The acute hemodynamic effects of the new vasodilating beta blocker carvedilol in comparison with combined administration of nifedipine and propranolol in patients with coronary heart disease

The acute hemodynamic effects of carvedilol, a new vasodilating betablocker, were assessed in comparison to the response to nifedipine or a combination of nifedipine and propranolol in patients with coronary artery disease. Either 5 mg carvedilol, 2 mg nifedipine or 2 mg nifedipine + 5 mg propranolol (N + P) were administered intravenously in a not randomized study within 30 min to 10 patients for each drug. Carvedilol reduced (comparable to the effect of N + P) the left ventricular afterload with a decrease of AOPm of 12.6%, p less than 0.001 (N + P -11.8%, p less than 0.001) and systemic vascular resistance of 9.1%, p less than 0.02 (N + P -10.0%, p less than 0.01) and no change of cardiac index. Single treatment with nifedipine leads to a reflex increase of heart rate which could not be observed after carvedilol or N + P as a result of the betablocking properties of carvedilol and propranolol. Therefore, the rate-pressure-product at rest was unchanged after nifedipine but decreased significantly after carvedilol (-10.9%, p less than 0.01) and N + P (-12.4%, p less than 0.01). Negative inotropic effects were significantly lower after carvedilol, with a 6.3% (p less than 0.05) decrease of LV dP/dtmax, compared to N + P (-12.0%, p less than 0.01). Since preload, afterload, and heart rate changes were equal in both groups negative inotropic effects can be compared on the base of dP/dtmax changes. The acute hemodynamic effects (vasodilation without reflex tachycardia, negative inotropic effects) of the new vasodilating betablocker carvedilol are comparable to a combined treatment with nifedipine and propranolol in patients with coronary artery disease and well preserved left ventricular global function.     

Antianginal efficacy of carvedilol, a beta-blocking drug with vasodilating activity

The efficacy of carvedilol, a new vasodilating beta-blocking drug, was evaluated in 20 patients with chronic angina using a single-blind, placebo-controlled protocol. A 2-week placebo phase was followed by therapy with carvedilol, 25 mg twice daily for 2 weeks, after which the dose was doubled. There was then a second placebo phase lasting 2 weeks. Treadmill exercise testing, 24-hour ambulatory electrocardiographic monitoring and drug blood level assays were performed at the end of each phase. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 minutes during placebo to 9.0 +/- 0.5 minutes carvedilol, 25 mg twice daily (p less than 0.001), and to 9.2 +/- 0.4 minutes with 50 mg twice daily (p less than 0.001). Mean time to 1 mm of ST depression in both bipolar leads CM5 and CC5 increased significantly, but peak ST depression did not change. Heart rate at rest was reduced at both dose levels, from 86 +/- 4 beats/min during placebo to 70 +/- 2 beats/min with 25 mg twice daily (p less than 0.001) and to 67 +/- 3 beats/min with 50 mg twice daily (p less than 0.001). Systolic blood pressure at rest was significantly reduced at both doses (p less than 0.05; p less than 0.01), but blood pressure during exercise was decreased only with the larger dose (p less than 0.001). The exercise rate-pressure product was 182 +/- 9 with placebo and decreased to 153 +/- 5 with 25 mg twice daily (p less than 0.001) and to 138 +/- 6 with 50 mg twice daily (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of carvedilol (BM 14,190), a new beta-blocking drug with vasodilating properties, in exercise-induced ischemia

The exercise response to a single oral dose (25 mg) of a new beta-blocking agent that also has potent vasodilating properties, carvedilol (BM 14,190), was assessed in 15 patients with stable exertional angina, positive exercise test responses (greater than or equal to 1 mm of ST depression) and coronary artery disease. A single-blind, placebo-controlled, randomized, crossover design was used. Compared with placebo, 25 mg of carvedilol significantly reduced both heart rate (HR) and blood pressure (BP) at rest (p less than 0.01). After administration of carvedilol, 10 of 15 patients did not have angina at peak exercise (p less than 0.01) and 5 had ST shifts of less than 1 mm (p less than 0.05). Total exercise time and time to 1 mm of ST depression were prolonged and ST-segment depression at peak exercise was significantly reduced (p less than 0.01). Systolic BP was reduced both at peak exercise and at 1 mm of ST depression (p less than 0.05), whereas mean HR at peak exercise did not change significantly compared with placebo. Overall, mean HR-BP product at peak exercise was significantly reduced by carvedilol compared with placebo (p less than 0.05). However, 4 patients actually achieved a higher HR-BP product but did not have angina and had less ST depression (or no ST-segment shifts) at peak exercise. This indicates an increase in their coronary flow reserve. These results suggest that carvedilol is effective therapy for effort-induced angina, and this may be related to its combined beta-blocking and potent vasodilatory properties.     

