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1 In 46 patients (16 female and 30 male), aged between 18 and 73 years and effect of acute beta-adrenoceptor blockade with i.v. pindolol, acebutolol and atenolol has been studied at rest and during ergometric exercise, during routine intracardiac His bundle investigations. 2 At rest the functional parameters of the sinus node were impaired most markedly by atenolol. A-V nodal conduction was more depressed with acebutolol and atenolol than with pindolol. The His-Purkinje system conduction remained unaffected by all three beta-adrenoceptor blocking agents. 3 During ergometric exercise the depressant action of beta-adrenoceptor blockade on sinus nodal function with lower heart rates and on A-V nodal conduction with slower conduction velocities was equieffective with pindolol, acebutolol and atenolol. His-Purkinje system conduction again remained unchanged with one exception that after administration of pindolol, conduction rate during exercise was faster than before beta-adrenoceptor blockade. 4 It may be concluded that, in patients with low heart rates, an antagonist such as pindolol with relatively pronounced intrinsic sympathomimetic activity can be considered to be the drug of choice. In contrast, patients with higher heart rates at rest should be treated with a cardioselective betablocker without ISA. Patients with overt Sick Sinus Syndrome should not be given beta-adrenoceptor blockers at all. 5 Physical activity may change (improve or impair) the antiarrhythmic potency of beta-adrenoceptor blockers used in the treatment of supraventricular tachycardias or tachyarrhythmias.

Increasing amounts of Digoxin, Lasix, Teofyllamin and CI-775 were added to human blood in vitro and the whole blood oxygen affinity was measured. We found no definite proof that any of the drugs was able to affect the oxygen affinity of the red cells even at unphysiologically high concentrations.

The purposes of this study were to evaluate the beta 1 and beta 2 adrenoceptor blocking properties of acebutolol and propranolol and measure the plasma levels of acebutolol, its acetylated metabolite and propranolol. Ten patients with reversible obstructive airways disease and hypertension received two separate dose levels of acebutolol and propranolol for five days each. Cardioselective properties were assessed by determining the beta 1 and beta 2 adrenergic-stimulating effects of terbutaline 5 mg before and at the end of each five-day treatment period. Both acebutolol and propranolol were clinically well tolerated. Following study drug there was a 100 percent inhibition of the beta 1 terbutaline effect, and an approximate 83 percent inhibition of the beta 2 terbutaline effect. There were no clinically significant differences between acebutolol and propranolol. The acetylated acebutolol metabolite accumulated levels two to three times higher than the parent compound, and its effects may have destroyed the cardioselectivity of acebutolol. Thus, acebutolol did not demonstrate clinically relevant cardioselectivity.

The effects of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the systolic blood pressure and heart rate were investigated in conscious Kyoto Wistar normotensive rats (WKY), spontaneously hypertensive rats (SHR) and DOCA-NaCl hypertensive rats (DOCA rats) and the results compared with those of propranolol and practolol. In WKY and DOCA rats, the intraperitoneal administration of acebutolol, propranolol and practolol (0.5 approximately 20 mg/kg) produced a hypotensive action, however, these effects were observed only with restricted doses and there was no evidence of a dose-dependency. The heart rate was decreased by acebutolol and propranolol, but was increased by practolol which possesses an intrinsic sympathomimetic activity. In SHR, propranolol produced a dual action, a slight rise followed by a slight fall, the change not being significant, while practolol induced a slight hypertension. On the other hand, acebutolol in high doses induced a dose-dependent hypotensive action. The heart rate was markedly and dose-dependently decreased by these three agents. Thus, while propranolol and practolol produced hypotensive effects in WKY and DOCA rats, acebutolol produced hypotensive effects in WKY, SHR and DOCA rats. These results suggest that acebutolol is a beta-adrenoceptor blocking agent which possesses hypotensive activity in hypertensive rats.

