observed in the propranolol and pindolol treated groups. Finally, reduced myocardial creatine kinase release and enhanced recovery of coronary flow indicated significant myocardial preservation by these beta-blockers. The efficacy of these beta-blockers were in the following order: propranolol, pindolol, metoprolol. These results suggest that beta-blockers could also protect an ischemic heart from reperfusion injury by preserving the membrane phospholipids.     

Beta Blockers as Anti-Arrhythmic Agents

Although beta-adrenergic blocking agents are not always considered anti-arrhythmic drugs, the results of several recent trials have suggested an anti-arrhythmic mechanism for at least part of their mortality benefit in the treatment of chronic congestive heart failure. We review background experimental and clinical evidence for the anti-arrhythmic actions of beta-blockers and then review the results of published beta-blocker heart failure trials. A majority of trials showed improvement in overall survival as well as reduction in sudden death and ventricular arrhythmias with beta-blocker treatment. Although different effects were seen with different specific agents, these trials overall support a clinically significant anti-arrhythmic effect of several beta-blockers.     

Efficacy of the combination of low doses of beta-blockers and amiodarone in the treatment of refractory ventricular tachycardia

Thirty one patients aged 56 +/- 16 years with chronic ventricular tachycardias (VT) refractory to 4.4 +/- 1.8 antiarrhythmic drugs, used alone or in combination, were managed by low doses of beta-blocker agents combined with oral amiodarone, either after loading (1.2 g for 7 days, n : 7) or reloading (1.2 g for 4 days, n : 24) of amiodarone. All patients proved refractory to amiodarone alone. Nine VT were also refractory to endocardial catheter fulguration in 8 patients. Twenty one patients had coronary artery disease, 4 had arrhythmogenic right ventricular dysplasia, 4 had dilated cardiomyopathy, 1 had valvular disease, and 1 had no structural heart disease. Twelve patients had an ejection fraction less than 30 p. 100. Ten patients were in NYHA functional class 3. VT was permanent in 3 patients, daily in 5, weekly in 7, paroxysmal in 16. In 14 patients, VT occurred both at day and night. Oral administration of a daily low dose of a beta-blocker agent (acebutolol 100 mg, betaxolol 5-10 mg, metoprolol 50-100 mg, nadolol 20-40 mg, pindolol 2.5 mg, propranolol 30 mg, sotalol 80-160 mg, tertatolol 2.5 mg) combined with 400 mg per day of amiodarone suppressed VT episodes in all patients. None presented heart failure or collapse. The mean reduction of the heart rate was about 17 p. 100. One patient need a definite pacemaker to correct sinus bradycardia. At discharge, exercise ECG (n: 20) induced non sustained VT in 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of beta-blockers in older adults with chronic heart failure

Most heart failure patients are older adults. Angiotensin-converting enzyme (ACE) inhibitors reduce mortality and morbidity in patients with systolic heart failure. However, the annual mortality rate in patients with systolic heart failure receiving ACE inhibitors is about 12%. Beta-blockers further reduce mortality rate by an additional 35% to 65%. Because of potential adverse effects, the rate of beta-blocker use is likely to be low in older adults with systolic heart failure. In this article, we review the findings of the major beta-blocker trials in systolic heart failure and discuss the potential benefits and adverse effects of beta-blockers, along with various practical aspects of their use in older adults with systolic heart failure. Subgroup analyses of these trials suggest that the survival benefits of beta-blockers observed in the main trials are also observed in persons 65 years of age and older. However, data are limited for heart failure patients 85 years of age and older. About half of the older adults with heart failure do not have systolic heart failure, and currently there is no evidence that beta-blockers also improve survival in these patients. Beta-blockers might play a beneficial role in heart failure patients without systolic heart failure by reducing high blood pressure, high heart rate, or myocardial ischemia, conditions known to impair ventricular relaxation. Adequate knowledge of the commonly used beta-blockers, along with careful patient selection and close monitoring for adverse effects will allow safe initiation and continuation of beta-blocker use for older adults with systolic heart failure. It is likely that lower doses of beta-blockers are as effective as higher doses.     

