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beta-Adrenergic blocking drugs are effective in reducing sudden cardiac death after acute myocardial infarction but the precise mechanism of this effect is unclear. We investigated the acute and chronic effects of acebutolol, a beta-adrenergic blocker, on electrocardiographic parameters, diastolic excitability threshold (DET), and right ventricular effective refractory period (RVERP) in chronically instrumented conscious dogs. These parameters were determined during spontaneous sinus rhythm and at a fixed pacing rate (200 beats/min). Acebutolol (0.5, 1, and 5 mg/kg i.v.) decreased the heart rate (HR) (by 23, 26, and 24%, respectively) without effects on any electrocardiographic parameters or on the DET. The maximal increases in ERP were 4.7, 7, and 7.8%, respectively, during pacing and 8.5, 13.3, and 10.3%, respectively, during sinus rhythm. Acebutolol, 10 mg/kg/day P.O. for 6 weeks, reduced the HR from the third day onward without altering the PR, QRS, QT, or QTc intervals or the DET. The increase in ERP was significant from the third day (14%) during pacing and from the seventh day (15.5%) during sinus rhythm. The degree of prolongation of the ERP subsequently remained stable during the 6 weeks of treatment. The ERP returned to the baseline value 7 days after acebutolol withdrawal. This increase in ERP, which was more marked during chronic oral treatment, could contribute to the documented protective effect of the beta-blocking drugs against sudden cardiac death after myocardial infarction.

The objective of this study was to compare the efficacy and the safety of bisoprolol (B) and acebutolol (A) on blood pressure at rest and during exercise in hypertensives. The design was a comparative, single-blind study with two phases following a 10-day washout period for pretreated patients: a 15 day-placebo phase and an 8-week therapeutic phase. Forty-six outpatients suffering from mild to moderate essential hypertension [diastolic blood pressure (DBP) ranging between 95 and 120 mm Hg] were randomly given either 10 mg of bisoprolol or 400 mg of acebutolol once a day for 8 weeks; this dosage was doubled after 4 weeks if DBP was still above 90 mm Hg. Blood pressure measurements were made 24 h after drug intake at rest and during exercise stress tests and were performed at the end of the placebo period and after 1 and 2 months of active treatment. Serum lipid levels were also measured before and at the end of the study. Forty-four patients (21 B/23 A) were analyzed for resting blood pressures and 33 (15 B/18 A) for exercise blood pressure profile. At the end of the first month of treatment, a significant decrease (p < 0.001) in supine and upright systolic (SBP) and DBP was noted in both groups. The reduction in supine DBP after 4 weeks was significantly greater with B (p = 0.036). A further decrease of blood pressure was observed in both groups during the second month of treatment, which was significant only in supine SBP (p < 0.05). After 2 months, the heart rate decreased by 24% with B and 13% with A (B vs. A; p = 0.002). Regarding the BP profile during exercise, B and A caused a similar and significant reduction in both SBP and DBP (p < 0.001). The reduction in heart rate during exercise was more marked with B, with no significant difference between the two groups. Side effects were reported in three patients on B and six on A. Both at rest and during exercise, at a level of effort similar to that of daily activities, B exerted a hypotensive effect at least equivalent to that of A in mild and moderate hypertensive patients.

In patients with acute myocardial infarction the haemodynamic relevance of the ancillary pharmacological properties of cardioselectivity and of intrinsic sympathomimetic activity (ISA) possessed by beta-blocking drugs is unclear. The dose-response effects of atenolol and acebutolol, two cardioselective compounds, the latter also possessing a degree of ISA, were therefore compared in a single-blind, dose-response, crossover study in patients within 18 h of suffering an uncomplicated acute myocardial infarction. The logarithmic cumulative dosage schedule achieved plasma concentrations in the clinical therapeutic ranges for both atenolol (0.05 +/- 0.04-0.19 +/- 0.03 micrograms/ml) and acebutolol (0.22 +/- 0.14-0.8 +/- 0.29 micrograms/ml). Incremental doses of intravenous atenolol (cumulative, 1-8 mg) resulted in significant decreases in systolic blood pressure, heart rate, cardiac output, stroke volume, and stroke work index (p less than 0.01 for each). Pulmonary artery occluded pressure (p less than 0.05) and systemic vascular resistance (p less than 0.01) increased. Incremental doses of intravenous acebutolol (cumulative, 10-80 mg) also resulted in significant decreases in systolic blood pressure, heart rate, cardiac output, stroke volume, and stroke work index (p less than 0.01 for each). Systemic vascular resistance increased (p less than 0.01); there was no consistent change in the pulmonary artery occluded pressure. Within the limits of the experimental protocol, the additional property of ISA possessed by acebutolol resulted in no statistically significant haemodynamic differences from atenolol. This may reflect either an insufficient degree of ISA possessed by acebutolol to confirm the original hypothesis, or its haemodynamic irrelevance in the presence of the increased sympathetic tone that is frequently present following acute myocardial infarction.