We used 31P NMR spectroscopy to study the effect of acebutolol on the metabolic disturbances caused by ischaemia in the isolated rat heart. The intracellular acidosis and high-energy phosphate compound depletion induced by global low-flow ischaemia were significantly attenuated in the presence of acebutolol 2.7 X 10(-5) and 1.35 X 10(-4) M. The drug displayed no significant effect either at the 5.4 X 10(-6) M concentration or when administered as pretreatment to the animals (50 mg X kg-1, 120 and 60 min before isolating the heart). Since acebutolol had no effect on the contractility of the isolated rat heart at the 2.7 X 10(-5) M concentration the present results suggest that the mechanisms through which acebutolol exerts its effects on energy metabolism are not related to a reduction of cardiac work. The possible contribution of the membrane-stabilizing property of the drug is suggested by the fact that high concentrations are needed and that a short pretreatment had no effect.

Acebutolol is a new hydrophilic, cardioselective beta-adrenergic-blocking agent that possesses partial agonist and membrane-stabilizing activities. In the treatment of mild to moderate essential hypertension, once-daily acebutolol as monotherapy provides effective control in a large majority of patients and produces a further reduction in blood pressure when used concomitantly with diuretics. Acebutolol is as effective as other beta-blocking agents, and in a large, double-blind, parallel study against propranolol was found to cause less reduction in heart rate, and fewer neurologic side effects and patient withdrawals due to adverse effects. Oral acebutolol is also effective in suppressing premature ventricular contractions, and in small numbers of patients generally beneficial results were obtained in supraventricular and ventricular arrhythmias with intravenous administration. These salutary effects are attributable to beta blockade. Controlled clinical trials documented the antianginal actions of oral acebutolol in chronic stable angina pectoris; its efficacy in this regard is comparable to that of other beta-blocking agents. The drug produces smaller decreases in heart rate and cardiac output and alterations in peripheral vascular hemodynamics than beta-blocking drugs without partial agonist activity, and because of its cardioselectivity, it may be used cautiously in patients with bronchospastic disease. Acebutolol has minimal metabolic effects and does not elevate levels of blood lipids during long-term therapy; high-density-lipoprotein cholesterol increased with acebutolol in a small number of patients.

Epidemiological and recent interventional studies have emphasised the relationship between plasma lipid parameters and the incidence of coronary heart disease. beta-Blockers, particularly those without intrinsic sympathomimetic activity (ISA), are generally reported to increase triglyceride levels and decrease high density lipoprotein (HDL)-cholesterol levels, both changes theoretically increasing the risk of coronary heart disease. A review of all published trials concerning the effects of acebutolol (a cardioselective beta-blocker with mild ISA) on the plasma lipid profile was carried out, with a particular emphasis on studies reporting a comparison with other beta-blockers. The results indicate that, on average, acebutolol does not have any adverse effects on plasma lipids and may even reduce total and low density lipoprotein (LDL)-cholesterol by 7 and 5%, respectively. In contrast, the other beta-blockers compared under the same conditions (propranolol, pindolol and penbutolol) tended to increase triglyceride levels (+19% when compared with acebutolol) and decrease HDL-cholesterol (-7% when compared with acebutolol) to an extent that was consistent with previous reports in the literature. In interpreting these differences in lipid parameters in the light of epidemiological and interventional study data, the use of acebutolol as opposed to the other beta-blockers could theoretically lead to a relative reduction in coronary risk of 20% or more.

The effect of nifedipine, a calcium-antagonistic drug, was studied on the electrophysiology of the right ventricle in the dog heart in situ. Monophasic action potential recordings were obtained by the suction electrode technique and refractoriness was measured by means of programmed electrical stimulation. Pentobarbital anaesthesia was used. As the basic cardiac effects of nifedipine can be altered by the release of catecholamines from sympathetic nerves of the heart and vessels, the dogs were pretreated with the beta-adrenergic receptor blocking agent acebutolol which increased the action potential duration and the refractoriness. Intravenous injection of nifedipine 30 microgram/kg body weight decreased the times for 50 and 90 per cent repolarization of the monophasic action potential and to a smaller extent the effective and functional refractory period. It is suggested that nifedipine decreases the action potential duration and the refractoriness of the right ventricle of the dog heart in situ due to a direct effect of the drug on the myocardium.

