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The effects of intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of beta-adrenoceptor agonists were evaluated on the reticulo-rumen and upper-gut myoelectrical activity in six ewes chronically fitted with intraparietal electrodes and a cannula in a lateral ventricle of the brain. Intravenous infusion of the beta 1 agonist dobutamine (30 micrograms/kg/min for 15 min) reduced the frequency of reticulo-ruminal and abomasal contractions and stimulated duodeno-jejunal motility, inducing a Phase III on the jejunum. These effects were reproduced by i.c.v. dobutamine at a dose of 10 micrograms/kg. Intravenous infusion of the beta 2 agonist ritodrine (15 micrograms/kg/min for 15 min) selectively inhibited antral and duodenal motility. Ritodrine i.c.v. (15 micrograms/kg) did not affect forestomach or gastrointestinal motility. The mixed beta 1, beta 2 agonist isoprenaline infused i.v. (0.6 micrograms/kg/min for 15 min) reproduced the effects of i.v. dobutamine, except at the antro-duodenal level which was strongly inhibited. The effects of i.v. dobutamine were antagonized by i.v. or i.c.v. acebutolol, a specific beta 1 antagonist. The effects of i.v. ritodrine were blocked by i.v. but not i.c.v. administration of propranolol, a mixed beta 1, beta 2 antagonist. These data indicate that the stimulation of central beta 1 adrenoceptors inhibits forestomach and antral motility and stimulates duodeno-jejunal motility. Stimulation of peripheral beta 2 adrenoceptors selectively inhibits duodeno-jejunal motility.

Thirteen beta-blocking agents with different pharmacological properties were administered orally to 161 outpatients with essential hypertension for 5 weeks to assess their hemodynamic effects. Cardioselective ones, such as atenolol, metoprolol and acebutolol, reduced mean blood pressure (MBP) and the cardiac index. (CI) without any changes of the total peripheral resistance index. (TPRI). In the total 44 patients treated with these drugs, a positive correlation (r = 0.529, p less than 0.005) was found between the decrease in MBP and that of TPRI, but the decrease in MBP did not correlate with that of CI. Effects of non-cardioselective ones were classified arbitrarily into the following 3 patterns: 1) reduction of CI of more than 0.50 L/min/m2 and a slight increase of TPRI by more than 150 dyne . sec . cm-5 . m2 (nadolol, propranolol, o.prenolol and penbutolol), 2) reduction of TPRI by more than 150 dyne . sec . cm-5 . m2 (pindolol, bunitrolol and labetalol) and 3) the intermediate hemodynamic responses between the two patterns described above (carteolol, bupranolol and bufetolol). In all these 3 groups, the decrease in MBP correlated with that of TPRI (the first group, n = 45, r = 0.557, p less than 0.005; the second, n = 37, r = 0.525, p less than 0.005; the third, n = 35, r = 0.612, p less than 0.005), but did not correlate with the decrease of CI. These results suggest that the antihypertensive effects of beta-blocking agents mainly depend on the reduction of peripheral resistance, although their pharmacological properties are not uniform and their cardiodepressant effects are variable. Reduction of cardiac performance with these beta-blocking agents seemed to be a consequence of overall pharmacological actions including beta-receptor blockade, central effects and membrane stabilizing effects, and it may be antagonized by intrinsic sympathomimetic activity and the reduction in afterload for the heart. Vascular beta-receptor blocking action may play a part in decreasing the degree of reduction of the total peripheral resistance index, while their intrinsic sympathomimetic action on the vascular site may induce vasodilating effects.

Six unselected males suffering from documented coronary insufficiency and grade II to III angina were submitted to graded multistage treadmill exercise test on 3 separate occasions, 3.5 hours after ingestion of either 0, 200 or 400 mg of acebutolol, a new cardioselective beta-blocker. Control measures included the random allocation to 6 balanced sequences of administration, the rigid standardisation of double-blind experimental conditions and measurements, and two types of variance analysis (latin-square and split-plot). Performance was evaluated by measuring time elapsed before occurrence of anginal pain and ECG changes, peak heart rate, peak double product (heart rate x systolic pressure), and peak oxygen consumption. The mean values for all 5 criteria showed improvement with the 200 mg dose of acebutolol, and even more so with 400 mg, but this overall effect resulted mainly from the excellent response of 3 of the patients. When patients were grouped into 2 categories of responders and non-responders, a significant Dose x Category interaction was found for all criteria. Furthermore, maximal response under acebutolol was negatively correlated with values under placebo (0 mg); this correlation reached significance for peak heart rate and peak double product. It is concluded that (a) in responders, the beneficial effect of acebutolol was significant on all 5 criteria (p less than 0.05), (b) patients definitely fell into 2 categories of responsiveness and (c) the sensitivity of responders was partly linked to their performance under placebo and partly to unidentified individual factors.