Long term use of a non-selective beta-blocker with vasodilating properties carvedilol in patients with severe heart failure

Results of drug treatment of 51 patients (41 men, 10 women) aged 35-86 years (mean age 62 years) included into COPERNICUS trial are presented. All patients had compensated NYHA class IV chronic heart failure and left ventricular ejection fraction less than 25%. For at least 2 months the patients received therapy with diuretics and angiotensin converting enzyme inhibitors (84%) or angiotensin receptor blockers (16%) and then were randomized to either carvedilol or placebo. Average duration of follow-up was 17 months. Carvedilol was well tolerated both during dose titration and during maintenance therapy. Addition of carvedilol to standard therapy of patients with severe heart failure was associated with increase of average ejection fraction from 21.7 to 30.3%. Rates of cardiovascular and sudden deaths, risk of hospitalization among carvedilol treated patients were 25, 33 and 57% less than among patients subjected only to standard therapy.     

Prevention of postischaemic ventricular fibrillation by long term beta adrenoceptor blockade with acebutolol in the anaesthetised dog

Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment underwent the same procedure. Coronary ligations in the randomised study were performed during seven consecutive days, and four dogs were operated on each day. This schedule was chosen in order to measure acebutolol plasma concentrations just before ligation from 60 to 540 min after the last dose of the drug. Long term oral treatment with acebutolol protected against postischaemic ventricular fibrillation and significantly reduced the incidence of both early phase (0-10 min postocclusion) ventricular arrhythmias and ventricular fibrillation. As a result the outcome was significantly improved after 60 min of ischaemia in acebutolol compared with placebo treated animals. The results in the control animals were similar to those in the placebo treated dogs. The protective effect of long term oral treatment with acebutolol lasted for nine hours and was apparently independent of the plasma concentrations of the drug. These data show that improved outcome in this canine model is due to the prevention of ischaemia induced ventricular fibrillation by long term beta adrenoceptor blockade, which is able to overcome the effect, if any, of partial agonist activity of acebutolol. A direct myocardial anti-ischaemic effect might explain the effectiveness of long term oral treatment, which is independent of plasma concentrations of the drug.     

Beta-blockade in heart failure: a comparison of carvedilol with metoprolol.

OBJECTIVES: This study was performed to compare the long-term clinical efficacy of treatment with metoprolol versus carvedilol in patients with chronic heart failure. BACKGROUND: Beta-adrenergic blockade is of proven value in chronic heart failure. Metoprolol, a selective beta-blocker, is widely used, but recent trials suggest carvedilol, a nonselective beta-blocker with alpha-1-receptor antagonist activity and antioxidant activities, is also effective. It is uncertain, however, if these additional properties of carvedilol provide further clinical benefit compared with metoprolol. METHODS: In this randomized double-blind control trial, 51 patients with chronic heart failure and mean left ventricular (LV) ejection fraction of 26% +/- 1.8% were randomly assigned treatment with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to standard therapy after a four-week dose titration period for a total of 12 weeks. Response was assessed by a quality of life questionnaire, New York Heart Association class, exercise capacity (6-min walk test), radionucleotide ventriculography for LV ejection fraction, two-dimensional echocardiography measurement of LV dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate variability. RESULTS: Both carvedilol and metoprolol produced highly significant improvement in symptoms (p < 0.001), exercise capacity (p < 0.05) and LV ejection fraction (p < 0.001), and there were no significant differences between the two drugs. Carvedilol had a significantly greater effect on sitting and standing blood pressure, LV end-diastolic dimension and normalized the mitral E wave deceleration time. CONCLUSIONS: Both metoprolol and carvedilol were equally effective in improving symptoms, quality of life, exercise capacity and LV ejection fraction, although carvedilol lowers blood pressure more than metoprolol.     

