Type Of Beta-blocker Research Articles

The role of beta-blockers in left ventricular dysfunction and heart failure.

It was first reported by our group in 1975 that heart failure due to idiopathic dilated cardiomyopathy (IDC) could be improved by long term treatment with a beta-blocker, starting at a low dose and continuing with a stepwise up-titration. Since then, many studies have been performed in patients with heart failure of various aetiologies and the beneficial effects of long term beta-blockade have been confirmed. About 3000 patients have been included in randomised studies in which beta-blockade, given for more than 2 months, mostly elicited significant improvements in functional class, exercise capacity, cardiac function, quality of life and/or morbidity. When started at a very low dose (one-tenth to one-twentieth of the doses generally used in angina or hypertension), the treatment is well tolerated in most patients. In these studies, various types of beta-blockers were used, including beta1-selective blockers and nonselective blockers with additional properties (vasodilator and antioxidative) such as metoprolol, bisoprolol, bucindolol and carvedilol. Several large studies have also reported benefits on mortality and morbidity. In the Metoprolol in Dilated Cardiomyopathy (MDC) trial, metoprolol treatment in patients with IDC resulted in a 34% reduction of the primary combined endpoint, total number of deaths and need for cardiac transplantation. In the Cardiac Insufficiency Bisoprolol Study (CIBIS), in patients with idiopathic as well as ischaemic cardiomyopathy, there was a nonsignificant 20% reduction in mortality. In the US carvedilol studies (n = 1094), also in patients with ischaemic and idiopathic cardiomyopathy, carvedilol reduced mortality by 65%, which was highly significant. A nonsignificant reduction in mortality was observed in the Australia-New Zealand (ANZ) Heart Failure Study with carvedilol. In all these studies there was a reduction in hospitalisations, with all drugs being generally well tolerated. It can thus be concluded that the beneficial effects of beta-blockers on cardiac function and morbidity have been documented in a large number of studies in selected groups of patients. The treatment has been accepted in some countries by the regulatory authorities. Larger, placebo-controlled studies are needed to convincingly demonstrate a reduction in total mortality as observed in the pooling of the 4 US carvedilol studies. Such studies are in progress for various beta-blockers, which may lead to acceptance of their routine clinical use in patients with congestive heart failure.

Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: A meta-analysis

A meta-analysis of 12 selected randomized trials was performed to assess the efficacy of beta-blockers in the prevention of rebleeding and the effect on long-term survival in patients with cirrhosis. Five end points were assessed: rebleeding, variceal rebleeding, death, death from bleeding, and adverse events. Analyses were performed according to the intention-to-treat method. For each end point, heterogeneity and treatment efficacy were assessed by the Der Simonian and Peto methods. When a significant difference was observed, sensitivity analyses were performed by successive stratifications according to treatment duration, cause of initial bleeding, use of placebo, type of beta-blocker, type of publication, certainty of randomization, severity of cirrhosis, interval between index bleed and randomization, and methodological quality. Beta-blockers significantly increased the mean percentage of patients free of rebleeding (21% mean improvement rate, CI 95%: 10%-32%, P < .001, relative risk 1.42), the mean percentage of patients free of variceal rebleeding (20% mean improvement rate, CI 95%: 11%-28%, P < .001), the mean survival rate (5.4% mean improvement rate, CI 95%: 0%-11%, P = .05, relative risk 1.27), the mean percentage of patients free of bleeding death (7.4%, CI 95%: 2%-13%, P < .01, relative risk 1.50). Five patients would need to be treated with beta-blockers to prevent one rebleeding episode, 14 treated to prevent one death, and 13 treated to prevent one death from bleeding. There was no significant heterogeneity among studies by both methods of analysis. In patients with esophageal varices, beta-blockers significantly increase the mean percentage of patients free of rebleeding and the mean survival rate at 2 years.(Hepatology 1997 Jan;25(1):63-70)

Antihypertensive Treatment and Serum Cholesterol: Results of Population-Based Surveys in the German Cardiovascular Prevention Study

