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Aim: The aim of the study was to develop new SIRT1 activator compounds, for this aim, we used virtual screening and molecular dynamics methods, which have been important tools for new hit compound searches., Background: Recently, with the progress of computing technology, it has been possible to obtain higher efficiency and lower costs for drug discovery. With in silico research and drug design, there is a reduction in time-consuming and expensive experimental work. An NAD+ dependent histone deacetylase enzyme, Sirtuin 1 (SIRT1), is involved in a variety of human disorders such as type II diabetes, cancer, obesity, and aging. Activation of SIRT1 could be useful for longevity and treating metabolic disorders., Objective: We used computational methods to develop new SIRT1 activator compounds., Methods: Firstly, virtual screening studies on the human SIRT1 enzyme were carried out. We used approximately 150.000 commercially available compounds from the Zinc database, which include FDA-approved drugs. According to virtual screening results, we selected seven potent activators. Then we compared these hit compounds with known activators by using docking methods. One of these hit compounds, acebutolol, is an FDA-approved drug, and was selected for additional studies using molecular dynamics simulations., Results: Seven hit compounds were identified with database screening. Each showed strong interactions with SIRT1, and acebutolol formed H-bonds with the important active site residues, Asn226 and/or Glu230 during the dynamics simulation., Conclusion: Based on our in silico studies, the seven most promising compounds, especially acebutolol, showed promising SIRT1 activator potency. The results may be used to design new selective and more potent SIRT1 activator drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher v max over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The K m was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in K m was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1*2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher v max for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher v max for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The structure-activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential β-blockers are described. The synthesized compounds possess an isopropyl or a tert-butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four-step method and their structures were confirmed by interpretation of their UV, IR, (1) H NMR and (13) C NMR spectra, and by elemental analysis. The β-adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (β1 ) and trachea (β2 ) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as β1 /β2 ratio and the values of compounds with an alkoxy group (CH3 O, iC3 H5 O, C5 H11 O, CH2 CHCH2 O, CH3 OCH2 CH2 O) in the lipophilic part and with tert-butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10(-7)  mol/dm(3) showed also negative chronotropic effects., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: The purpose of this study was to analyse P-glycoprotein (P-gp) expression in different human in-vitro cornea models (HCE-T epithelial model and Hemicornea construct) after stimulation with P-gp substrates (rhodamine 123, levofloxacin and acebutolol)., Methods: The influence of P-gp substrates on mRNA expression was analysed using reverse transcriptase polymerase chain reaction (PCR) and real-time PCR. The effect of stimulation on the transporter functionality was estimated with a digoxin efflux assay. The Caco-2 cell line was used as positive control., Key Findings: The reverse transcriptase PCR results showed an increase in band intensity compared with the control medium for all substrates. The real-time PCR for the Caco-2 and HCE-T epithelial model yielded a similar outcome, in which all tested substrates upregulated P-gp. In contrast, the Hemicornea construct showed no significant increase in the mRNA expression after stimulation. Both in-vitro models possessed similar drug transport profiles after stimulation. A significantly increased efflux of digoxin was measured after 24 and 72 h of stimulation with levofloxacin and acebutolol., Conclusions: The expression and functionality of the P-gp in corneal tissue can be influenced through time exposure with specific substrates. However, the exact mechanism still requires further elucidation., (© 2015 Royal Pharmaceutical Society.)

The aim of this study is to investigate the active components of representative drugs for blood pressure regulation by applying quantum mechanical computer codes and comparison of the same for the sake of obtaining knowledge about the properties associated with the electronic structure of given molecules. The study included three well-known, but not theoretically investigated enough, active components of β-blockers: acebutolol, metoprolol and atenolol. The results are in agreement with the experimental data and were used for initial assumptions concerning the degradation of these compounds.