The cardiovascular risk of hypertension depends not only on blood pressure under resting conditions, but particularly on blood pressure increases induced by daily physical and emotional activity. Therefore, the ability of the beta 1-receptor antagonist acebutolol (400 mg/day) and of the alpha 1-receptor antagonist prazosin (4 mg/day) to reduce exercise-induced increases in blood pressure and pressure-rate product during and after standardized ergometric work (50-100 W) was compared in an intrapatient study including 20 outpatients with arterial hypertension (WHO stage 1-2) aged 29-55 years. Both drugs resulted in a significant reduction of systolic (p less than 0.01) and diastolic (p less than 0.001) blood pressure at rest. However, systolic blood pressure (p less than 0.001) and pressure-rate product (p less than 0.001) during exercise were only significantly reduced by acebutolol. The strongest blood pressure lowering effect under all conditions could be achieved by the combination of prazosin and acebutolol. From these findings it is concluded that: (1) beta-adrenoreceptor-blocking agents are the drugs of first choice in the baseline therapy of mild to moderate arterial hypertension, and (2) prazosin potentiates the antihypertensive effect of beta-blocking agents. This therapeutic regimen is recommended especially for hypertensives with ischemic heart disease, because prazosin fails to reduce pressure-rate product as a measure of myocardial O2-consumption.

beta-Blockers are used as if they were equivalent. With ECG recordings in 42 patients we investigated the effect on sinus heart rate of four beta-blockers given at three successive daily doses. Heart rate was dose-dependently decreased by all drugs except acebutolol, the effect of which decreased at a higher dosage. The maximal effects of metoprolol, nadolol, and propranolol were similar but the drugs differed in potency (dosage producing 50% of maximal effect, calculated from the dose-effect relationships; nadolol, 0.3 mg/day; metoprolol, 120 mg/day; propranolol, 47 mg/day). Similar relationships were found with drug plasma concentrations (concentration producing 50% of maximal effect: nadolol, 3.5 ng/ml; metoprolol, 21 ng/ml; propranolol, 36 ng/ml) and with supine or upright heart rates and blood pressures. However, the drugs were not equivalent: In addition to its greater potency, nadolol differed from propranolol and metoprolol in the slope of its dose-response curve. We conclude that beta-blockers can be compared by ECG recordings and that nadolol is different from the other beta-blockers without intrinsic sympathomimetic activity.

In 2 patients with phaeochromocytoma, effective beta-blockade was obtained with propranolol (40 mg twice a day for 3 days) or acebutolol (400 mg twice a day for 3 days) without any effect on the blood pressure. In both patients the excretion of noradrenaline predominated over that of adrenaline, a picture found in most cases of phaeochromocytoma. A hypertensive response to beta-blockade might be expected in patients with an adrenaline-secreting tumour. It cannot be a regular event or constitute a diagnostic test in patients with suspected phaeochromocytoma.

1. During a 28-day treatment period, 10 healthy volunteers in a cross-over, double-blind study received at random 200 mg of either acebutolol or labetalol twice a day. Each treatment period was followed by administration of a placebo over an equal length of time. 2. Only acebutolol reduced heart rate measured in the supine position significantly at rest, whereas acebutolol and labetalol reduced it significantly after exercise on the treadmill. 3. Only acebutolol lowered humeral pressure at rest but not after exercise. Neither drug produced a change in blood pressure in the ankle or in the first toe at rest or after exercise. 4. Blood flow measured by plethysmography was increased by labetalol in the calf by comparison with placebo and in the first toe by comparison with placebo and acebutolol. 5. Labetalol lowered peripheral resistance significantly in comparison with placebo in the calf and first toe. Acebutolol tended to lower the resistance insignificantly in the calf but to increase resistance in the first toe.