We analyzed the data from three cross-sectional, population-based surveys in West Germany to evaluate the effect of antihypertensive drug therapy on the level of serum cholesterol in German residents (18,344 males; 19,137 females) aged 25-69 years, after excluding persons with missing values (N = 5529) for any study variable. The data were obtained from the national and regional health surveys that were conducted during the years 1984-1992, within the framework of the German Cardiovascular Prevention Study (GCP). The response rates were between 66.0% and 71.4% for the national surveys and between 65.9% and 83.3% for the regional surveys. Blood-pressure and non-fasting cholesterol measurements were carried out under strictly standardized conditions. Multiple linear regression analysis was used to compare the age-adjusted mean value and prevalence for each of the following study variables: total serum cholesterol, HDL-cholesterol, non-HDL cholesterol, and the ratio of HDL cholesterol/total cholesterol for users and non-users of antihypertensive medications. Antihypertensive medications were reportedly taken during the seven days preceding the survey examination by 7.8% of all males and 10.4% of all females. The beta-blocker type of medication was prescribed most frequently for lowering high blood pressure. In both genders, the strongest age-adjusted effect of an increase in cholesterol level was found for beta-blockers. The difference in the age-adjusted means for non-HDL cholesterol values between users and non-users of beta-blockers was 9.2 mg/dL (p < 0.001) in males and 9.0 mg/dL (p < 0.001) in females. Regression analysis carried out to control for several potential confounders confirmed the results. The findings suggest that mass treatment of hypertension with beta-blockers may be associated with reductions in benefit because of an increase in non-HDL and a decrease in HDL cholesterol levels.

Treatment of essential and parkinsonian tremor with nipradilol.

Nipradilol is a new type of beta-blocker which possesses nitroglycerin-like vasodilating action in addition to beta-blocking action. We investigated the efficacy and safety of nipradilol for treating tremor in 20 patients with essential tremor (ET group) and 20 patients with Parkinson's disease (PD group). All patients received nipradilol (6 mg per day) for more than 8 weeks. Improvement of tremor appeared within 2 or 4 weeks after the start of nipradilol therapy, and the efficacy rate, defined as "moderately effective" or over, was 42.5% in all 40 patients, while that defined as "slightly effective" or over was 87.5%. The efficacy rate tended to be higher in the ET group compared with the PD group. Mean blood pressure was significantly decreased from the 4th week after the start of treatment and heart rate was significantly reduced from the 2nd week of treatment. Laboratory examination showed no significant changes.

Metabolic effects of antihypertensive drugs.

There is a well defined relationship between diuretic treatment and impaired glucose tolerance and dyslipidaemia. These effects, which are seen with thiazide diuretics and loop diuretics but not with spironolactone, are independent of body weight but are strongly dose-related. beta-BLOCKING AGENTS: beta-Blockers without intrinsic sympathomimetic activity have adverse effects on lipid metabolism, but beta-blockers with intrinsic sympathomimetic activity do not. From the metabolic point of view, the latter type of beta-blockers represent the ideal choice, but they are rarely used today. All types of beta-blockers can cause an increase in fasting blood glucose and impaired glucose tolerance. ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS AND CALCIUM ANTAGONISTS: Neither ACE inhibitors nor calcium antagonists show any negative effects on glucose and/or lipid metabolism. ACE inhibitors have even been shown to improve insulin sensitivity. ACE inhibitors and calcium channel blockers are metabolically neutral, and there is evidence that combining an ACE inhibitor or calcium antagonist with a diuretic can reduce the adverse effects of the latter. ANTI-OXIDATION: Some calcium antagonists show a dose-dependent anti-oxidative activity. Lacidipine has the greatest anti-oxidative activity of the commonly used calcium channel blockers. Among ACE inhibitors, only captopril has anti-oxidative activity. Both genetic and modifiable factors may contribute to the metabolic effects of antihypertensive drugs.

The effects of p-octopamine on salivary flow rates and protein secretion by rat submandibular glands.