The cardioselectivity and specificity of diacetolol, the major metabolite of the beta-adrenoceptor blocking drug acebutolol, was studied in the isolated right atrium of the guinea-pig and rat and the papillary muscle and trachea of the guinea-pig. The beta-adrenoceptor blocking potency of diacetolol is about ten times lower than that of acebutolol. Like acebutolol, diacetolol was a more effective isoprenaline antagonist in the heart than in the trachea, thus showing relative cardioselectivity. The high water solubility of diacetolol and acebutolol led to a much faster disappearance of the beta-blockade after washout than the blockade by the lipid soluble agents propranolol and penbutolol. Like acebutolol, diacetolol had a weak intrinsic sympathomimetic activity. Cardiac depressant effects, e.g. decrease of maximum upstroke velocity and duration of the action potential and reduction in force of contraction, occurred with concentrations 100-1000 times higher than those needed for beta-blockade, thus indicating relative specificity.

The acute hemodynamic effects of intravenous acebutolol, 50 mg, and propranolol, 10 mg, were evaluated in 12 patients undergoing diagnostic cardiac catheterization. Each patient received acebutolol or propranolol according to a list of randomization. Both acebutolol and propranolol depressed left ventricular function. There was a significant increase in left ventricular end-diastolic pressure at rest and after isometric exercise, with a concomitant decrease in cardiac index. Systemic vascular resistance was increased by both drugs. The increment after patients received acebutolol was not statistically significant; however, with propranolol it was statistically significant. The overall hemodynamic effects of acebutolol and propranolol are similar, but a quantitative difference exists in their effect on systemic vascular resistance. Acebutolol, a cardioselective agent, produces less of a peripheral vascular beta 2-blockade than does propranolol.

Acebutolol was given to a group of 23 subjects with essential arterial hypertension associated with tachycardia at rest. In 70 p.cent of the cases, arterial blood pressure was rapidly influenced by the treatment. The favorable results are mostly-but not exclusively-found among the subjects with the highest initial sympathetic reactivity and renin plasmatic activity. However, there is no correlation between the quality of the result and the degree of reduction of renin activity or heart rate.

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.

1 The acute cardiovascular effects of acebutolol were measured at constant paced heart rate in thirteen patients investigated for possible coronary artery disease, six of whom showed significant coronary stenosis with regional myocardial dysfunction, seven of whom proved normal. Acebutolol 0.75 mg/kg i.v. was given to three patients with coronary artery disease and three normals, and 1 mg/kg i.v. to the other patients.2 Measurements were made of cardiac output, left ventricular and arterial pressures, and left ventricular angiography. Isovolumic and ejection phase parameters of left ventricular function, and systemic vascular resistance were derived. Plasma levels of acebutolol were measured. 3 The acute effects of acebutolol were a slight fall in cardiac output, LV dp/dt and dP/dt/P. There was no change in LV or arterial pressures, no consistent change in LVEDP or EDV, and no consistent change in ejection fraction or mean VCF. These changes imply a small negative inotropic effect, more marked at the higher dose. 4 The effects of acebutolol differed in patients with ischaemic heart disease compared with normals in that LVEDP and EDV increased, mean VCF decreased and cardiac output was lowered more. 5 These data are consistent with myocardial and vascular effects of beta-adrenoceptor blockade more marked at the higher dose and more marked in patients with ischaemic heart disease.

In the course of routine screening of beta-adrenoceptor blocking compounds, it was found that a number of compounds did not block the vascular and cardiac effects of isoprenaline in proportion. Moreover, it was also found that the anti-arrhythmic action was not wholly related to the beta-adrenoceptor blocking potency. In particular, the anti-ouabain arrhythmia properties were not dependent upon beta-blocking potency. It was, therefore, possible to select a compound which had both cardioselective beta-adrenoceptor blocking and anti-ouabain arrhythmic activities. The chosen compound was acebutolol. Acebutolol is a cardioselective beta-adrenoceptor blocking agent which has marked anti-arrhythmic against arrhythmia induced by methylchloroform and adrenalin in the cat, and also arrhythmia induced by ouabain in dogs and rabbits. It has less pronounced membrane stabilising properties than propranolol and has no demonstrable sympathomimetic action in normal anaesthetised cats or dogs. Bronchial beta-adrenoceptor blockade has been investigated in anaesthetised cats in which bronchoconstriction is evoked by PGF2 alpha. Isoprenaline prevents the effect of PGF2 alpha and this is restored by pre-treatment with propranolol. Acebutolol is 100 times less active than propranolol in these experiments.