Infantile haemangioma (IH) is the most common tumour during early childhood. Although these benign lesions resolve spontaneously, up until recently laryngotracheal sites of IH required invasive management. The dramatic efficacy of β-blockers on IH has radically changed the prognosis. Surgery is now no longer indicated as first-line therapy, but should only be performed for difficult, refractory cases, or in the presence of absolute contraindications to β-blockers. Long-term steroid therapy is also no longer indicated. Propranolol can be used as first-line, single-agent therapy., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

This study analysed the effect of selective beta(1)-blockade on neuromuscular recruitment characteristics during progressive endurance exercise. Ten healthy subjects ingested a selective beta(1)-blocker, acebutolol (200 mg b.d.), for 7 days (for one of two cycling trials), with a 10-day wash-out period between trials. On the last day of acebutolol ingestion subjects performed three successive 15-min rides at 30%, 50% and 70% of their peak power output and then cycled at increasing (15 W min(-1)) work rates to exhaustion. Force output, heart rate, submaximal VO(2), rate of perceived exertion (RPE), electromyographic (EMG) data and blood lactate were captured during the cycling activity. Peak work rate [270 (111) W vs 197 (75) W, CON vs BETA, P <0.01], time to exhaustion [49.7 (23.2) min vs 40.3 (23.7) min, CON vs BETA, P <0.05] and heart rate [mean, for the full ride 135.5 (38.3) beats min(-1) vs 111.5 (30.0) beats min(-1) CON vs BETA, P <0.05] were significantly lower for the group who ingested beta(1)-blockade (BETA) compared to the control group (CON). Although not significant, submaximal VO(2)was reduced in BETA during the ride, while RPE was significantly higher during the ride for BETA (P <0.01). Mean integrated electromyography was higher in the BETA group although these differences were not significant. Mean power frequency values of the BETA group showed a significant (P <0.05) shift to the upper end of the spectrum in comparison to the control group. Lactate values [11.7 (3.5) mmol x l(-1) vs 7.1 (4.1) mmol x l(-1)CON vs BETA] were significantly lower (P <0.05) at exhaustion in BETA. Significant reductions in cycling performance were found when subjects ingested beta(1)-blockers. This study has shown significant shifts to the upper end of the EMG frequency spectrum after beta(1)-blocker ingestion, which could be caused by a change in neuromuscular recruitment strategy to compensate for the impaired submaximal exercise performance.

Smith-Magenis syndrome (SMS) is a clinically recognisable contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Patients have a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Serum melatonin levels and day-night behaviour were studied in nine SMS children (aged 4 to 17 years) given acebutolol, a selective beta(1)-adrenergic antagonist (10 mg/kg early in the morning). Cardiac examination, serum melatonin, motor activity recordings, and sleep diaries were monitored before and after drug administration. The present study shows that a single morning dose of acebutolol suppressed the inappropriate secretion of melatonin in SMS. A significant improvement of inappropriate behaviour with increased concentration, delayed sleep onset, increased hours of sleep, and delayed waking were also noted. These results suggest that beta(1)-adrenergic antagonists help to manage hyperactivity, enhance cognitive performance, and reduce sleep disorders in SMS.

The effect of an alpha-blocking agent and of a beta-blocking agent on the biosynthesis of extracellular matrix macromolecules of the arterial wall was investigated. Rabbit aorta explants were cultured up to 48 hours with radioactive proline, lysine or glucosamine. In presence of these drugs, at concentration shown to be effective for the inhibition of platelet-endothelial cell interactions (10(-7) M), the incorporation of 14C proline in total macromolecular proline was higher than in macromolecular hydroxyproline suggesting a relatively higher rate of biosynthesis of non-collagenous proteins as compared to collagens. The alpha-blocking increased the incorporation of 14C proline in collagenous and non-collagenous proteins after 18 hours of incubation. beta-blocking also increased the incorporation of proline in macromolecular proline and hydroxyproline as compared to control cultures. Both increased the incorporation of 3H glucosamine in newly synthesised glycosaminoglycans. beta-blocking increased mainly the neosynthesis of heparan sulphate, alpha-blocking that of hyaluronan. The incorporation of 14C-lysine in crosslinked, insoluble elastin was not modified. These experiments confirm that alpha and beta-blocking agents can influence not only the tonus of aortic smooth muscle cells but also the relative rates of biosynthesis of extracellular matrix macromolecules. This effect should be taken in consideration for the evaluation of the long range effect of alpha and beta-blocking drugs on the vascular wall.