Verification of a canine model of transient exercise induced myocardial dysfunction: antianginal effects of flestolol, an ultra short acting beta adrenoceptor antagonist

STUDY OBJECTIVE - The aim of the study was to verify the reproducibility of a canine model of treadmill exercise induced regional myocardial dysfunction designed to mimic exertional angina pectoris in man. DESIGN - Dogs trained to run on a treadmill were chronically instrumented with a microtip manometer in the left ventricle, a hydraulic occluder around the circumflex branch of the left coronary artery, two pairs of crystals for sonomicrometry, and arterial and venous catheters. Experiments were started 10 d after surgery, when the animals were submitted to seven treadmill exercise cycles, each of 3 min, with a 7 min recovery period. Ischaemia was adjusted so as not to impair regional function at rest but to produce progressive dysfunction with increasing work load. Flestolol (1 microgram.kg-1.min-1) was infused intravenously during the third and fourth exercise cycle. SUBJECTS - Six mongrel dogs, 13.5-29.5 kg, were used. MEASUREMENTS and RESULTS - Flestolol caused a marked reduction in the exercise induced increase in left ventricular positive dP/dtmax, and minor reductions in heart rate and systolic blood pressure, resulting in a decrease in myocardial oxygen demand and an improvement in regional function in the circumflex area of the left coronary artery. The functional improvement was transient and disappeared entirely after termination of flestolol infusion. CONCLUSIONS - The results show that flestolol is beneficial in conditions of limited coronary reserve and exercise induced myocardial dysfunction. The fact that the extent of regional myocardial dysfunction was comparable before and after flestolol infusion confirms the stability and usefulness of this experimental model in the evaluation of antianginal drugs.     

Evaluation of a new vasodilating beta-blocking agent, carvedilol, in exertional angina using holter monitoring

Antianginal and antiischemic effects and clinical pharmacologic actions of carvedilol, a novel beta-blocking agent with a vasodilator action, were determined by Holter electrocardiographic monitoring in 13 patients with exertional angina. The patients were observed for 1 week prior to entry into the study, followed by 1 to 2 weeks of treatment with carvedilol. During the observation period the patients received one placebo tablet daily, and during the treatment period one 20 mg tablet of carvedilol daily. Before and after the treatment 24-hour Holter electrocardiographic tracings were obtained. The mean interval of Holter monitoring was 11.2 +/- 4.5 days for the observation and treatment periods, and the mean time of drug administration was 8:25 a.m. (+/- 30 min). The Holter electrocardiographic tracings which were obtained twice in 9 patients during the observation period showed a high degree of reproducibility with respect to the frequency, magnitude and duration of ST-segment depression. The total frequency of ST depression per patient was 4.5 +/- 3.4 events/day pre-drug and 2.1 +/- 2.1 events/day post-drug. There was a significant reduction in total frequency of ST depression post-drug (p less than 0.01). The frequency of asymptomatic ST depression was similarly decreased post-drug (p less than 0.01), and the total magnitude and duration of ST depression were significantly improved post-drug (p less than 0.01 and p less than 0.05, respectively). These effects of carvedilol lasted for 24 hours after administration. Considering that the heart rate was not excessively reduced during the night, and nocturnal myocardial ischemic episodes were not exacerbated, the mode of action of this drug seems to be based on not only a beta-blocking action but also on a vasodilator action. Carvedilol benefits exertional angina when used in a 20 mg s.i.d. regimen.     