The effects of p-octopamine injected i.v. and i.p on salivary flow rates and proteins secreted by the submandibular glands of rats were studied with and without various types of autonomic blockers at different doses, and with two enzyme inhibitors. The salivary flow rates and the amounts of protein secreted progressively increased with increasing doses injected both i.v. and i.p., whereas they were dramatically reduced with almost all autonomic blockers and disulfiram, a dopamine-beta-hydroxylase inhibitor. Salivation was completely abolished in response to p-octopamine in combination with metoprolol or phenoxybenzamine at high doses, and simultaneous injections of prazosin and propranolol. The concentration of protein in submandibular saliva in response to p-octopamine injected i.v. and i.p. was not dose-dependent and significantly increased with all of the alpha-blockers except yohimbine, and with atropine and disulfiram. The protease activity was dose-dependent but was reduced significantly with alpha-blockers except yohimbine and with two enzyme inhibitors. The alpha-type of protein was secreted in response to p-octopamine injected i.v. and i.p. at all doses except with the lowest dose i.p., which caused the beta-type to be secreted. The alpha-type was completely replaced by the beta-type with all alpha-blockers at all doses, except with yohimbine, but no change was observed with various types of beta-blockers, yohimbine, atropine, and two enzyme inhibitors. Thus, p-octopamine could stimulate both the alpha- and beta-adrenoceptors in the submandibular glands of rats.

Acute and chronic hemodynamic effects of drugs with different actions on adrenergic receptors: A comparison between alpha blockers and different types of beta blockers with and without vasodilating effect

The regulation of vascular resistance, cardiac output, and thus blood pressure can be influenced by antihypertensive drugs acting at central and peripheral adrenergic receptors. The results presented here are from acute or chronic studies in 205 patients with mild or moderately severe essential hypertension: beta blockers (N = 101); alpha blockers (N = 36); a separate alpha- + beta-blocker combination or the combination agent labetalol (N = 37); prizidilol, a beta-blocker/vasodilator (N = 14); and dilevalol, a beta blocker/beta 2-stimulator (N = 17). Beta blockers without strong intrinsic sympathomimetic activity reduce heart rate and cardiac output immediately, but due to a reflex increase in total peripheral resistance index, blood pressure is unchanged or only slightly reduced. During chronic use, total peripheral resistance drops towards pretreatment level and pressure falls. Beta blockers with strong intrinsic sympathomimetic activity do not reduce heart rate or cardiac output at rest when sympathetic tone is low. During exercise, heart rate and cardiac output are reduced, but less than with conventional beta blockers, and resistance is unchanged or slightly reduced. An acute and chronic reduction in blood pressure can be produced by alpha-adrenergic receptor blockers (prazosin, doxazosin, trimazosin), and in these cases the fall occurs via a reduction in total peripheral resistance index without reflex tachycardia. These drugs tend to increase exercise stroke volume and cardiac output during chronic treatment. Free combinations of beta and alpha blockers or the use of the fixed combination drug, labetalol, induce marked reductions in blood pressure at rest and during exercise, mainly through a reduction in total peripheral resistance index. During chronic treatment, exercise stroke volume and cardiac output are well maintained. In acute studies with dilevalol, systolic blood pressure, diastolic blood pressure, and mean arterial pressure were reduced (p less than 0.001) within 1 hour in 17 males with essential hypertension (WHO stage I) who received 200-400 mg oral dilevalol. The reduction in MAP was around 16-17% and was associated with an immediate fall in the total peripheral resistance index of the same magnitude (14%, p less than 0.001) after 1 hour at rest. There were no significant changes in heart rate or cardiac index.(ABSTRACT TRUNCATED AT 400 WORDS)