Beta-adrenoceptor blocking drugs are widely used as effective antihypertensive and antianginal agents. We have determined the effect of beta-blockade in the rat to ascertain whether there are differences between metoprolol (MET) and acebutolol (AC) with respect to regional blood flow (RBF). Both AC and MET were administered as a single or multiple intravenous (iv) doses in Sprague-Dawley rats. Microspheres labelled with (85)Sr and (141)Ce were used to measure cardiac output (CO) and RBF before and after drug administration. CO and RBF were measured 1 and 10 min after the i.v. administration of AC (30 mg/kg) and MET (10 mg/kg). After acute administration of MET, CO decreased by 65% and 31% after 1 and 10 min measurements, respectively. These values were 54% and 28% for AC as compared with baseline values. After chronic administration of either AC or MET, however, there were no significant reductions in CO as compared with saline. Both MET and AC significantly reduced RBF in most organs either after 1 or 10 min measurements when compared with the baseline values. It is concluded that both AC and MET reduced CO and RBF after acute administration. The CO and RBF however, returned to normal after chronic administration., (Copyright 2000 John Wiley & Sons, Ltd.)

Endothelin-1 (ET-1) (10 pmol) microinjected into the superficial layer of superior colliculus induces decreases in blood pressure (control, 108 +/- 5 mmHg, n=6; ET-1, 71 +/- 4 mmHg, n=5). The effects on blood pressure induced by endothelin-1 were significantly (p<0.05) reduced by pre-administration into the superior colliculus of the alpha1-adrenoceptor agonist phenylephrine (1 nmol) (46 +/- 5%, n=5), beta1-adrenoceptor antagonist acebutolol (5 nmol) (51 +/- 6%, n=5) or beta1/beta2-adrenoceptor antagonist propranolol (3.4 nmol) (51 +/- 11%, n=5). In contrast, endothelin-1-induced effects were increased (p<0.05) by microinjections into the superior colliculus of prazosin (2.4 nmol) (49 +/- 7%, n=5), an alpha1-adrenoceptor antagonist; dobutamine (4 nmol) (51 +/- 9%, n=5), a beta1-adrenoceptor agonist or isoprenaline (1 nmol) (49 +/- 6%, n=5), a beta1/beta2-adrenoceptor agonist. No involvement of alpha2- or beta2-adrenoceptors has been detected. Therefore, ET-1 induces decreases in blood pressure with selective involvement of alpha1- and beta1-adrenoceptors.

Chronic stress-induced behavioral disturbances have been used as experimental models of depression. One of them is the deficit of fighting behavior induced by 16-day application of various unpredictable stressors. In the present study we investigated the effect of beta-adrenoceptor antagonists (propranolol, pindolol, nadolol and acebutolol) on electric footshock-induced fighting behavior in chronically stressed (14 various stressors over 16 days) male Wistar rats. It was found that the number of fighting attacks was reduced by about 50-80% in the rats submitted to chronic stress. Prolonged, 14-day, but not acute, treatment with propranolol, pindolol or nadolol (but not acebutolol) counteracted the deficit of aggression induced by chronic stress. It is suggested that beta-adrenoceptor antagonists which penetrate the blood-brain barrier may prevent the behavioral changes induced by chronic stress.