Effect of intrinsic sympathomimetic activity on the ability of hypertensive patients to derive a cardiorespiratory training effect during chronic beta-blockade

The effect of intrinsic sympathomimetic activity (ISA) on the ability of patients with high blood pressure (BP) to derive a cardiorespiratory training effect during long-term beta-blocker therapy was studied. Fifty sedentary hypertensive subjects were randomly assigned to propranolol (n = 23) or pindolol (n = 27) therapy for a 22 week double-blind parallel study. Over the first 2 weeks, during which subjects remained sedentary, drug doses were titrated to produce equipotent, clinically significant BP reductions. Subjects subsequently continued drug therapy and completed 20 weeks of exercise training. Although pindolol tended to preserve submaximal exercise heart rates to a greater degree than propranolol, the initial 2 weeks of drug therapy resulted in equivalent reductions in maximal oxygen uptake with propranolol (6% reduction) and pindolol (8% reduction). Likewise, 20 weeks of training induced similar, statistically significant (P = .0001) increases in maximal oxygen uptake during propranolol (10% increase) and pindolol (11% increase) treatment. We therefore conclude that ISA does not confer any advantage to patients with high BP who receive chronic beta-blocker therapy and wish to improve their cardiorespiratory fitness by participating in exercise training.     

Beta-blockers: propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol, manifest atherogenicity on in vitro, ex vivo and in vivo models. Elimination of propranolol atherogenic effects by papaverine.

The addition of the beta-blockers propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol to a culture of peritoneal macrophages or smooth muscle cells induced an increase in the intracellular cholesterol content. Blood serum obtained from a rabbit after a peroral administration of beta-blockers also induced cholesterol accumulation. This property of drug or blood serum obtained after peroral administration is conventionally referred to as atherogenic potential or atherogenicity. Regular administration of propranolol during a 21-day period evoked stable atherogenicity of rabbit blood serum. This was accompanied by stimulation of manifestations of atherosclerosis in the aorta deendothelialized with a balloon catheter. Propranolol increased neointimal thickening, lipid accumulation, an increase in cell number and in the collagen content. In vitro, the combination of propranolol with papaverine eliminated the atherogenic effect of propranolol which manifested itself as stimulation of cholesterol accumulation in cultured cells. Simultaneous peroral administration of propranolol and papaverine prevented the appearance of serum atherogenicity. Papaverine eliminated neointimal thickening, an increase in cell number and in the lipid and collagen contents evoked by propranolol. Papaverine itself had no effect on these parameters. Thus, the atherogenicity of propranolol as well as capacity of papaverine to eliminate beta-blocker atherogenicity revealed in cell culture was confirmed in vivo. We hope that these results may be useful in the development of new drugs and optimization of antiatherosclerotic drug therapy.     

Beta-adrenoceptor blockers and terbutaline in patients with chronic obstructive lung disease. Effects and interaction after oral administration

We studied the effects of a combined treatment with beta 2-stimulating and beta-blocking drugs in 35 patients suffering from chronic obstructive lung disease (COLD) and ischemic heart disease, and/or arterial hypertension. The drugs used were equipotent repeated oral doses of metoprolol (100 mg twice daily [bid]), propranolol (80 mg bid), and a matching placebo for beta-adrenoceptor blockade given in a double-blind and crossover fashion. The intake period of each beta-blocker was two days with consecutive two-day-washout period; 2.5 mg terbutaline and beta-stimulator placebo, respectively, were given throughout the whole trial three times daily (tid). Propranolol alone caused severe deterioration of lung function. After 18 patients had been studied, this drug had to be excluded from the trial. When compared with placebo, metoprolol provoked increasing obstruction, too, but to a significantly lesser degree than propranolol. These negative effects on FEV1 and FRC were completely equalized by terbutaline. Predictive factors for the tolerability of beta-blockers in patients with COLD could not be found. Therefore, careful observations in the initial phase of the treatment with beta-selective blockers are necessary.     

Acute hemodynamic effects of propranolol, glycerylnitrate, and exercise in coronary patients with left ventricular dysfunction

Some adverse effects of beta-blockers in heart failure are counteracted by glycerylnitrate. However, the hemodynamics in this condition after giving both drugs are not well known. We examined the drug combination in exercising coronary patients with left ventricular dysfunction. Elevated left ventricular end-diastolic pressure was a measure of dysfunction. A right-heart catheterization with three successive exercise stress tests was done in 40 patients. At repeated exercise without drugs a "warming up" phenomenon was observed, consisting of small but statistically significant reductions in pulmonary capillary wedge pressure, and heart rate. At exercise propranolol reduced heart rate, cardiac output, systemic blood pressure, left ventricular work, and increased arteriovenous oxygen difference. Glycerylnitrate reduced pulmonary capillary wedge pressure at exercise, but, contrary to the findings at rest, it did not increase heart rate or reduce cardiac output. The drug combination resulted in hemodynamics that were similar to those after propranolol alone, except for a lower pulmonary capillary wedge pressure. The drug combination allowed the patients to exercise with the benefits of the beta-blocker, but at a lower ventricular filling pressure. Thus, the potential hazard of giving beta-blockers to patients with left ventricular dysfunction may be reduced by adding glycerylnitrate.     