In six conscious dogs we compared the hemodynamic effects of propranolol, acebutolol, and acebutolol's primary metabolite at equipotent beta-blocking doses. Aortic pressure, heart rate, left ventricular end-diastolic pressure, dP/dt, and aortic flow velocity were measured 3 weeks after sterile surgery during three infusions of each drug. Only one drug was given on each day. The equipotent beta-blocking dose of each drug was obtained by comparing isoproterenol dose-response curves. All three drugs produced a fall in dP/dt. Left ventricular end-diastolic pressure increased in most dogs, but this was only significant for acebutolol. The heart rate tended to fall and the blood pressure rise, but this was variable and not significant. The concentration of the equipotent blocking dose of acebutolol was 44 times that of propranolol, and while the concentration of acebutolol's metabolite was 1.6 times that of acebutolol. In conclusion, at a concentration similar to acebutolol, acebutolol's metabolite has heart rate blocking and myocardial depressive effects similar to those of propranolol and acebutolol.

Several drugs used for antihypertensive therapy may interact with lipoprotein metabolism and may increase associated coronary risk levels. beta-Blocker monotherapy with selective or nonselective beta-blockers without intrinsic sympathomimetic activity (ISA) usually increases serum triglyceride and decreases high-density lipoprotein (HDL), especially HDL2 cholesterol concentration. With the exception of the nonselective beta-blocker sotalol, beta-blocker therapy has little influence on the serum total cholesterol or low-density lipoprotein (LDL) cholesterol concentrations. The magnitude of these changes in serum lipids did not distinctly differ between selective and nonselective beta-blockers. Two beta-blockers possessing ISA, acebutolol, and pindolol did not show the increase in serum triglycerides and in serum total cholesterol or LDL cholesterol. Acebutolol showed the nonsignificant decrease in HDL cholesterol level. Pindolol with marked ISA exhibited the most favorable lipid profile, increasing serum HDL cholesterol and the ratio of HDL cholesterol to total cholesterol. The concentration of apolipoprotein A-I increased slightly during pindolol therapy. beta-Blockers with the exception of pindolol decrease the concentration of serum free fatty acids. beta-blocker therapy has little influence on the adipose tissue lipoprotein lipase activity, but lecithin cholesterol acyltransferase activity may increase during pindolol therapy.

In essential hypertension, calcium-influx-dependent vasoconstriction is enhanced, and free calcium concentration in platelets is elevated. To investigate calcium-influx-dependent vasoconstriction as related to platelet calcium concentration blood pressure, forearm blood flow (FAF) and free calcium concentration in platelets were measured in five patients with essential hypertension before and after a 6-week treatment with nitrendipine or acebutolol. Starting from comparable basal values, the increase in FAF (ml/min/100 ml tissue) to intraarterially infused nitrendipine (20 micrograms/100 ml tissue) was 40.7 +/- 6.1 before and 30.7 +/- 12.3 after chronic nitrendipine treatment (p less than 0.05) and 41.6 +/- 6.2 before and 34.6 +/- 14.9 after chronic acebutolol treatment. The "nonspecific" vasodilator response to intraarterial sodium nitroprusside or to postischaemic reperfusion were similar before and during treatment. Platelet-free calcium concentration fell on nitrendipine (p less than 0.05) and on acebutolol (p less than 0.01) treatment. Antihypertensive treatment with calcium entry as well as beta-adrenoceptor blockade resulted in a reduction of calcium-influx-dependent vasoconstriction and a fall in free calcium concentration in platelets. Thus, increased calcium platelets may reflect increased calcium in vascular smooth muscle cells and arteriolar tone.