The effect of beta-blockers (alprenolol, oxprenolol, atenolol, acebutolol) and the non-steroidal anti-inflammatory drug, diclofenac, on modification of low-density lipoproteins (LDL) by sodium hypochlorite (NaOCl) was investigated in vitro. Beta-blockers and diclofenac inhibit the formation of thiobarbituric acid reactive substances in LDL modified by NaOCl. Beta-blockers, but not diclofenac, inhibit the hypochlorite-induced aggregation of LDL which was determined by photon correlation spectroscopy. The intracellular accumulation of cholesterol esters in J774 macrophages is inhibited by addition of beta-blockers, but not diclofenac, to LDL prior to the addition of NaOCl. The modification inhibiting effect of beta-blockers is inversely correlated to the binding capabilities of these substances to LDL which were assessed by laser electrophoresis. Inhibition of LDL modification in vivo by beta-blockers may reduce the risk of atherosclerosis and, therefore, compensate for the cholesterol-raising effect of these drugs in human plasma.

The relationship between the Ki of the B2 adrenoceptor and EC50 values characterizing receptor down-regulation induced by isoproterenol and six beta antagonists classified as having weak to strong intrinsic sympathomimetic activity (ISA) was determined using L6 myoblasts. It was hypothesized that if receptor loss induced by beta antagonists with ISA was mediated through cAMP, EC50 = Ki. EC50/Ki ratios for (-)isoproterenol, (-) and (+) celiprolol were 0.006, 0.01 and 0.08, respectively (p < 0.05); ratios for (-)pindolol and dilevalol were 19 and 9.5, respectively (p < 0.05). EC50/Ki ratios for acebutalol and (-)alprenolol were not significantly different from 1.0. Isoproterenol and dilevalol maximally down-regulated receptor density 89 and 83%, respectively, followed by (+)celiprolol, 54%; (-)celiprolol, 53%; acebutalol, 41%; (-)pindolol, 36% and (-)alprenolol, 31%. Receptor loss was blocked in each case by ICI118,551 or sotalol. A sensitive radioimmunoassay failed to detect increased cAMP accumulation following pretreatment with concentrations of acebutalol, (-)alprenolol, celiprolol and (-)pindolol 100 times their respective Ki values. Isoproterenol and dilevalol stimulated cAMP accumulation 100- and 2-fold over basal, respectively. We conclude that receptor loss induced by beta antagonists with ISA is mediated through the beta 2 adrenoceptor and in at least some cases is cAMP-independent.

Using beta-adrenergic agonists and antagonists this study investigated the importance of three different adrenoceptor subtypes for the regulation of migrating myoelectric complexes (MMCs) of the upper small intestine in conscious, naive rats. After a control period of 60 min with four activity fronts, agonists were given as an intravenous infusion for another 60 min. The non-selective beta-adrenoceptor agonist isoprenaline (1 microgram kg-1 min-1) inhibited MMCs and induced irregular spiking during the infusion period. This effect was blocked by intravenous administration of a bolus dose of either the non-selective beta-adrenoceptor antagonist propranolol (1 mg kg-1), or the beta 2-antagonist ICI 118 551 (1 mg kg-1), both given prior to isoprenaline. However, acebutolol (1 mg kg-1), a selective beta 1-antagonist, failed to antagonize the effect of isoprenaline. Furthermore, prenalterol, a selective beta 1-agonist (12.5-800.0 micrograms kg-1 min-1), had no effect on the MMC pattern, whereas the beta 2-selective agonist ritodrine (25-100 micrograms kg-1 min-1) induced a myoelectric pattern similar to one induced by isoprenaline. The partial beta 3-adrenoceptor agonist D7114 (50-100 micrograms kg-1 min-1), disrupted the MMCs and induced quiescence. Neither of the antagonists, i.e. propranolol (1 mg kg-1), acebutolol (1 mg kg-1) nor ICI 118 551 (1 mg kg-1), given alone induced changes in the MMC pattern. In conclusion, beta 2-adrenoceptors in particular but also beta 3-adrenoceptors seem to be of importance in the regulation of small intestinal motility by disrupting the regular MMC pattern in rats.