A delay in the onset of isoniazid-induced convulsions was found in rats pretreated with the beta 2-adrenoceptor blocker, butoxamine and the nonspecific beta-blocker, propranolol. In these animals the convulsive responses were inhibited in a dose dependent manner. These compounds were found to be effective even after the induction of convulsions. The beta 1-blocker, acebutolol was able to protect rats only when injected prior to the challenge. The anticonvulsant effect of acebutolol and propranolol but not that of butoxamine was found to be enhanced in animals pretreated with a gamma-aminobutyric acid (GABA) elevating agent, aminooxyacetic acid (AOAA). The findings indicate that the GABA-mediated anticonvulsant action of AOAA seems to be additive with that resulting from beta 1 but not beta 2-blockade.

Acebutolol, a beta blocking agent, was injected at a dose of 1 mg/day, every day for 6 months in C57B1/6 and OF1 mice. No antinuclear antibodies were induced but a transient induction of anti-single stranded DNA antibodies and an increase of IgM, IgA and IgG2a levels were observed during the first 3 weeks in some treated mice as compared to control mice. This effect was more pronounced in C57B1/6 than in OF1 mice and in the C57B1/6 mice, was more frequently observed in female than in male mice. It was further found by cellular studies done in C57B1/6 female mice, that daily i.p. or oral administration of Acebutolol induces a transient polyclonal stimulation of lymphocytes. It is concluded that certain beta blockers might possess some in vivo effects on the immune system.

The hypotensive effect of different adrenergic agonists and antagonists were screened both in normo- and hypertensive rabbit eyes. The drugs were applicated topically and intraocular pressure (IOP) was monitored constantly with a manometric method. Subsequently the inhibitory effect of the antagonists on isoproterenol-stimulated adenylate cyclase activity in the ciliary processes was analyzed in vitro. In normotensive eyes agonist isoproterenol (beta) and antagonists labetalol (alpha beta), metoprolol (beta 1) and acebutolol (beta 1) decreased significantly IOP. In hypertensive eyes only isoproterenol and labetalol decrease IOP markedly. Timolol (beta) did not decrease IOP, although it inhibited adenylate cyclase activity as actively as labetalol. The other antagonists showed no inhibitory effect on in this respect. The results indicated that alpha-activity (labetalol, alpha beta) seems to potentiate the beta-activity (timolol, beta) in decreasing IOP. Whether this alpha-effect is a presynaptic effect (adrenergic denervation destroys it) is not yet clear. Similarly the beta 1-effect (metoprolol), without affecting adenylate cyclase activity, decreased IOP as well. This might be due to pre-synaptic release of endogenous transmitter(s) which in turn stimulate post-synaptic adenylate cyclase and induce the decreased IOP. Besides this, the possible role of blood vessels and CNS must also be kept in mind.

1 The degree of beta-adrenoceptor blockade of isoprenaline-induced tachycardia has been determined in three healthy volunteers after the administration of single oral doses of acebutolol, practolol or propranolol. 2 Plasma levels of these drugs were determined either colorimetrically (acebutolol and practolol) or fluorimetrically (propranolol). The colorimetric assay of acebutolol in plasma is fully described but the other drugs were assayed by published methods. 3 The degree of beta-adrenoceptor blockade and the plasma level for acebutolol and practolol were well correlated, whereas in the case of propranolol correlation was poor, due in part to the presence in plasma of active metabolites not detected by the fluorimetric assay. The plasma levels of practolol and propranolol are in agreement with those previously reported. 4 The maximum cardiac beta-adrenoceptor blockade achieved in this study with the respective single oral doses of acebutolol (300 mg), practolol (400 mg) or propranolol (40 mg) were similar in each of the three subjects. Therefore the beta-adrenoceptor blocking potencies of these drugs against isoprenaline-induced tachycardia are inversely related to these doses; indicating that propranolol is 7-8 times more potent than acebutolol and the latter slightly more potent than practolol.