The effects of the beta-adernergic blocking drug acebutolol were studied in 23 patients with angina pectoris and angiographically documented coronary artery disease. Patients were evaluated clinically, by graded treadmill testing and by 24-hour Holter monitoring in the control state, after 2 weeks treatment with placebo, and after 2 weeks treatment with 600 mg. and then 1,200 mg. of acebutolol. Acebutolol (in a daily dose of 600 mg.) was an effective antianginal drug: the number of clinical attacks of angina pectoris (p less than 0.001) and the consumption of sublingual nitrate decreased (p less than 0.01), there was a significant increase in the treadmill effort tolerance as measured by the time to appearance of ischemic ECG changes (p less than 0.001) and the total work performed (p less than 0.001), and there was also a significant decrease in ischemic ST segment depression on 24-hour Holter monitoring. Treatment with 1,200 mg. acebutolol was associated with a further decrease in heart rate and a further improvement in effort tolerance on treadmill testing (p less than 0.05). On the large dose of the drug, however, there was no further clinical improvement, and no further improvement on 24-hour ECG monitoring; several patients complained of weakness and fatigue. Graded treadmill testing was an excellent objective method for assessing physical effort tolerance and its improvement after treatment with the beta-blocking drug. Twenty-four-hour Holter monitoring was a useful and complementary test, especially in patients who stopped exercising on the treadmill because of fatigue or weakness, and especially for assessing the efficacy of beta-blockade in controlling emotionally induced tachycardia and ischemia in the patient's own daily environment.

A study was carried out, of the changes of renal functional value and of urinary electrolytes excretion after rapid intravenous injection of acebutolol in twelve subjects with various glomerular filtration. Renal functional value was estimated by measuring inuline. P.A.H., urea and creatinin clearances during a control period of thirty minutes and during the four hours following administration of acebutolol. The variations in the excretion of electrolytes: chloride, sodium, potassium, calcium and phosphorus were measured during the same periods. The following results were obtained: in subjects with normal renal functional value, administration of acetubolol brings about: a variation which is under 20 p.cent of glomerular filtration and P.A.H. clearance; a 50 p.cent average decrease of natriuresis. in cases of renal insufficiency: clearances of inuline and P.A.H. are unchanged. There is a 20 p.cent average decrease of natriuresis. There is a decrease of urinary output (35-45 p.cent) and of urea clearance (20-50 p.cent).

The authors studied the variations in the effects of isoprenaline hydrochloride on heart rate (beta 1) and on peripheral blood flow of the upper extremity (beta 2), determined by plethysmography, in a group of 5 men with a mean age of 31 +/- 3 years. The trial was conducted on a single-blind cross-over basis, each subject being infused over 30 min with propranolol (30 microgram/kg), acebutolol (150 microgram/kg) or a placebo (isotonic glucose solution) with at least an 8-day interval between each administration. At the end of the infusion they received isoprenaline (0.01 to 0.075 microgram/kg, in logarithmic progression) every 15 min, for 1 hour. The doses of isoprenaline were injected randomly using a latin square design. The peripheral flow, assessed by the curve of the initial part of the plethysmogram for the first 10 sec, increased with the dose of isoprenaline in the placebo series (Tg alpha = 219.9 log d + 583.4; p less than .01), did not increase in the propranolol series and increased with the dose in the acebutolol series (Tg alpha = 221.5 log d + 567.7; p less than .01); the variations in flow with isoprenaline after placebo and after acebutolol, did not differ significantly. The hear rate increased with the dose of isoprenaline in the placebo series (+55%) although tachycardia was inhibited by propranolol and acebutolol. Under the experimental conditions of this trial, propranolol inhibited beta 1 and beta 2 receptors at the same time, whereas acebutolol inhibited only beta 1 receptors.

1. The effects of single oral doses of 10 mg bisoprolol and 400 mg acebutolol on respiratory function were studied in nine smokers with airway obstruction in a double-blind, placebo-controlled experiment. 2. The effects of the drugs were assessed by measuring specific airway conductance (sGaw) for 3 h after their administration and by studying their interaction with the bronchodilator response to inhaled salbutamol. 3. sGaw did not change for 3 h after bisoprolol or acebutolol administration. The bronchodilator response to inhaled salbutamol was not affected by bisoprolol but significantly reduced by acebutolol (P less than 0.05 vs placebo). 4. Under these conditions, bisoprolol behaves like a selective beta 1-adrenoceptor antagonist but acebutolol exhibits less beta 1-adrenoceptor selectivity.

The effect on plasma apoproteins A-I and B and HDL cholesterol subfractions of acebutolol given orally over a 6-month period to 18 patients with essential hypertension was studied. The concentration of apoprotein A-I decreased during acebutolol treatment: statistical significance was reached at 3 (p less than 0.05) and 6 months (p less than 0.01). The level of apoprotein B increased slightly but not significantly. The ratio of apo A-I to apo B decreased significantly during acebutolol treatment. The concentration of total HDL cholesterol tended to be slightly but not significantly higher during therapy than before it. This increase was due to the increase of HDL3 cholesterol and this increase was significant (p less than 0.05) at 3 months. The level of HDL2 cholesterol did not change significantly during acebutolol therapy.