Effects of a new vasodilating beta-blocking drug,carvedilol, on left ventricular function in stable angina pectoris

The effects of a new vasodilating β-blocking drug, carvedilol, were studied in 20 patients with chronic stable angina using a single-blind, placebo-controlled protocol. Two doses of carvedilol, 25 mg twice daily and 50 mg twice daily, were compared with placebo using analysis of variance. The study design consisted of 2 weekly phases of initial placebo followed by carvedilol, 25 mg twice daily and then 50 mg twice dally, and a second placebo period. Supine rest and exercise radionuclide ventriculography was performed at the end of each phase. Carvedilol produced a significant dose-related reduction in rest and exercise heart rate and blood pressure (p < 0.01 to < 0.0001). Ejection fraction at rest increased significantly, from a mean (± standard error) of 53 ± 3 % with placebo to 58 ± 3 % with carvedilol, 50 mg twice daily, but no improvement was noted in ejection fraction on exercise. Relative, counts-based end-systolic and end-diastolic volumes were significantly reduced at rest (p < 0.001). Rest peak filling rate index, first-third filling fraction and ejection rate index increased significantly with carvedilol. A dose-related change was observed with rest ejection fraction, peak filling rate index and ejection rate index. Exercise-induced ST-segment depression improved significantly with both doses of carvedilol compared with placebo. Carvedilol was well tolerated and produced significant hemodynamic improvement. This salutary effect on left ventricular function may confer advantages in long-term treatment of patients with chronic stable angina.     

CI-930, a new cardiotonic and vasodilating agent: hemodynamic comparison to dobutamine and long-term clinical effects

The hemodynamic and clinical effects of parenteral and oral CI-930, a new phosphodiesterase type III inhibitor with combined vasodilator and inotropic properties, were studied in 12 patients with severe congestive heart failure refractory to therapy including captopril. The maximum response to dobutamine was also determined. Intravenous CI-930 increased cardiac index from 1.73 +/- 0.48 to 2.38 +/- 0.55 L/min/m2, and reduced pulmonary capillary wedge pressure from 19.2 +/- 7.9 to 12.5 +/- 6.4 mm Hg, mean right atrial pressure from 7.5 +/- 6.3 to 3.6 +/- 4.0 mm Hg, and systemic vascular resistance from 2288 +/- 860 to 1711 +/- 611 dynes . sec . cm-5 (p less than 0.001 for all). Heart rate and mean systemic arterial pressure were unchanged. The increment in cardiac index produced by dobutamine was higher than for CI-930, 2.68 +/- 0.55 vs 2.38 +/- 0.55 L/min/m2, p less than 0.001. However, reduction in pulmonary capillary wedge pressure tended to be less with dobutamine, 15.7 +/- 7.9 vs 12.5 +/- 6.4 mm Hg (NS). Hemodynamic benefits of oral CI-930 were equivalent to that of the parenteral drug. Duration of action was 9 to 12 hours. Chronic therapy resulted in subjective improvement in approximately 50% of patients. Exercise capacity, assessed by maximum oxygen consumption, was unchanged, 8.4 +/- 3.3 vs 9.8 +/- 3.4 ml/kg/min (NS). No overt laboratory manifestations of toxicity were observed.     

β受体阻滞剂对动脉粥样硬化家兔血管内皮依赖舒张功能的影响

目的:对比观察β受体阻滞剂卡维地洛、普萘洛尔与阿替洛尔对动脉粥样硬化家兔血管内皮舒张功能的影响。方法:30只雄兔随机分为高脂组、高脂加卡维地洛组(10mg.kg-1.d-1)、高脂加普萘洛尔组(10mg.kg-1.d-1)、高脂加阿替洛尔组(20mg.kg-1.d-1)和正常对照组。前4组给予相应处理1周后,行腹主动脉球囊损伤术,并继续相应处理10周;正常对照组给予假手术及正常饮食。干预结束时,测定血脂及一氧化氮(NO)水平,取动脉组织检测血管内皮依赖舒张功能、内皮源性NO释放量。结果:与正常对照组相比,高脂组血TC、TG、NO水平均明显升高,而内皮源性NO释放量均明显降低(均P<0.01)。与高脂组相比,3种β受体阻滞剂在所用剂量内均未对血脂产生显著性影响。卡维地洛明显升高内皮源性NO释放量1.6倍(P<0.05),而普萘洛尔与阿替洛尔均未对上述指标产生明显影响。与正常对照组相比,高脂组家兔血管内皮依赖舒张功能明显减弱(P<0.01),所用干预药物中,只有卡维地洛明显改善高脂家兔内皮依赖舒张功能(P<0.05)。结论:与普萘洛尔、阿替洛尔相比,卡维地洛更能增强内皮源性NO活性,改善NO介导血管内皮依赖舒张功能。     

Effects of xamoterol, a beta 1 adrenoceptor partial agonist, in patients with ischaemic dysfunction of the left ventricle.