An open randomized study involving 57 subjects, 40 euthyroid and 17 hyperthyreotic, was undertaken to compare the effect of two beta-adrenergic blocking drugs, propranolol (120 mg/day) and acebutolol (600 mg/day), on the thyroid hormones serum level. In hyperthyreotic as well as in euthyroid subjects, propranolol evoked a fall in T3, an increase in reverse T3 and therefore a decrease in the T3/rT3 ratio. Acebutolol caused a decrease in T3 and in the T3/rT3 ratio only in euthyroid subjects. The only significant variation in the hyperthyroid acebutolol treated group was a decrease in reverse T3, perhaps spontaneous. TBG and TSH concentrations remained stable under treatment in all the groups. The relation of these effects with the existence of a membrane stabilizing activity displayed by propranolol as well as by acebutolol is discussed.

The effect of propranolol, carazolol and acebutolol on the heart rate and blood pressure responses to intravenous adrenaline were examined in conscious Pietrain pigs. All three drugs blocked the tachycardia and vasodilatory responses to adrenaline and induced an increase in vasopressor responsiveness. The likely complications from using non-cardioselective beta blockers for preventing stress-induced deaths in pigs are discussed.

Ten healthy adult male volunteers were studied to assess the urinary effects of a single dose of a combination of hydrochlorothiazide 12.5 mg and acebutolol 200 mg (HZAL). The formation induced a significant increase in the 24-hour urinary output of sodium. Outputs of fluid, chloride, potassium, calcium, magnesium, zinc, total inorganic phosphate and creatinine were unaffected. With the exception of Mg2+ flow, times to maximal urinary flows of fluid and solutes were shortened by HZAL. These qualitative changes resemble those induced by hydrochlorothiazide but did not achieve quantitative significance, either because the constituent diuretic dose was too small or because acebutolol compensated for some of its effects.

In order to evaluate the long-term effects of propranolol and acebutolol on serum lipoprotein lipids, a double-blind clinical trial was carried out. Fifteen patients with stable angina pectoris, aged 32 to 79 years (mean = 53), were randomized to propranolol (80 to 160 mg/day) or acebutolol (400 mg/day) treatment groups, and followed for approximately 1 year (mean = 371 days). Blood was collected on the day treatment was begun, after approximately 5 months (mean = 158 days), and on completion of the trial. Very low-density lipoproteins (VLDL) (alpha less than 1.006), low-density lipoproteins (LDL) (1.006 to 1.063), and high-density lipoproteins (HDL) (1.063 to 1.125 [HDL2] and 1.125 to 1.21 [HDL3]) were isolated by sequential preparative ultracentrifugation, and their cholesterol and triglyceride quantified by enzymic procedures. After 1 year propranolol had raised the mean VLDL triglyceride concentration by 79% (p less than 0.005) and had lowered total HDL cholesterol by 24% (p less than 0.005). As LDL cholesterol was unchanged, the LDL cholesterol/HDL cholesterol ratio was increased by 26% (p less than 0.005). Mean values at 5 months were intermediate between those at baseline and those at 1 year. In contrast to these changes, acebutolol had no significant effect on any measured lipoprotein lipid.

The electrophysiological effects of acebutolol were studied in 12 patients. Heart rate and systemic arterial pressure were monitored. Plasma acebutolol levels were estimated. The first 6 patients (group A) received 0.3 mg/kg body weight I.V. The subsequent 6 patients (group B) received 0.5 mg/kg body weight I.V. Acebutolol delayed both antegrade and retrograde conduction through the AV node. The effect was greater in group B patients. Effective and functional refractory periods of the AV node were also increased after acebutolol. Intraatrial and intraventricular conduction and the effective refractory periods of the atrium and ventricle were not affected. Acebutolol did not alter significantly the sinus node recovery time or the QTc interval. Heart rate fell, especially where initial rates were fast. Systolic arterial pressure was lowered in group B patients. Peak mean levels of acebutolol were reached 5 min after injection of the drug. In the doses used, acebutolol, although well tolerated, failed to demonstrate electrophysiological evidence of a membrane-stabilizing effect and is therefore unlikely to add to the areas of success achieved by other beta-blocking drugs in the management of arrhythmias.