β-Blocker Effects on Plasma Lipids in Antihypertensive Therapy

The aim of this study was to evaluate the effects of long-term monotherapy with four beta-blockers provided with different pharmacological properties on plasma lipids in both normocholesterolemic and hypercholesterolemic hypertensive patients. After a 1-month run-in period on placebo, 70 hypertensive patients with basal total cholesterol (TC) < or = 220 mg/dl were treated for 3 years with propranolol 160 mg/day or atenolol 100 mg/day or bisoprolol 10 mg/day or mepindolol 10 mg/day, while 59 hypertensive patients with basal TC > 220 mg/dl were given the same beta-blockers at the same dosage for 6 months. In both normocholesterolemic and hypercholesterolemic hypertensive patients. HDL-C and triglyceride (TG) levels showed significant changes that appeared to be related to the type of beta-blocker used and to the duration of therapy. Nonselective, non-ISA (intrinsic sympathomimetic activity) propranolol caused the most pronounced changes, decreasing HDL-C and increasing TG concentrations; beta1-selective atenolol and bisoprolol had similar, but less remarkable effects; even more discrete changes were observed on mepindolol (with ISA). The variations in HDL-C and TG values reached their peak in 6-12 months of beta-blocker therapy; then, after a plateau phase, they showed a progressive trend toward pretreatment levels. In hypercholesterolemic patients, the percent change in both HDL-C and TG values was lower compared to normocholesterolemic patients.

Beta-adrenoceptor blockade and exercise. An update.

Blockade of beta-adrenoceptors interferes with haemodynamic and metabolic adaptations and ion balance during dynamic exercise. After administration of a beta-blocker exercise heart rate is reduced. Exercise cardiac output and blood pressure are reduced also, but to a lesser extent than heart rate. At submaximal exercise intensities blood flow to the active skeletal muscle is also reduced. The availability of non-esterified fatty acids for energy production is decreased, due to inhibition of beta-adrenoceptor-mediated adipose tissue lipolysis, and possibly also of intramuscular triglyceride breakdown. During submaximal exercise muscle glycogenolysis is unaffected, but there are indications that the maximal glycogenolytic rate at high exercise intensities is decreased. In normally fed subjects plasma glucose concentration is maintained at a normal level during submaximal endurance exercise after beta-blocker administration, although lower glucose concentrations are found in fasting subjects and during high intensity exercise after beta-blocker administration. Plasma lactate concentrations tend to be somewhat lower after beta-blocker administration while plasma potassium concentration during exercise is increased. beta-Blocker administration may also interfere with thermoregulation during prolonged exercise. Maximal aerobic exercise capacity is reduced in normotensive and probably also in hypertensive subjects after beta-blocker administration. Submaximal endurance performance is impaired to a much more important extent in both groups of subjects. In patients with coronary artery disease, on the other hand, symptom-limited exercise capacity is improved during beta-blocker treatment. Studies on trainability during beta-blocker treatment show inconsistent results in healthy subjects, although the majority of studies suggest a similar training-induced increase in VO2max during placebo and beta-blocker treatment. In patients with coronary artery disease the training effects are also similar in patients treated with beta-blockers and those without. The negative effects of beta-blockers on maximal and especially submaximal exercise capacity should be considered when prescribing beta-blockers to physically active hypertensive patients. The negative influence is shared by all types of beta-blockers, although the impairment of submaximal exercise capacity is more pronounced with non-selective than with beta 1-selective beta-blockers. beta-Blockers with intrinsic sympathomimetic activity have similar effects during exercise to those without intrinsic sympathomimetic activity.

陳旧性心筋梗塞を伴った狭心症におけるＮｉｐｒａｄｉｌｏｌの運動負荷時血行動態に及ぼす影響

Nipradilol (K-351) is a new type of beta-blocker with vasodilating action. The effect of nipradilol on hemodynamics at rest and during exercise with a multi-stage bicycle ergometer in supine position was studied in 8 male patients suffering from angina pectoris with old myocardial infarction.Nipradilol was orally given at the daily dose of 12mg (b.i.d.) for one week, and various hemodynamic parameters were measured at rest and during exercise before and after the treatment with nipradilol. At rest, the blood pressure was almost unchanged, heart rate was significantly reduced, cardiac output tended to decrease, and the pulmonary blood pressure and left ventricular ejection fraction (EF) were almost unchanged. At peak exercise, the blood pressure tended to decline, heart rate was significantly reduced, cardiac output tended to decrease and the pulmonary blood pressure and EF increased significantly.Consequently, the antianginal effect of nipradilol is considered to be attributable to the reduction in myocardial oxygen consumption caused due to decrease in double product. It is thus suggested that nipradilol exerts antianginal effect without adversely affecting the cardiac performance.