Clinical trial data on the cardioprotective effects of beta-blockade

In most patients with heart failure the underlying cause is coronary artery disease (CAD). They have a poor prognosis and die slowly from deteriorating cardiac function or suddenly from ventricular fibrillation or atheromatous plaque rupture. Two key aims of treatment, therefore, are to slow the progression of underlying CAD and the resulting heart failure and to reduce the risk of sudden death. The impact of drugs on CAD and sudden death can be assessed most effectively in patients who have recovered from a myocardial infarction (post-MI patients). Beta-blockers have been studied in at least 25 trials in post-MI patients and their capacity to reduce mortality and re-infarction has been well documented. About 50% of those who die in post-MI trials die suddenly and beta-blockers particularly propranolol, timolol and metoprolol have been shown to reduce the risk of sudden death significantly. Further evidence that beta-blockers are cardioprotective in post-MI patients can be obtained from trials of other drugs by noting the mortality rates in those patients who were also on a beta-blocker. In three trials of antiarrhythmic drugs and two trials of ACE inhibitors, those on beta-blockers had a better prognosis. There is therefore good evidence that in a patient population known to have serious CAD, beta-blockers can effectively reduce the risk of major coronary events and are particularly effective in reducing the risk of sudden death.     

The effects of beta-blockers on morbidity and mortality in a population-based cohort of 11,942 elderly patients with heart failure

PURPOSE: Randomized trials have shown that beta-blockers prevent morbidity and mortality in heart failure. However, whether beta-blockers are effective in older patients or those with conditions that would have led to their exclusion from these trials remains unclear. SUBJECTS AND METHODS: The associations between beta-blocker use and outcomes were examined in a population-based cohort of 11,942 older (age >/=65 years) patients with incident heart failure between 1994 and 1999. Cox proportional hazards models were used to adjust for propensity scores, age, sex, comorbid conditions, and other medications. RESULTS: The mean (+/- SD) age of the patients was 79 +/- 8 years, 5819 (49%) were men, and 2569 (22%) had Charlson comorbidity scores of at least 2. During follow-up (median, 21 months), 3539 patients were hospitalized for heart failure and 6757 died. Overall, 1162 patients received beta-blockers. After adjustment, beta-blocker use was associated with substantial reductions in all-cause mortality (hazard ratio [HR] = 0.72; 95% confidence interval [CI]: 0.65 to 0.80), mortality due to heart failure (HR = 0.65; 95% CI: 0.47 to 0.90), and hospitalizations for heart failure (HR = 0.82; 95% CI: 0.74 to 0.92). These endpoints were less frequent in patients treated with beta-blockers than in untreated patients in all examined subgroups. All doses of beta-blockers were associated with benefit, but there was a trend towards greater benefit in patients prescribed higher doses. CONCLUSIONS: The benefits of beta-blockers seen in randomized trials extend to older patients and to those with conditions that would have led to their exclusion from the trials. There is a need for a randomized trial comparing different doses of beta-blockers in heart failure.     

Comparison of hypersensitivity to adrenergic stimulation after abrupt withdrawal of propranolol and nadolol: influence of half-life differences

To test whether a beta-blocker's pharmacokinetics has an effect on the development of the beta-blocker withdrawal syndrome, we compared response to exercise and isoproterenol after abrupt withdrawal of two beta-blockers, one with a short half-life (propranolol) and one with a long half-life (nadolol). Eight normal males participated in the randomized cross-over trial. They took propranolol, 40 mg every 6 hours for 6 days, and nadolol, 80 mg daily for 7 days. Exercise- and isoproterenol-induced changes in heart rate and pulse pressure were significantly less than control values during treatment with both drugs (p less than 0.05). Significant hypersensitivity of heart rate response was seen on days 2, 3, and 7 after propranolol withdrawal (p less than 0.05) and on day 6 after nadolol withdrawal (p less than 0.005). Hypersensitive responses to isoproterenol were seen after propranolol withdrawal; no evidence of hypersensitivity to isoproterenol was seen after nadolol withdrawal. The area under the heart rate response, time curve after nadolol withdrawal was significantly less than that after propranolol withdrawal (20.3 beats/min.day vs 44.9 beats/min.day, respectively, (p less than 0.05). There was a significant inverse correlation between the degree of hypersensitivity and nadolol pharmacokinetic half-life (r = -0.80, p less than 0.02). We conclude that abrupt withdrawal of a beta-blocker with a long half-life may protect against the development of the beta-blocker withdrawal syndrome.     