Twelve unselected males suffering from documented coronary insufficiency and moderately severe angina submitted to graded multistage treadmill exercise testing on 3 separate days, 3.5 hr after a single dose of 0,200, or 400 mg of acebulolol, a cardioselective beta blocker. Control measures included random allocation of 2 patients to each of 6 balanced sequences of administration, standardized double-blind conditions, and variance analysis for Latin-square design with repeated measures on each subject. Performance was evaluated by measuring time elapsed until anginal pain, peak heart rate, peak product of heart rate and blood pressure, and peak oxygen consumption. Mean values for all criteria were significantly atered by 400 mg of acebutolol. Seven out of twelve patients were classified as responders (i.e., exercise duration increased 100% or more). The response after acebutolol was correlated with the performance on placebo in the base of exercise duration, peak heart rate, and peak product of heart rate and blood pressure. It is concluded that: (1) performance criteria are useful predictors of response to beta blockade and (2) acebutolol is a potent antianginal agent when judged by an objective treadmill exercise test.

The effects of intraperitoneal administration of isoproterenol (a mixed beta 1- and beta 2-agonist), dobutamine (a selective beta 1-agonist) and clenbuterol (a selective beta 2-agonist) on gastric emptying were investigated in mice killed 30 min after gavage with a 51Cr radiolabeled milk meal. Administered 30 min prior to the meal, isoproterenol (2 mg/kg) and dobutamine (1 and 2 mg/kg) accelerated gastric emptying and clenbuterol (0.05 and 0.1 mg/kg) slowed it. The stimulation of gastric emptying by isoproterenol (2 mg/kg) and dobutamine (2 mg/kg) was blocked by the previous administration of either mixed beta 1- and beta 2-antagonist, propranolol (1 mg/kg), or a specific beta 1-antagonist, acebutolol (1 mg/kg). Only propranolol (1 mg/kg) antagonized the decrease of gastric emptying induced by clenbuterol. A high dose of propranolol (10 mg/kg), injected alone, reduced gastric emptying. It is concluded that the increase in gastric emptying caused by beta-adrenergic drugs is mediated through beta 1-adrenoceptors, while beta 2-receptors are involved in the inhibition of this function. The lack of effects of propranolol at doses able to block the action of beta 1- and beta 2-adrenoceptor agonists suggests that beta-adrenoceptors are not physiologically involved in the control of gastric emptying.

Two adrenergic receptor antagonists, acebutolol and propranolol, were observed to depress rabbit heart contractile force and adrenaline-stimulated adenylate cyclase activity at 1 X 10-(5) to 1 X 10-(3) M and 1 X 10-(6) to 1 X 10-(3) M concentrations, respectively. Acebutolol depressed sarcoplasmic reticular and mitochondrial calcium uptake at 5 X 10-(3) to 10-(2) M concentrations. On the other hand, propranolol was found to decrease calcium uptake activities of sarcoplasmic reticular and mitochondrial fractions at 1 X 10-(4) to 1 X 10-(2) M and 1 X 10-(3) to 1 X 10-(2) M concentrations, respectively. On the basis of these results with calcium transport systems, it is proposed that beta-antagonists with a mild depressant effect, such as acebutolol, may be called beta-moderators, whereas those with a strong effect, such as propranolol, may be called beta-blockers.

The purpose of the study was to determine the early haemodynamic effects of injectable acebutolol and to study in parallel the changes in plasma renin activity (P.R.A.) in 11 patients, most of whom were affected with labile arterial hypertension. The haemodynamic measurements and P.R.A. determinations were carried out before and 5 and 15 mn after very slow intravenous injection of 10 mg acebutolol. The results obtained under these conditions were as follows: 1) Decrease in cardiac index (I.C.). It was particularly significant after 5 mn, since the I.C. decreased from 4.43 to 3.75 1/mm (p less than .01). It was essentially due to a decrease in heart rate, that fell from 90.45 to 77 beats/mn (p less than .001), while stroke volume changed virtually not. 2) Decrease in blood pressure, more marked on systolic blood pressure (110 mm Hg after 15 mn as against 154 mm Hg before injection; p less than .001), associated with a decrease in left ventricular work (4.7 kgm/mn/m2 after 5 mn as against 6.2 kgm/mn/m2 before injection; p less than .001), without significant changes in total systemic arterial resistances. 3) Increase in diastolic pulmonary arterial pressure (10.4 mm Hg after 5 mn against 8.09 mm Hg before injection; p less than .001), testifying to a slight left ventricular myocardial depression. 4) Decrease in supine P.R.A. level (0.72 nanogram/1/mn after 5 mn as against 1.15 nanogram/1/min before injection; p less than .01). A significant correlation was found between this decrease in P.R.A. and that in I.C., testifying to a close parallelism between the inhibition of cardiac beta-1 receptors and that of the receptors involved in renine secretion. 5) The tolerance of injectable acebutolol appeared to us to be excellent.

We have performed studies on blood hormone dynamics following intravenous administration of acebutolol, a newly synthesized beta-blocker, and its direct action on the adrenal medulla in vitro. Intravenous injection of acebutolol into anesthetized dogs almost doubled the plasma adrenaline and noradrenaline concentrations within 5 to 15 minutes, while renin activity was reduced to approximately two-thirds of the pre-administration level. When arrhythmia was induced in dogs with ouabain, the plasma adrenaline and noradrenaline levels increased to 220 +/- 109 and 392 +/- 84 pg/ml, respectively, from the basal levels of 44 +/- 24 and 140 +/- 43 pg/ml. The restoration of sinus rhythm following the administration of acebutolol was accompanied by a further increase in the plasma adrenaline and noradrenaline levels to 797 +/- 364 and 1226 +/- 263 pg/ml, respectively. A perifusion experiment indicated that acebutolol directly accelerated catecholamine release from the adrenal medulla in pigs.