本態性高血圧症におけるＮｉｐｒａｄｉｌｏｌ（Ｋ‐３５１）経口使用時の血行動態に及ぼす影響

Nipradilol (K-351) is a new type of beta-blocker with vasodilating action. In this paper, the hemodynamic effect of nipradilol was studied non-invasively using 10 hypertensive patients. Nipradilol was orally given to patients with mild or moderate essential hypertension for about 3 months, and blood pressure (BP), heart rate (HR), cardiac output (CO), and systolic time intervals (STI) were measured, respectively. As results in the responder patients, both BP and HR decreased significantly, CO remained unchanged, and the total peripheral resistance (TPR) tended to decrease. In STI, the ejection time (ET) prolonged, the preejection period (PEP) shortened slightly, and ET/PEP increased.Accordingly, the hemodynamic effect of nipradilol was different from that of propranolol, probably due to the vasodilating action of nipradilol.

Cetamolol: cardiovascular effects of a new cardioselective beta-adrenoceptor blocker possessing partial agonistic activity and lacking membrane-stabilizing activity.

The cardiovascular effects of cetamolol, a new beta-adrenoceptor blocker, were studied in the anesthetized dog and cat and in the conscious dog and monkey. The compound was compared with other beta-blockers known to possess various degrees of cardioselectivity, partial agonistic effects, and membrane-stabilizing activity. In the anesthetized open-chest dog, cetamolol and pindolol produced similar cardiovascular effects in that the partial agonistic activity predominated over the blockade of beta-adrenoceptors. The partial agonistic activity of pindolol was greater than that of cetamolol. Unlike pindolol, cetamolol had no significant vasodilating property. However, the beta-blocking effects of these two drugs predominated in the anesthetized closed-chest dog, conscious dog and monkey. Atenolol, nadolol, and propranolol, which lack partial agonistic activity, produced cardiovascular changes characteristic of this type of beta-blocker in the animal preparation in which they were tested. In the anesthetized cat, comparison of the mean effective doses for the heart rate and blood pressure responses induced by isoproterenol showed that cetamolol was more cardioselective than metoprolol but less than acebutolol and atenolol. Evidence of the cardioselectivity of cetamolol was also obtained in the anesthetized closed-chest dog, although the degree of cardioselectivity of both cetamolol and atenolol was less marked than in the cat. When given orally to the conscious dog and monkey, cetamolol appeared to be well absorbed. The peak effect was observed after 1-2 h and persisted for the 5-h test period. It is concluded that cetamolol is a potent beta-blocker with a moderate degree of partial agonistic activity and cardioselectivity in in vivo experiments.

Effects of Beta Blockers on Cardiac Function and Myocardial Oxygen Consumption in the Isolated Supported Heart Preparation of the Dog

Effects of 2 different types of beta blockers, CS-359 and practolol, on mechanical performance and myocardial oxygen consumption (MVO2) in the isovolumic contraction of the isolated, blood-perfused canine heart with a support dog were studied. Two dose levels of the beta blockers were given intravenously to the support dog, one of which was enough to produce a significant beta adrenergic blocking action and other of which was a higher dose to reveal a direct depressant action on the isolated heart. CS-359 in the lower dose produced significant decreases in heart rate (HR), peak ventricular systolic pressure (peak VSP), and peak dp/dt while practolol caused no change in these parameters. The HR of the support dog was significantly decreased to the same degree in the lower dose of respective blocker. In the higher dose CS-359 decreased all parameters more definitely whereas practolol diminished peak VSP and peak dp/dt but did not significantly HR. MVO2 was decreased dose-relatedly by CS-359, but not affected significantly by practolol. From the analysis of relationships of MVO2 to peak VSP and HR in the isolated heart it is concluded that the effective reduction in MVO2 by CS-359 resulted mainly from a reduction in the peak VSP in the lower dose and additional decrease in HR in the higher dose of CS-359.