Effect of pindolol and propranolol on sinus node recovery time and atrioventricular conduction intervals

In a randomized, observer-blind study, the effect of incremental doses of pindolol 0.001, 0.002, 0.003, and 0.004 mg/kg IV and propranolol 0.01, 0.02, 0.03, and 0.04 mg/kg IV on SA nodal recovery time (SNRT) and atrioventricular conduction interval (AH) was assessed in 20 patients (15 men and 5 women age range thirty to seventy-two, mean age fifty-three). AH and His bundle-to-ventricle (HV) intervals and SNRT were measured at spontaneous heart rate and at incremental atrial pacing rates (80, 100, 120, 140 bpm). Both drugs caused significant beta blockade as estimated by the percentage suppression of heart rate increment induced by 3 mcg isoproterenol administered intravenously (pindolol 67.6 +/- 5.3%, P less than 0.007; propranolol 38.6 +/- 10.6%, P less than 0.001). Propranolol significantly prolonged SNRT (P less than 0.05) and AH interval (P less than 0.05). Pindolol did not significantly affect either SNRT (P = 0.25) or AH intervals (P = 0.78). Significant effects on HV interval were not seen. Thus, in the doses tested that resulted in significant beta blockade, propranolol prolonged SA nodal recovery times and depressed AV nodal conduction while pindolol did not affect these variables.     

Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 6. A comparison of pindolol and propranolol in treatment of patients with angina pectoris. The role of intrinsic sympathomimetic activity.

Pindolol, a new beta-adrenergic blocking drug with intrinsic sympathomimetic activity, and propranolol were given in increasing equipotent doses (pindolol: 2.5 to 10 mg. every 6 hours; propranolol: 10 to 40 mg. every 6 hours) over 12 weeks in a double-blind randomized trial to 41 patients with angina pectoris. The drugs were then gradually withdrawn over a two week period. With maximum doses, both pindolol and propranolol increased exercise capacity, compared to control, on multistage treadmill testing (pindolol: 8.0 ± 0.4 to 9.7 ± 0.3 mets, p < 0.01; propranolol: 8.0 ± 0.4 to 9.6 ± 0.3 mets, p < 0.05). At each exercise level both pindolol and propranolol decreased the heart rate, systolic blood pressure, and rate-pressure product (HR × BP). At the 9 met exercise level, the HR × BP decreased from 17,420 ± 850 to 13,205 ± 510 mm. Hg min.^?1 with pindolol (p < 0.002); with propranolol; 18,106 ± 440 to 13,205 ± 480 mm. Hg min.^?1 (p < 0.01). At the same level the magnitude of exercise-induced ECG ST depression decreased from 1.3 ± 0.3 to 0.4 ± 0.15 mm. with pindolol (p < 0.05), and from 1.3 ± 0.3 to 0.8 ± 0.2 mm. with propranolol (p < 0.05). Both drugs reduced the number of spontaneous attacks of angina pectoris per week. Pindolol did not appreciably decrease the resting heart rate (66.8 ± 1.9 vs 64.6 ± 1.2) or HR × BP (8,254 ± 418 vs 7,651 ± 210 mm. Hg min.^?1 in contrast to propranolol, which reduced both (heart rate: 70.5 ± 2.2 to 62.2 ± 2.4, p < 0.01; HR × BP: 8,677 ± 423 to 7,338 ± 455 mm. Hg min.^?1, p < 0.005). In addition, pindolol slightly increased the echocardiographically estimated ejection fraction at rest (0.59 ± 0.02 to 0.62 ± 0.02, p < 0.02), while propranolol depressed it (0.57 ± 0.02 to 0.51 ± 0.01, p < 0.04). Both pindolol and propranolol could be safely withdrawn over a gradual two week withdrawal interval.