The effects of xamoterol (200 mg twice a day) in 21 patients with left ventricular dysfunction were studied in a double blind, randomised, crossover, placebo controlled trial with treatment periods of four weeks. Most patients had moderate heart failure (New York Heart Association class II), all had ischaemic heart disease, a history of a myocardial infarction, and symptoms of dyspnoea on exertion. Patients were assessed in terms of exercise duration (bicycle ergometer), clinical signs of heart failure, symptoms and activities, and ejection fraction. Xamoterol increased exercise duration (mean (SD] (from 445 (8) seconds to 484 (8) seconds) and ejection fraction (from 41.9 (1.3)% to 46.6 (1.3)%) and reduced the signs and symptoms of heart failure. The results of this study show that xamoterol is a safe and effective treatment for left ventricular dysfunction resulting from ischaemic heart disease.     

Metabolic properties of vasodilating beta blockers: management considerations for hypertensive diabetic patients and patients with the metabolic syndrome

Type 2 diabetes and hypertension are both insulin-resistant states that impose an excessive risk burden for future major cardiovascular events, including coronary heart disease, stroke, and heart failure. beta-adrenergic receptor antagonists are effective for the treatment of hypertension, but they are underused in diabetic patients because of possible adverse effects on carbohydrate and lipid metabolism, including insulin resistance, glucose intolerance, and dyslipidemia. Traditional beta blockers, both nonselective and selective, are vasoconstrictive due to unopposed alpha1 activity; however, vasodilating beta blockers are not associated with these negative metabolic effects. This review discusses the background of insulin resistance and its link to diabetes and hypertension, emphasizing the role of vascular control by the renin-angiotensin and sympathetic nervous systems on insulin sensitivity and glucose utilization. Clinical evidence is reviewed for the use of vasodilating beta blockers in the treatment of hypertension and in reducing cardiovascular risk in the diabetic population.     

Effect of low dose beta blockers on atrial and ventricular (B type) natriuretic factor in heart failure: a double blind, randomised comparison of metoprolol and a third generation vasodilating beta blocker.

OBJECTIVES--This study examines the acute effects of two differing beta adrenergic blocking agents (metoprolol and a third generation vasodilating beta blocker) on plasma concentrations of atrial natriuretic factor (ANF), brain (ventricular) natriuretic factor (BNF), and haemodynamic variables in patients with heart failure. SETTING--University teaching hospital. METHODS--20 patients with impaired left ventricular systolic function [ejection fraction 32 (SEM 2.3)%] were randomised in a double blind manner to receive either oral metoprolol 6.25 mg twice daily or celiprolol 25 mg daily. Haemodynamic variables were evaluated by Swan-Ganz pulmonary artery catheter over 24 hours. ANF and BNF concentrations were measured at baseline, 5 h, and 24 h by radioimmunoassay. RESULTS--At baseline ANF and BNF concentrations were considerably raised compared to the normal range. Treatment with metoprolol caused ANF to rise further to 147% of the basal level at 5 h (P = 0.017) and 112% at 24 h (P = 0.029). This was associated with a small but non-significant rise in pulmonary capillary wedge pressure. Cardiac output and systemic vascular resistance were unchanged at 24 h. In contrast, after celiprolol ANF fell to 90% of basal levels at 5 h and to 74% of basal level at 24 h (P = 0.019), associated with a small but non-significant fall in pulmonary capillary wedge pressure [-3.3 (2.7) mm Hg] and systemic vascular resistance, and rise in cardiac output from 3.2 (0.2) to 4.0 (0.4) l/min (P = 0.04). BNF concentrations rose to 112% of baseline at 5 h (P = 0.09) after metoprolol but fell slightly, to 91% of baseline values, after celiprolol (NS). CONCLUSIONS--Metoprolol, even in very low doses (6.25 mg), produced a rise in ANF and BNF, although minimal haemodynamic changes were detected. In contrast, a vasodilating beta blocker was associated with a significant fall in ANF and BNF and a small rise in cardiac output. This study confirms both the advantages of vasodilating beta blockers over metoprolol for initial treatment of heart failure and the usefulness of ANF and BNF measurements for the assessment of drug effects in heart failure compared to traditional haemodynamic measurements.     