Recording by means of echography the motions of the posterior wall of the left ventricle makes it possible to compare in subjects acting as their own controls the amplitude of the movement, contraction and decontraction time of the myocardium before and after medication. This report concerns the variations recorded in 10 healthy patients before and after oral administration of 200 mg/day of acebutolol for 10 days. A statistically significant decrease of 8-9 p.cent of the various parameters was found. It probably reflects the negative inotropic action exerted by the drug.

1 Nine hypertensive patients received by mouth daily doses of 400 mg of acebutolol and then, after a 2 week washout period, 80 mg of propranolol for 2 week periods in an open study. 2 Both treatments caused equivalent cardiac blockade as assessed by reduction in exercise tachycardia. 3 Both treatments lowered blood pressure, although this effect on pressure was better maintained in the case of acebutolol. 4 Forearm blood flow, at rest, was significantly reduced at 2 h after dosing with propranolol, but not after acebutolol. 5 This difference between the two drugs is probably due to the cardioselectivity of orally administered acebutolol in man.

We assessed the effects of acebutolol, a cardioselective beta blocker, on global and regional left ventricular function in 26 patients with chronic angina pectoris. All patients underwent rest and maximal supine bicycle exercise radionuclide angiography while on placebo and oral acebutolol (400 mg three times a day). Resting ejection fraction on placebo was 51 +/- 3% and on acebutolol was 54 +/- 3% (p less than 0.05). No resting ejection fraction decreased greater than or equal to 7%. Only one patient (resting ejection fraction 28% on placebo and 21% on acebutolol) developed signs of fluid retention. Exercise nuclear studies on placebo revealed responses consistent with coronary artery disease (abnormal ejection fraction response to exercise and regional wall motion abnormalities) in 24 of 26 patients. Peak exercise ejection fraction was of the same order on placebo and acebutolol (51 +/- 3% and 54 +/- 3%, p = NS). In four patients the ejection fraction response to exercise became normal and in five patients all regional wall motion abnormalities became normal on acebutolol. Cardioselective beta blockade with acebutolol in effective antianginal doses is safe and may improve resting and exercise ventricular function.

Description of a non invasive model to determine the negative-chronotropic effect, which leads to well stabilized parameters by tailoring. Basis of the model is the work-induced tachycardia at which the work-induced increase of frequency is measured at a specified time after 10 preliminary ergometries for the elimination of training effects. The parameter for the effect is the difference of frequencies at nominal time before and after administration of beta-adrenolytic drug. The relevance of the model is shown at the example of acebutolol (Neptal 400) in various high dosages.

The effects of selective and nonselective beta adrenergic drugs on the renin secretion rate (RSR) in isolated perfused rat kidneys were studied. Both isoproterenol (Ipr) (nonselective agonist) and salbutamol (Salb) (beta-2 selective agonist) stimulated RSR in a dose-dependent manner. The lowest doses able to induce a significant RSR increase were 5 nM for Ipr and 50 nM for Salb. A 5-fold increase in RSR was induced by 500 nM Ipr and a 3.2-fold increase by 5 microM Salb. Renin stimulation by both agonists was suppressed by propranolol (nonselective) and by acebutolol and its derivative M&B 16,942 (beta-1 selective antagonists). Thus, renin release was stimulated or inhibited effectively by all the drugs tested, regardless of the beta selectivity of agonists and antagonists. There were no consistent relationships observed between changes in renal hemodynamics and in RSR, suggesting that the used drugs affected renin release from in vitro-perfused rat kidney through their direct effects on juxtaglomerular cells. These results indicate that renal beta adrenoreceptors involved in renin release do not fall into two distinct beta subtypes.