Objective: - To compare long-term plasma lipid changes among 6 antihypertensive treatment interventions for stage I (mild) hypertension., Design: - Multicenter, randomized, double-blind, parallel-group clinical trial., Setting: - Four academic clinical research units in the United States., Participants: - A total of 902 men and women, aged 45 to 69 years, with stage I diastolic hypertension (diastolic blood pressure <100 mm Hg), recruited from 11914 persons screened in their communities., Interventions: - Participants were randomized to 1 of 6 treatment groups: (1) placebo, (2) beta-blocker (acebutolol), (3) calcium antagonist (amlodipine), (4) diuretic (chlorthalidone), (5) alpha1-antagonist (doxazosin), and (6) angiotensin-converting enzyme inhibitor (enalapril). All groups received intensive lifestyle counseling to achieve weight loss, dietary sodium and alcohol reduction, and increased physical activity., Main Outcome Measures: - Changes in plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides from baseline to annual visits through 4 years., Results: - Mean changes in all plasma lipids were favorable in all groups. The degree of weight loss with fat-modified diet and exercise was significantly related to favorable lipid changes. Significant differences (P<.01) among groups for average changes during follow-up in each lipid were observed. Decreases in plasma total cholesterol and LDL cholesterol were greater with doxazosin and acebutolol (for plasma total cholesterol, 0.36 and 0.30 mmol/L [13.8 and 11.7 mg/dL], respectively), less with chlorthalidone and placebo (0.12 and 0.13 mmol/L [4.5 and 5.1 mg/dL], respectively). Decreases in triglycerides were greater with doxazosin and enalapril, least with acebutolol. Increases in HDL cholesterol were greater with enalapril and doxazosin, least with acebutolol. Significant relative increases in plasma total cholesterol with chlorthalidone compared with placebo at 12 months were no longer present at 24 months and beyond, when mean plasma total cholesterol for the chlorthalidone group fell below baseline. Analyses of participants continuing to receive chlorthalidone throughout the 4 years of follow-up indicated this was not due solely to an increasing percentage of participants changing or discontinuing use of medication during follow-up., Conclusions: - Weight loss with a fat-modified diet plus increased exercise produces favorable long-term effects on blood pressure and all plasma lipid fractions of adults with stage I hypertension; blood pressure reduction is enhanced to a similar degree by addition of a drug from any one of 5 classes of antihypertensive medication. These drugs differ quantitatively in influencing the degree of long-term favorable effects on blood lipids obtained with nutritional-hygienic treatment.

We examined the influence of hypotension by infusion of acebutolol hydrochloride (AH), a cardioselective beta-receptor antagonist, on cochlear blood flow in guinea pigs with various hematocrit values. AH infusion lowered the mean blood pressure to almost the same degree in all animals, regardless of the hematocrit level. The degree of the concomitant decrease of CBF varied with the hematocrit, being greater in animals with a higher hematocrit. In those with the highest hematocrit CBF did not return to the initial level. From these values we calculated the O2 transport capacity after AH infusion and found it to be lower than in animals without AH infusion. The difference was greater at higher hematocrits. These findings suggest that the microcirculation of the inner ear is responsive to transient decreases of perfusion pressure at high hematocrits.