Extent of beta1- and beta2-receptor occupancy in plasma assesses the antagonist activity of metoprolol,pindolol, and propranolol in the elderly

Summary We estimated antagonist activity of metoprolol, pindolol, and propranolol in elderly cardiovascular patients by determining the extent to which the drugs occupied rabbit lung beta₁- and rat reticulocyte beta₂-adrenoceptors in plasma samples during drug treatment. The randomized, double-blind, crossover study was carried out by administering twice daily 100 mg metoprolol, 5 mg pindolol, and 80 mg propranolol for 7 days to 20 hypertensive subjects with a mean age of about 70 years. A 2-week interval was kept between administration of the different regimens. Receptor occupancy was measured at 1 hour before and 2 hours after administration of the last dose of each regimen by adding rabbit lung beta₁- and rat reticulocyte beta₂-receptors to plasma samples and by labeling the receptors with a radiolabeled beta-antagonist, (–)-[³H]CGP-12177. The results and conclusions were the following: (a) The extent to which metoprolol, pindolol, and propranolol occupied rabbit lung beta₁-and rat reticulocyte beta₂-adrenoceptors in plasma samples estimated accurately the intensity of beta-receptor antagonism in the patients who did not tolerate physiological and pharmacological tests measuring the degree of beta₁- and beta₂-adrenoceptor blockade. (b) The mean beta₁- and beta₂-receptor occupancy of pindolol and propranolol varied between 76% and 99% during the treatments. The mean beta₁-receptor occupancy of the metoprolol regimen varied between 54% and 92%, and its beta₂-receptor occupancy varied between 6% and 38%. Thus the antagonist activity of the metoprolol regimen differed significantly from that of the other regimens (ANOVA for repeated measures, p<0.05 and 0.001, for the beta₁- and beta₂-occupancy, respectively). (c) The extent of beta₁- and beta₂-receptor occupancy in plasma samples was in conformity with the literature on the intensity, selectivity, and duration of beta-blockade after similar drug doses. (d) The data on the receptor occupancy of beta-blocking drugs in plasma samples appear to be valuable in analyzing their effects, and it may be a method for optimizing drug therapy for aged cardiovascular patients.     

Labetalol therapy in patients with systemic hypertension and angina pectoris: effects of combined alpha and beta adrenoceptor blockade

The effects of oral labetalol, an alpha-beta adrenoceptor blocker, were evaluated in 10 patients with angina pectoris and hypertension. After 3 weeks of placebo, increasing doses of labetalol (300 to 1,200 mg/day) were given over 4 weeks followed by a rapid drug withdrawal phase. The frequency of anginal attacks and exercise tolerance were measured as were noninvasive indexes of left ventricular function (echocardiography, systolic time intervals), plasma renin activity and platelet function (aggregability). Compared with placebo, during labetalol therapy the frequency of anginal attacks was reduced, exercise time increased (from 351.6 ± 56.2 to 463.2 ± 45.2 seconds, P < 0.005) and exercise work increased (from 3,470 ± 910 to 4,920 ± 1,020 kilopond-meters, p < 0.01). Labetalol (mean dose 1,050 mg/day) reduced resting supine and standing blood pressures and heart rate in all patients: supine systolic pressure from 166.5 ± 6.3 to 142.2 ± 4.9 mmHg (mean ± Standard error of the mean) (p < 0.01), supine diastolic blood pressure from 102.7 ± 2.6 to 87.7 ± 1.5 mmHg (p < 0.01), supine heart rate from 80.8 ± 4.6 to 65.6 ± 2.3 beats/min (p < 0.05), standing systolic blood pressure from 156.8 ± 4.2 to 127.5 ± 5.3 mmHg (p < 0.01), standing diastolic blood pressure from 101.4 ± 2.3 to 83.9 ± 3.0 mmHg (P < 0.01) and standing heart rate from 81.5 ± 4.9 to 69.0 ± 2.8 beats/min (p < 0.01). The increments in systolic blood pressure with exercise were significantly blunted; those for heart rate were not affected. There was a significant reduction in resting heart rate-blood pressure product and an inhibition of heart rate-blood pressure increments with exercise. Compared with placebo, labetalol had no effects on platelet function or on resting noninvasive indexes of left ventricular function. The three patients with elevated plasma renin activity demonstrated a marked reduction after labetalol; the seven patients with normal or low plasma renin activity were not affected by labetalol. No “rebound” effects were seen after withdrawal of labetalol. Combined alpha and beta adrenergic blockade with labetalol is effective for relieving anginal symptoms, improving exercise tolerance and reducing elevated systemic blood pressure.     