Twenty outpatients with mild angina were prescribed placebo tablets b.i.d. for 7 weeks followed by acebutolol, a cardioselective beta-blocker, 200 mg b.i.d. for 21 weeks under single-blind conditions. One graded multistage treadmill test was carried out after each treatment period and an angina diary was filled daily for the 6 months of the trial. Attack frequency declined by 71% from 2.59 per week on placebo to 0.76 per week on acebutolol (p less than 0.05). Exercise duration on the treadmill increased by 56%, from 5.95 minutes on placebo to 9.32 minutes on acebutolol (p less than 0.001). A satisfactory clinical response (50% or greater decline in attack frequency per week) occurred in 15 out of 19 patients (79%; a 100% or greater increase in exercise duration on the treadmill was observed in 10 out of 19 cases (53%). Exercise responsiveness was well predicted by exercise duration on placebo (r = 0.91, p less than 0.0005), patients with the least initial tolerance being the most improved. Clinical responsiveness was not well predicted by initial exercise tolerance (r = 0.38, N;S.) or by the improvement in exercise tolerance (r = 0.33, N.S.). It is concluded that acebutolol substantially reduces anginal attack frequency even in patients in whom exercise tolerance is not significantly improved, at the dose of 400 mg/day.

Acebutolol is a cardioselective beta-adrenoceptor blocking drug possessing both partial agonist (intrinsic sympathomimetic) and membrane stabilising activity. In hypertension, it can be administered once or twice daily with equal effectiveness, and has been as effective at lowering blood pressure as propranolol, diuretics, and other beta-blocking drugs (metoprolol, labetalol and atenolol) and more effective than methyldopa. Acebutolol has a significantly smaller effect on resting heart rate than propranolol, metoprolol and atenolol, although direct comparisons with drugs with intrinsic sympathomimetic activity have yet to be undertaken. In both angina and arrhythmia, when administered twice daily it has been as effective as standard therapeutic agents. The side effect profile of acebutolol appears to be comparable to that of other cardioselective beta-blockers. Its relative cardio-selectivity, partial agonist and membrane stabilising activity, hydrophilicity, and considerable extrarenal excretion may offer advantages over some beta-blocking drugs in specific patients. Choosing a beta-blocking agent, however, should be made with a knowledge of pharmacodynamic and pharmacokinetic properties of the various agents and careful consideration of how such properties may be of benefit to an individual patient.

A double-blind, placebo-controlled study of the haemodynamic and ventilatory effects of two beta 1-selective adrenoceptor blockers and their interaction with the beta 2-adrenoceptor agonist terbutaline was carried out in eight asthmatic patients. One hour after intake of placebo, metoprolol 100 mg or acebutolol 400 mg, increasing doses of terbutaline were infused. Before and one hour after ingestion of the medication and after each infusion of terbutaline, ventilatory and haemodynamic indices were measured. The two beta-blocking agents caused equal changes in basal ventilatory and haemodynamic indices. Terbutaline infusion caused a dose dependent increase in forced expiratory volume in one second (FEV1) and peak expiratory flow rate (PEFR), both during placebo and beta-blockade. Metoprolol did not affect the terbutaline-induced bronchodilatation. During acebutolol medication, however, the increase in FEV1 and PEFR induced by terbutaline was partly inhibited. Terbutaline infusion during placebo caused a dose-dependent increase in heart rate (HR) and systolic blood pressure (BP), and a decrease in diastolic BP. During acebutolol medication, these haemodynamic effects of terbutaline were completely blocked, but during metoprolol medication terbutaline still caused small changes in the same direction as during placebo, presumably because the vasodilator action of terbutaline was not inhibited. A negative correlation was found between the plasma levels of acebutolol and its metabolite N-acetyl acebutolol at the end of the study and changes in FEV1 and PEFR induced by terbutaline during acebutolol therapy as compared with placebo. The ventilatory and haemodynamic findings suggest a lower degree of beta 1-selectivity after oral administration of acebutolol as compared to metoprolol.

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.

The effects of two new beta blockers on renal function have been studied. There were significant decreases in urine flow, urea clearance, sodium and chloride excretion rates after acute administration. Fractional excretion of sodium (FeNa) fell significantly but did not continue to fall during chronic administration. Blood pressure and plasma renin activity decreased significantly after two months' therapy. These findings suggest that beta blockers in patients with unstable cardiovascular function increase the need for concomitant diuretic therapy.