1 The effects of beta-adrenoceptor blockade on the metabolic responses to isoprenaline have been studied in an in vitro system of isolated fat cells and in six normal subjects. 2 The inhibitory effects of varying concentrations of acebutolol, practolol and propranolol on free fatty acid (FFA) release produced by isoprenaline (10(-7) M) were compared in isolated fat cells prepared from rat epididymal adipose tissue. Acebutolol and practolol, at equimolar concentrations, showed a similar inhibitory effect whilst propranolol was approximately 100 times more potent then either drug. At 10(-5)M concentration of propranolol, lipolysis was virtually abolished whilst at the same molar concentration, acebutolol and practolol halved the response. 3 Six healthy volunteers received three successive 15 min intravenous isoprenaline challenges (0.03 mug kg-1 min-1) per individual experiment. The first acted as a control whilst the following two were given either after single oral doses of placebo, acebutolol or practolol. The mean (+/- s.e. mean) basal FFA level was 0.77 +/- 0.06 mE1/1 and subsequent resting values after the administration of placebo or beta-adrenoceptor blocker were not significantly different. 4 Acebutolol inhibited the respective mean rises in FFA, produced by both post-control isoprenaline challenges, by (mean +/- s.e. mean) 70 +/- 4% and 84% +/- 5%. The comparable figures for practolol were 33 +/- 15% and 24 +/- 20%. The higher serum concentration of acebutolol produced greater inhibition but correlation of log serum concentration of the drug with percentage inhibition of FFA rise did not achieve significance. 5 Administration of isoprenaline, acebutolol or practolol did not significantly alter serum glucose, triglyceride or cholesterol levels. 6 Acebutolol and practolol effectively blocked the isoprenaline-induced tachycardia. The degree of blockade produced by practolol was greater than its inhibitory effect on FFA release. The diatolic fall in blood pressure in response to isoprenaline was abolished by acebutolol suggesting that its beta-adrenoceptor blocking action encompasses peripheral vascular sites. The comparable effect with practolol was a partial inhibition of the diastolic fall.

A study on the effect of acebutolol, a new beta receptor antagonist, on the resting and post-exercise heart rate and rate-pressure product was carried out in 8 normal volunteers. Intravenous administration of 10 and 20 mg acebutolol was compared with 10 and 20 mg practolol administered at weekly intervals. In the oral study, increasing doses of acebutolol were administered over a period of 20 days. The heart rate and blood pressure was recorded before and at the completion of 4-minute exercise period. The exercise was carried out on a bicycle ergometer at 150 watt per minute for 4 minutes. In a dose to dose comparison, the potencies of acebutolol and practolol administered intravenously were of the same order, in decreasing the resting and post-exercise heart rate and rate pressure product. Their duration of action was also similar. In the oral study, the peak effect was achieved at a dosage of 200 mg per day (100 mg twice daily) of acebutolol. Acebutolol decreased the resting as well as post-exercise rate-pressure product (cardiac work load). This may be the mechanism for the reported beneficial effect in angina pectoris. Acebutolol was well tolerated and no serious side-effects were observed.

The aim of this study was to assess the effects of the association of sublingual nifedipine and intravenous acebutolol on left ventricular inotropism. A series of 30 randomised patients underwent hemodynamic investigation repeated after a 30 minute interval comprising measurement of left ventricular (LVP) and aortic (AoP) pressures and ventriculography (Vo). Between the two Vo, Group I (N = 10) were given 20 mg sublingual nifedipine (N), Group II (N = 0) were given I mg/Kg acebutolol (A) intravenously in 5 minutes, and Group III (N = 10) the association of 20 mg sublingual N and I mg/Kg intravenous A. All patients had normal resting left ventricular function (ejection fraction greater than 0,55). In Group I, a significant improvement in left ventricular function with reduction of end diastolic pressure, increase ejection fraction, VCF and cardiac index was observed. THese changes were secondary to the reduction in aortic impedence with no effects on the contractile element (assessed by end systolic pressure/end systolic volume - ESP/ESV - ratio). In Group II, a significant reduction in these indices of left ventricular function was recorded secondary to a reduction in contractility. Group III had a special hemodynamic profile comprising: a reduction in afterload identical to that observed in Group I; a significantly greater reduction in the ESP/ESV ratio than in Group II; a greater reduction in the indices of left ventricular function (especially EF, VCF and CI) than in Group II, but the difference was not significant. The data obtained under the conditions of this acute hemodynamic investigation in patients with normal basal left ventricular function may be summarised thus: 1) Nifedipine alone has no detectable negative inotropic effects. 2) The association with acebutolol, nifedipine seems to potentiate myocardial depression (ESP/ESV). 3) This therapeutic association, the value of which has already been demonstrated in coronary insufficiency should be used carefully without precise knowledge of the left ventricular function.