Medical treatment of patients with severe exertional and rest angina: double blind comparison of beta blocker, calcium antagonist, and nitrate.

The role of medical treatment of patients who had resting nocturnal angina as well as exertional angina was investigate. The effects of atenolol 100 mg a day, nifedipine 20 mg three times a day, and isosorbide mononitrate 40 mg twice a day were investigated in a double blind, triple dummy randomised study. Nine patients with coronary artery disease, early positive exercise tests, and transient daytime and nocturnal ambulatory ST segment changes were initially assessed off all antianginal medication. They were then treated with each drug for three five day periods. Angina diaries were reviewed and maximal treadmill exercise tests and 48 hour ambulatory ST segment monitoring were performed at the end of each treatment period. Resting and exercise heart rate and blood pressure were significantly lower on atenolol than on either isosorbide mononitrate or nifedipine. The duration of exercise to 1 mm ST segment depression was significantly greater on atenolol than on isosorbide mononitrate. Only one patient had an improvement in exercise tolerance on nifedipine that was greater than the improvement on atenolol; this patient had single vessel disease. The total number and duration of episodes of ST segment change during ambulatory monitoring were significantly lower with atenolol than on either isosorbide mononitrate or nifedipine. Nocturnal ST segment changes were abolished in six patients on atenolol, in six patients on nifedipine, and in five patients on isosorbide mononitrate. When nocturnal ST segment changes occurred, their frequency was reduced with all three drugs. Pain was abolished in four patients on atenolol and pain relief was significantly better on atenolol than on isosorbide mononitrate. There was no significant difference in pain relief between isosorbide mononitrate and nifedipine. Thus beta receptor blockade with atenolol was the most effective means of reducing myocardial ischaemia both during exercise and at rest at night without causing deterioration in any patient. Nocturnal myocardial ischaemia in patients with severe coronary artery disease can be effectively treated with beta receptor antagonists and vasodilators.     

Beta-blocking agents in patients with insulin resistance: effects of vasodilating beta-blockers

Essential hypertension is--at least in many subjects--associated with a decrease in insulin sensitivity, while glycaemic control is (still) normal. It seems that in hypertensive patients, two major functions of insulin are impaired: there is insulin resistance of peripheral glucose uptake (primarily skeletal muscle) and insulin resistance of insulin-stimulated vasodilation. In view of some retrospective data and meta-analyses, which showed a less than expected reduction in coronary events (coronary paradox), the metabolic side effects of the antihypertensive treatment have received more attention. Many groups have shown that conventional antihypertensive treatment, both with beta-blockers and/or diuretics, decreases insulin sensitivity by various mechanisms. While low-dose diuretics seem to be free of these metabolic effects, there is no evidence for this in the beta-adrenergic blockers. However, recent metabolic studies evaluated the effects of vasodilating beta-blockers, such as dilevalol, carvedilol and celiprolol, on insulin sensitivity and the atherogenic risk factors. None of them decreased insulin sensitivity, as has been described for the beta-blockers with and without beta1 selectivity. This supports the idea that peripheral vascular resistance and peripheral blood flow play a central role in mediating the metabolic side effects of the beta-blocking agents, as the vasodilating action (either via beta2 stimulation or alpha1-blockade) seems to more than offset the detrimental effects of the blockade of beta (or beta1) receptors. Further studies are needed to elucidate the relevance of the radical scavenging properties of these agents and their connection to their metabolic effects. Therefore, the beneficial characteristics of these newer beta-adrenoreceptor blockers suggest that the vasodilating beta-blocking agents could be advantageous for hypertensive patients with insulin resistance or type 2 diabetes.