The efficacy of single daily doses of acebutolol, alone or combined with chlorexolone, was investigated in a group of 20 ambulant patients with uncomplicated hypertension of mild-to-moderate severity. severity. Patients were seen at fort-nightly intervals when doses were adjusted. Blood pressure was measured in all instances at 2 and 8 hours after medication, and after it had stabilized, at 26 hours after the last dose. The results indicate that a single dose of acebutolol alone produces significant lowering of supine and erect blood pressures for 24 hours (P less than 0,005). Combining chlorexolone with acebutolol does not improve the hypotensive effect of the beta-blocker significantly, but makes a smaller dose effective.

1. Administration of adrenocorticotropic hormone (ACTH) to sheep produced increases in mean arterial pressure within 24 h associated with an increase in cardiac output and cardiac rate. Both cardiac output and blood pressure remained elevated over the 5 days of ACTH treatment. 2. Administration of ACTH during beta-adrenoreceptor blockade resulted in an increase in blood pressure without changes in cardiac output at 24 h. 3. Administration of a combined steroid infusion over 5 days produced increases in cardiac output identical with the effects of ACTH but with a substantially smaller effect on blood pressure. 4. These data suggest that the observed changes in cardiac output produced by ACTH treatment may be associated with high blood concentrations of adrenocortical steroids rather than being necessary for the development of the hypertension.

Fifty hypertensive patients were given a beta-blocker, acebutolol, alone or in association with other hypotensive drugs, in an open therapeutic trial lasting for a year. The results of treatment were considered to be good or moderate in 74 p.cent of the patients. Treatment failures were recorded in 26 p.cent. The mean dosage of acebutolol was 10 mg/kg (maximum 22 mg/kg) and the drug was very well tolerated. Hypertension with an increased cardiac index and reno-vascular hypertension with increased plasma renin activity are good indications for acebutolol.

Pharmacodynamic data correlating beta-adrenoceptor blockade with plasma level of drug were obtained in healthy male volunteers (3). Direct comparison of the inhibition of isoprenaline induced tachycardia was achieved in each volunteer after the administration of single doses of either acebutolol (300 mg), practolol (400 mg) or propranolol (40 mg). These drugs were approximately equipotent at these doses, at the times of maximum beta-adrenoceptor blockade. Pharmacokinetic data were obtained in hypertensive male patients (4) after treatment with 14C-radioactively labelled acebutolol hydrochloride. Both 'total-14C' levels and specific '14C-acebutol' levels were determined in plasma, urine and faeces. It was shown, by calculation from the renal clearance, that the late biological half-life for the decline of 14C-acebutolol in plasma was 9.4 h and 13.2 h, respectively, in two of these patients treated with a single oral dose (200 mg) of 14C-acebutolol hydrochloride. In one of the patients treated by intravenous infusion (20 mg/10 mn), the late biological half-life plasma was calculated to be 7.5 h. Renal clearance of acebutolol was shown to be close to a mean of 83 ml plasma/mn for each of three patients (two oral and one intravenous) in spite of the fact that one of the orally treated patients had an elevated level of urea in his plasma (47 mg/100 ml) indicative of some impairment of kidney function. The recovery of 14C-radioactivity in the urine (29 p. cent) and faeces (64 p. cent) was 93 p.cent of the dose of labelled acebutolol in one of the orally treated patients. The overall proportion of the dose excreted as unchanged 14C-acebutolol was 62 p.cent. The major metabolite was the product formed by shortening of the butyramido-group of acebutolol to form an acetamido-group. This metabolite was also readily excreted in both urine and faeces and was also detected in an extract of the 4 h plasma from an orally treated patient. It was identified by co-chromatography as the acetyl analogue (M & B 16 942) of acebutolol. It would be detected by the colorimetric assay of acebutolol in plasma because the same aromatic amino-compound (M & B 17 127) would be formed during the acid hydrolysis procedure. A small quantity of an other unidentified metabolite was detected in an extract of freeze-dried urine after autoradiography of a two dimensional thin layer silica-gel chromatogram.