In 7 asthmatic patients, intravenous injection of acebutolol resulted in a slowing of the heart rate by blocking the cardiac beta-receptors. An aerosol of isoprenaline, which accelerated the heart, is without effect after intravenous injection of acebutolol. On the contrary, isoprenaline caused similar changes in the FEV1 before and after acebutolol injection in the same patients. This effect confirms the slight action of the compound on the beta2-adrenergic receptors. Prolonged oral administration did not cause any adverse clinical effects in 6 asthmatic patients.

Acebutolol (Sectral) was used successfully in a clinical trial involving thirty-two hypertensive patients. Twenty-three patients received acebutolol at a dosage of 400--800 mg daily as sole treatment and nine patients received concurrent treatment with thiazide diuretics. In both groups of patients there was a substantial fall in diastolic and systolic pressure to levels within the normotensive range. The combination of acebutolol with thiazide diuretics was a particularly effective form of anti-hypertensive treatment where a greater anti-hypertensive effect was required. Acebutolol did not significantly slow the heart rate. The only side-effect was slight pitting oedema of both legs in one patient. Acebutolol appears to be a useful anti-hypertensive in the management of hypertension.

Acetubolol was administered intravenously to 11 patients with various heart disorders, without any adverse effects. The bradycardic effect of this compound is slight. It did not change the auriculo-ventricular conduction in 10 patients with sinus rhythm. The effect of acebutolol on myocardial efficacy is slight or absent in controls. At the doses studied, it did not alter systolic arterial pressure. Furthermore, the effect on the myocardial contractility is slight (-10 p.cent, mean). The important point noted is that the drug does not increase the pressure in ventricular filling, the first sign usually of left ventricular insufficiency caused by most other drugs of this pharmacological type.

An intravenous infusion of isoprenaline (1 mug/kg/mn during 4 h) elicited a rise in serum free fatty acids (FFA) and glucose in anaesthetised cats. The effect reached a peak in 1 h and was then maintained at a plateau level for the remainder of the infusion. Acebutolol and practolol (0,1-10 mg/kg, p.o.) were more potent in reducing the concentration of free fatty acids (FFA) than in lowering glucose. Propranolol was roughly equipotent on FFA and glucose. In 6 fasted human volunteers, an intravenous infusion of isoprenaline (0,03 mug/kg/mn during 15 min) stimulated a rise in serum FFA. Peak values were attained rapidly and FFA levels began to fall soon after the end of the infusion. Blood glucose concentration was not changed. A placebo, given after the first infusion of isoprenaline, did not significantly affect the response to 2 further infusions at 2 and 4 h later. An oral dose of acebutolol (300 mg) largely suppressed the lipolytic effect of the 2nd and 3rd isoprenaline infusions, the degrees of inhibition being 70 p.cent and 85 p.cent respectively. The same dose of practolol was considerably less effective in inhibiting lipolysis (37 p.cent and 25 p.cent inhibition).

In a double-blind randomised study, single intravenous doses of propranolol (0-1 mg. per kg.), practolol (1 mg. per kg.), acebutolol (1 mg. per kg.), or placebo were each administered at weekly intervals to six healthy volunteers. Forced expiratory volume in 1 second (F.E.V.1), resting and exercise heart-rate, and resting and exercise peak flow-rate (P.F.R.) were determined before and at 2, 3, 4, and 6 hours after each treatment. Venous blood-samples were also obtained at these times. Compared with placebo, resting heart-rate was reduced after all three drugs, but the corresponding differences in exercise heart-rate were much greater, more consistent, and of greater statistical significance. At 2, 3, and 4 hours when acebutolol and propranolol produced equivalent cardiac beta-blocking activity (judged by reductions in exercise heart-rate), their mean plasma concentratios were in the ratio of about 8/1; and at 2 hours when practolol and acebutolol gave rise to almost equivalent cardiac beta blockade, their mean plasma concentratio ration was 3/1. At times, reductions in F.E.V.1 and resting P.F.R. after propranolol (but not after practolol or acebutolol) were significantly greater than the corresponding changes after placebo. The reductions in exercies P.F.R. after propranolol (6 hours) and acebutolol (4 hours) (but not after practolol) were significantly greater than the changes after placebo. Changes in F.E.V.1, resting and exercise P.F.R. after propranolol, and the corresponding changes after practolol, were significantly different, all of which confirmed that practolol was more cardioselective than propranolo. In general, the reductions in F.E.V.1 and resting P.F.R. after acebutolol were slightly smaller than after propranolol, excepting at 6 hours when the difference between them was significant. The reductions in exercise P;F.R. after acebutolol and propranolol were of the same order, there being no significant differences between the two, whereas the reductions after acebutolol were clearly greater than the corresponding changes after practolol, the differences being significant at 2, 3, and 4 hours.

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.