We have previously shown that baroreceptor control of the cardiovascular system and the cardiopulmonary receptor control of peripheral circulation are preserved or only moderately reduced during antihypertensive treatment with acebutolol or nadolol, which indicates that treatment with beta blockers with or without intrinsic sympathomimetic activity does not impair fundamental neural mechanisms involved in circulatory homeostasis. In the present study we have investigated the reflex control of circulation before and during antihypertensive treatment with celiprolol, which, in addition to its beta-blocking action, has vasodilator properties that may stem from interference with neural cardiovascular control. In six essential hypertensive subjects we measured blood pressure (intraarterial catheter), heart rate (ECG recording), central venous pressure (right atrial catheter), and forearm blood flow and resistance (plethysmography) before and during alterations in the activity of the arterial baroreceptors obtained by means of lower body suction and passive leg raising. The study was performed before and after 5-7 days of oral administration of celiprolol at 200-400 mg once a day. Compared to the values obtained in the control, condition celiprolol caused a reduction in blood pressure, a slight change in heart rate, and an increase in forearm blood flow, which indicated the occurrence of a clear-cut forearm vasodilatation. The heart rate responses to arterial baroreceptor manipulation were unchanged by celiprolol which reset the carotid baroreflex so that its tonic restraint on blood pressure increased despite the hypotension induced by the drug. The inhibitory restraint tonically exerted by the cardiopulmonary receptors on peripheral circulation was also increased by celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been suggested that beta-adrenoceptor blocking agents may impair the training response but that this may not occur if the agent possesses partial agonist activity (PAA). We tested these hypotheses in 39 male patients, following myocardial infarction or coronary artery bypass graft surgery, who underwent structured exercise training three times a week for 8 weeks. Exercise tolerance was assessed before training, within 5 days after training, and again 2 weeks after training in 14 patients receiving acebutolol (with PAA), 12 patients receiving sotalol (without PAA), and 13 patients receiving placebo. Blood levels of both agents confirmed that steady states sufficient to produce beta-blockade were achieved during training. All three groups of patients demonstrated statistically significant improvements in exercise duration, energy expenditure, heart rates attained performing equal work loads, and percentage functional aerobic impairment. No significant differences were found between the three groups before or after training. We conclude that beta-adrenoceptor blocking agents in standard therapeutic doses do not cause impairment of exercise training and that PAA affords no enhancement of the training response.

Acebutolol is a relatively new beta-adrenoceptor blocking antagonist, possessing both beta 1-adrenoceptor selectivity and partial agonist activity (PAA). Its acute (24 h, 400 mg, twice daily) and long-term effects (3 weeks) on systemic and renal hemodynamics, body fluid volumes, hormones, and beta-adrenoceptor density on lymphocytes were studied in a single-blind placebo-controlled trial, in 10 hypertensive patients. The initial response to acebutolol (1-2 h) was a fall in heart rate (HR) (-9.6 +/- 2.7%), cardiac output (-16.0 +/- 3%), and stroke volume (SV) (-10.7 +/- 0.2%), and an increase in systemic vascular resistance (SVR) (18.0 +/- 3.9%). Mean arterial pressure (MAP) began to fall 2-3 h after dosing in parallel with a decrease in SVR. At the end of the acute study, MAP and SVR were decreased by 18.1 +/- 2.7% and 15.6 +/- 5.6%, respectively. By that time, HR and SV had returned to control values despite blockade of beta-adrenoceptors. After 3 weeks of treatment (mean dose of acebutolol 480 mg twice daily), the fall in MAP was 10.1 +/- 2.7% and HR was decreased by 13.0 +/- 2.3%. Renal blood flow and glomerular filtration rate did not change. Acute and long-term treatment had no effect on the density of lymphocyte-membrane beta-adrenoceptors. This could be explained by acebutolol's beta 1 selectivity or, alternatively, this could be due to the drug's PAA.