The association between torsade de pointes and experimentally induced early afterdepolarizations in isolated fibres is well documented. The effect of eight beta-adrenoceptor-blocking drugs (sotalol, nifenalol, acebutolol, dichloroisoproterenol, propranolol, oxprenolol, pindolol, atenolol), and of amiodarone, was studied in isolated spontaneously beating guinea-pig Purkinje fibres by the intracellular microelectrode technique. Phase 3 early afterdepolarizations were initiated by nifenalol hydrochloride (n = 18; 10 mumol/l: 0/18, 40 mumol/l: 3/18, 80 mumol/l: 8/18, 160 mumol/l: 11/18), rac.-(+/-)-sotalol hydrochloride (n = 28; 20 mumol/l: 0/28, 40 mumol/l: 9/28, 80 mumol/l: 20/28), (R)(+)-sotalol hydrochloride (n = 12; 40 mumol/l: 1/12, 80 mumol/l: 4/12), and (S)(-)-sotalol hydrochloride (n = 10, 40 mumol/l: 1/10, 80 mumol/l: 4/10). The arrhythmogenic effect was reversible after a washout period of one hour and early after-depolarizations could be terminated by tetrodotoxin (0.4-1.6 mumol/l, n = 6). Amiodarone only induced early afterdepolarizations at a low extracellular potassium concentration of [K+]o = 1.35 mmol/l (n = 5; 150 mumol/l: 0/5, 300 mumol/l: 1/5). The initiation of early after-depolarizations by sotalol and nifenalol might be induced by an imbalance of sodium inward current and potassium outward currents, and early afterdepolarizations are blocked by tetrodotoxin.

The latency time and escape ability of rats with learned helplessness behavior were studied after 1, 6 and 14 days of oral treatment with beta-adrenergic blockers propranolol (1 and 3 mg/kg) and acebutolol (10 and 30 mg/kg). A dose-dependent significant decrease in latency time and increase in number of avoidances was established after single, 6 and 14 days propranolol treatment. The selective beta 1-blocker acebutolol did not change the escape characteristics. These results suggest a greater impact of beta 1- than beta 2-adrenergic receptors for escape performance after unescapable foot shock, i.e., learned helplessness behavior.

Acebutolol induces transient polyclonal B cell activation in C57B1/6 mice but down-modulates the spontaneous polyclonal activation of NZBxNZW lupus mice. The immunomodulatory effects of this beta-blocker were studied in C57l/6 mice injected with LPS or immunized with sheep red blood cells. The effect of acebutolol on the polyclonal activation of lymphocytes induced by LPS was also investigated in heterozygous and nu/nu C57BL/6 mice. Finally, the direct effect of acebutolol on spleen cells was studied in vitro. Acebutolol treatment for 15 days (50mg/kg/day) inhibited the polyclonal activation of lymphocytes induced by LPS in C57BL/6 and in C57BI/6 nu/nu mice, but increased the humoral response to sheep red blood cells in C57Bl/6 mice. Moreover, spleen cells from C57Bl/6 mice treated for 15 days with acebutolol showed an increased number of CD5+ and CD4+ lymphocytes, as well as an increased reactivity to concanavalin A but not to LPS. In vitro, acebutolol at 10(-5)-10(-7) M induced an increased reactivity of spleen cells from naive mice to concanavalin A, whereas it did not affect the B cell responsiveness to LPS. These results indicate that acebutolol modulates both T-cells and non T-cells in the immune system.

Short-term fluctuations in blood pressure (BP) and heart rate (HR) were analysed in a group of twelve males with essential hypertension. Indirect finger BP was measured by a Finapres device. The effect of a 7-day administration of a cardioselective beta-adrenoceptor blocker, acebutolol (400 mg/day), was studied in a double-blind, randomized, placebo-controlled cross-over study. Compared with placebo, acebutolol caused a significant decrease in BP and HR. In addition, the standard deviation (SD) of BP and HR were reduced after acebutolol in the standing position. Spectral analysis of fluctuations in BP showed a reduction in the variability underlying the SD changes of BP and HR. This reduction predominated in the mid frequency (MF) region corresponding to Mayer waves. This effect was marked for HR since the MF component for standing HR after acebutolol was 46% the placebo level. The average reduction in MF component for standing Systolic BP (SBP) was 36%. No significant correlation was found between the Mayer wave reduction and the systolic, diastolic BP or HR lowering effect of acebutolol. No significant changes in the gain of the transfer function between MF SBP and HR fluctuations in the standing position were observed. The reduced MF component of HR and BP variability after acebutolol could be due to a peripheral cardiac and non-cardiac sympatholytic effect of chronic beta-adrenoceptor blockade.