The effects of acute introduction and withdrawal of 2 new beta-adrenergic blockers, acebutolol and metoprolol, on sleep in normal subjects were investigated. Both the subjective effects of the drug and EEG sleep variables were determined during a baseline period with placebo and in relation to the drug. The results showed that neither drug had a significant effect on sleep pattern in normal subjects. However, a transient effect on certain sleep parameters was seen on the first night of drug administration, with complete return to baseline, on the following night without any evidence of rebound. Possible mechanisms to explain the central actions of beta-adrenergic blockers are briefly discussed.

Antihypertensive effects of three beta-adrenergic blocking drugs, acebutolol, propranolol, and practolol were studied for 11 weeks. Spontaneously (SHR); one-clip, two-kidney (CLIP); and deoxycorticosterone and salt (DOC) hypertensive rats were used. The drugs were given orally, 100 mg/kg per day, 5 days per week before development of hypertension. Propranolol inhibited blood pressure (BP) increase significantly in SHR. Acebutolol and practolol also lowered BP in SHR. Three drugs did not affect BP in CLIP, but an apparent inhibition was seen when the results were analyzed including the cases of which BP stayed below 150 mmHg. Either of three drugs did not show antihypertensive effects in DOC. Acebutolol rather increased BP more rapidly. Practolol also increased BP slightly more rapidly. Cerebral stroke was seen in DOC. The incidences of the stroke in the groups given the solvent, acebutolol, propranolol, and practolol were 3/6, 4/7, 2/6, and 3/6, respectively. Acebutolol seemed to cause stroke earlier with the more rapid BP elevation. Acebutolol, propranolol, and practolol decreased incidence of the vascular disease in CLIP. Propranolol also decreased it in DOC. Plasma renin activity was suppressed by these drugs in SHR and CLIP. The mechanisms of antihypertensive effects of beta-adrenergic blocking drugs are unknown. The present study denies those due to inhibition of cardiac function, or renin release from the kidney. A better experimental model is necessary to study this. The possibility that acebutolol and other beta-blockers might accelerate BP elevation and incidence of stroke must be reexamined.

The effects of some Class I antiarrhythmics (quinidine, procainamide and lidocaine) and some Class II antiarrhythmics (propranolol, atenolol and acebutolol) on canine cardiac sarcolemmal Na+-Ca2+ exchange activity were studied. Both quinidine (5-100 microM) and procainamide (1-100 microM), unlike lidocaine, inhibited Na+-dependent Ca2+ uptake in sarcolemmal vesicles. The effective concentrations of these agents were well within their respective therapeutic ranges; about 30% inhibition was seen by 10 microM quinidine or procainamide. Propranolol showed a 25% inhibition of the Na+-Ca2+ exchange activity at 100 microM, which concentration is well above its therapeutic range. Acebutolol (0.1-100 microM) had no significant effects, whereas atenolol (10-100 microM), which appeared to inhibit Na+-dependent Ca2+ uptake, also stimulated nonspecific Ca2+ uptake. These results indicate that the cardiac sarcolemmal Na+-Ca2+ exchange system may be one of the sites for the antiarrhythmic actions of quinidine and procainamide.

1. The beta-adrenoceptor antagonists atenolol, metoprolol, acebutolol, practolol, propranolol and pindolol have been tested for their ability to reduce isoprenaline-induced bronchodilation and tachycardia in the anaesthetized dog. 2. Atenolol, metoprolol, acebutolol and practolol all possessed a similar degree of cardioselectivity in this animal model.

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodyanmic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodyanmic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verampamil are administered either acutely by the intravenous route or chronically by the oral route.

The use of four cardioselective beta-blockers in a group of patients with chronic obstructive bronchopneumopathies was examined. Of the 4 drugs the only possible one for use in this patient category was atenolol which produced significant bronchial dilation after spray treatment, thus demonstrating the responsiveness of beta 2-receptors to pharmacological stimulus.

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.

The clinical effects of a new cardioselective beta-adrenergic blocking drug, acebutolol hydrochloride (SECTRAL), were studied in 18 patients with angina pectoris, using graded treadmill testing according to a modified Bruce protocol. Measurements were made in the control state, after two weeks' treatment with placebo and after two more weeks of constant oral dose of the drug. Acebutolol produced a significant increase in the treadmill work performed before the onset of ischemic ECG changes and chest pain. The heart rate and blood pressure responses to exercise were depressed, so that the greater work load was achieved at a lower double product. Graded treadmill testing is a useful method for assessing the efficacy of treatment with a beta-blocking drug.

Acebutolol, a cardioselective beta-blocker, was studied at doses of 600 to 800 mg in a double-blind trial against placebo in 33 patients with essential hypertension. A moderate reduction in the arterial pressure was seen with placebo, but the pressure was greatly reduced by treatment with acebutolol (p less than 0,01). The heart rate was unchanged after placebo and was reduced by about 10 p.cent by acebutolol. Similarly plasma renin activity, in both lying and standing subjects, was not changed by the placebo, but it was greatly reduced by acebutolol. In the 33 patients studied, the arterial pressure returned to normal in 13 cases (39 p.cent), an improvement was obtained in 12 cases (36 p.cent) but in 8 cases (24 p.cent) the hypertension was not modified by acebutolol. The tolerance to acebutolol was excellent in all cases. No relationship was found between the hypotensive effect of acebutolol and the heart rate or its augmentation induced by orthostatism nor with the levels of plasma renin activity.

The effect of nifedipine (BAY 1040), a calcium-antagonistic inhibitor of the electromechanical coupling process was tested on atrioventricular conduction and refractoriness of the dog heart in situ by means of His-bundle electrography and programmed electrical stimulation. The animals were anaesthetized with sodium pentobarbital. As the basic effects of the compound can be altered by release of catecholamines from sympathetic nerves of heart and vessels, the dogs were pretreated with acebutolol, a beta-adrenergic receptor blocking agent, which decreased heart rate and prolonged atrioventricular conduction and refractoriness. Nifedipine 1,6 and particularly 30 microgram/kg body weight increased the heart rate and decreased atrioventricular conduction time during atrial pacing, whereas atrioventricular conduction time during sinus rhythm and atrioventricular refractoriness were only affected by nifedipine 30 microgram/kg. In this respect, nifedipine differs distinctly from another calcium antagonistic compound, verapamil.

A double-blind randomized study was designed to investigate differences in the recovery of finger skin temperature after finger cooling during dosing with placebo or one of four beta-blockers: propranolol, atenolol, pindolol, and acebutolol. In 11 normotensive nonsmoking subjects, finger skin temperature was measured with a thermocouple before and 20 minutes after immersion of one hand in a water bath at 16 degrees C. This finger cooling test caused no significant changes in systemic hemodynamics such as arterial blood pressure, heart rate, and forearm blood flow. The recovery of finger skin temperature during propranolol dosing was better than that during pindolol and atenolol dosing. There were no differences between the recoveries of skin temperature during pindolol, atenolol, and acebutolol dosing. Thus we could demonstrate no favorable effect of intrinsic sympathomimetic activity or beta 1-selectivity on the recovery of finger skin temperature after finger cooling.

During 10 years of clinical use involving almost 3 million patient-years, acebutolol has become established as a remarkably safe and well-tolerated beta-blocking agent, effective in treating essential hypertension and cardiac arrhythmias. The existence of a long-lived active metabolite (diacetolol) confers a 24-hour duration of action, which permits effective use of a once-daily regimen, particularly for hypertension. Acebutolol has low lipid solubility and low protein binding; the former property reduces the risk of central side effects, and the latter means that displacement interactions with other drugs are unlikely. Because acebutolol and its metabolite normally have both renal and hepatic excretion pathways, an alternative pathway is available should either be compromised through disease. Acebutolol is cardioselective, and clinical use has borne out the low incidence of bronchospasm in patients with impaired lung function. The possession of intrinsic sympathomimetic activity (ISA) leads to only modest reductions in cardiac output, which in turn reduces the chance of excessive bradycardia and the likelihood of precipitating heart failure. A combination of selectivity and ISA may be responsible for the low incidence of tiredness and cold extremities observed with acebutolol compared with other beta blockers. The unique pharmacologic and pharmacokinetic profile of acebutolol confers several therapeutic advantages and may be responsible for the generally low level of side effects experienced in clinical use.

Acebutolol ('Sectral'), a cardioselective beta-blocking drug, was administered intravenously in a dose of 25 mg to 10 patients with congestive cardiomyopathy. All of them were in a stable condition on antifailure regimens. The drug resulted in a statistically significant decline in left ventricular contractility as judged by peak left ventricular dP/dT and the contractility index. The mean aortic blood pressure also fell. There was a significant increase in end-diastolic and end-systolic left ventricular volumes. Mean values for heart rate, ejection fraction, left ventricular stroke work index, and cardiac output also fell, but the results were not statistically significant. Left ventricular distensibility as judged by the slope of the diastolic pressure-volume relation also improved significantly. A reduction in myocardial energy requirements, improved compliance, and lowering of arterial pressure would be haemodynamically advantageous. However, further cardiac dilatation and reduction contractility--the basic defects in congestive cardiomyopathy--could lead to further deterioration.

1 The cardiovascular effects of the beta-adrenoceptor blocking drugs, propranolol and acebutolol, on regional coronary blood flow and left ventricular function have been investigated in the conscious dog with developing myocardial infarction. 2 Propranolol (1 to 1.5 mg/kg) or acebutolol (4 to 5 mg/kg) were administered intravenously 2 to 3 h after occlusion of the left anterior descending coronary artery. 3 Propranolol or acebutolol administration resulted in a relative increase in flow to the ischaemic area of the myocardium, particularly to the subendocardium. 4 Propranolol produced a greater reduction in heart rate and myocardial contractility than acebutolol. 5 These results demonstrate that beta-adrenoceptor blocking drugs reduce myocardial oxygen consumption and increase coronary flow to the ischaemic area of the myocardium after coronary artery occlusion in the conscious dog.