Previous studies in other systems have shown that beta-receptor blockers may effectively inhibit oxygen radical-induced lipid peroxidation. On the other hand, it has been recently proposed that oxygen free radicals can induce peroxidation of human low density lipoproteins (LDL), and that peroxidized LDL may be an atherogenic stimulus. Chemically modified LDL are internalized by macrophages via a specific cell surface receptor that was termed the scavenger receptor. This phenomenon may induce foam cells transformation in vivo. In the present study we investigated whether beta-blockers may reduce oxygen radical-mediated LDL peroxidation. Purified human LDL were oxidized by exposure to oxygen free radicals generated by xanthine (0.2 mM) and xanthine oxidase (100 mU) at 37 degrees C after a pre-incubation (30 min) in presence of different concentrations (from 1 to 30 microM) of acebutolol, metoprolol or propranolol, three agents with a different degree of lipophilicity. Peroxidation was measured from malonyldihaldehyde (MDA) production. Data have shown a significant percent inhibition of MDA formation in presence of beta-blockers (from 33 to 85%). Thus, beta-blockers reduced peroxidation of human LDL in vitro at clinically relevant concentrations. The order of potency appears to follow the degree of lipophilicity. These data suggest that, although beta-blockers are known to adversely effect lipid metabolism, these agents might on the other hand prevent atherogenesis via a mechanism of inhibition of LDL peroxidation in vivo and reduced foam cells formation.

Objective: Nitric oxide released by a calcium dependent constitutive NO synthase in endocardial endothelial cells exerts characteristic effects on myocardial contraction. Interleukin 1 beta (IL-1) induces the expression of a different calcium independent NO synthase in several tissues. Activity of the latter enzyme has recently been identified in cardiac myocytes but its functional effects are unknown. The aim of this study was to investigate the effects of IL-1 on contraction of isolated ferret papillary muscle preparations., Methods: Electrically stimulated preparations were studied in the presence of acebutolol (1 microM), indomethacin (10 microM), and polymyxin (10 micrograms.ml-1). After a 3 h equilibration period, IL-1 (10 ng.ml-1) was added and contractile behaviour monitored over the next 3 h. The following groups were studied: (1) no IL-1; (2) IL-1 alone; (3) IL-1 in the presence of dexamethasone (3 microM); (4) IL-1 in the presence of NG-monomethyl-L-arginine (L-NMMA, 50 microM); (5) IL-1 in the presence of L-NMMA (50 microM) and L-arginine (500 microM). Cyclic GMP content was measured by radioimmunoassay in all preparations., Results: No significant contractile changes were noted in group 1. In group 2, IL-1 raised myocardial cyclic GMP and induced a progressive abbreviation of isometric twitch, starting 30 min after addition, with a small decrease in peak isometric tension but no change in rate of tension development. These effects were similar to those previously documented for endocardial endothelial NO but were not inhibited by endocardial endothelial denudation. IL-1 effects were inhibited in groups 3 and 4, and partially restored in group 5., Conclusions: IL-1 activates a dexamethasone sensitive myocardial L-arginine-NO pathway which raises myocardial cyclic GMP and induces marked twitch abbreviation. These effects could potentially lead to cardiac depression by limiting systolic ejection, and may be relevant in conditions where IL-1 levels are increased.

Hypertensive patients treated with nonselective beta adrenergic blocking agents may show remarkable hemodynamic changes with administration of epinephrine clinically. We have attempted to investigate the effects of the interaction between beta blockers (a nonselective beta blocker, pindolol, and a cardioselective beta blocker, acebutolol) and a solution of 2% lidocaine containing 1:80,000 epinephrine on the hemodynamics of conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), as compared with the normotensive rats. The blood pressures (systolic and diastolic) and heart rate were measured indirectly by the photoplethysmographic tail cuff method. All drugs were administered intraperitoneally. We found that: (1) epinephrine with pindolol or acebutolol pretreatment did not cause significant hemodynamic changes in WKY; (2) in SHR, epinephrine in combination with pindolol induced remarkable hemodynamic changes (in particular, increase in diastolic blood pressure), which were prevented by phentolamine pretreatment, whereas epinephrine with acebutolol pretreatment induced no significant hemodynamic changes in these animals; (3) epinephrine in combination with pindolol caused pulmonary congestion or edema in SHR; this was confirmed by both quantitative analysis and histological investigations. These results suggest that pindolol blocked both beta 1 and beta 2 receptors, and therefore, this resulted in exaggerated alpha effects of epinephrine, a remarkable systemic vasoconstriction, and pulmonary congestion. In a clinical setting, great caution should be paid to the hypertensive patients, who are being treated with nonselective beta blockers, if epinephrine-containing local anesthetics are administered.

The antihypertensive efficacy of single-drug therapy with nifedipine (N), prazosin (P), or acebutolol (A) and the influence of these agents on coronary risk factors including hypoglycemia, hyperuricemia, and hyperlipidemia, were studied in adolescents with hypertension. Ninety patients (73 girls and 17 boys) aged 14 to 18 years with idiopathic hypertension (IH) were randomized into three groups. Each group received N, P, or A as single-drug therapy for six months. Systolic and diastolic blood pressures fell in all three groups, from 152/90 mmHg to 127/70 mmHg* with N, from 150/90 mmHg to 121/70 mmHg* with P, and from 148/92 mmHg to 122/74 mmHg* mmHg with A. In 17% of cases, N failed to reduce blood pressures below the 90th centiles. Heart rate was not influenced by N or P but decreased from 84 to 75 bpm with A. Although none of the drugs modified serum uric acid levels, fractional uric acid secretion rose with P and A (from 4.1% to 6% with P; and from 4.4% to 6% with A). The lipid profile remained unchanged under N and P, whereas a decrease in serum LDL-cholesterol from 99.6 to 88.8% mg* was seen with A. Fasting serum glucose levels increased from 86.4 to 92.7 mg %* in the group given A. N, P, and A are suitable for single-drug therapy of IH in adolescents; the most appropriate drug should be selected on the basis of medical history.

A relationship between individual variations of the oxidative and acetylating metabolism rates of penbutolol, propranolol, acebutolol which produce a hypotensive effect was studied in patients with arterial hypertension. A study was performed in groups of patients, which comprised 22, 22, and 20 males, respectively. They all suffered from Stage II hypertensive disease. There was a predominant number of patients with partial and complete antihypertensive benefits in those with low oxidation rates than in those with high oxidative metabolism rates when penbutolol (89 and 54%, respectively; p < 0.05) and propranolol (78 and 31%, respectively; p < 0.01) were given. A graphic analysis of changes in blood pressure, which had been observed during a course monotherapy with penbutolol and propranolol identified two groups of patients differing in having benefits. Within each group, the relationship between the decrease in diastolic blood pressure to the elimination half-life of parmidine is described by a linear regression equation and it has a high positive correlation coefficient.

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 cardioselective beta-adrenoblocker acebutolol used as a course therapy for 12 weeks was found to be a highly beneficial antihypertensive agent. The antihypertensive effect of the agent given in doses of 400-800 mg/day was as pronounced and prolonged as that of propranolol, 80-160 mg/day, though there is a tendency for acebutolol to show its complete or partial antihypertensive effect rather at the end of monotherapy than propranolol. At the same time the bradycardiac effect was more pronounced in propranolol therapy. The antihypertensive effect of acebutolol, 400-800 mg/day, was revealed after 2 weeks of its use and persisted within the entire 12 weeks of therapy. The drug was well tolerated. In contrast to propranolol, a non-selective beta-adrenoblocker having no intrinsic sympathomimetic activity, acebutolol failed to produce adverse effects, such as by decreasing cardiac output and increasing total peripheral vascular resistance. The agent had a less negative chronotropic effect.

We compared the antihypertensive effects of acebutolol and metoprolol during 2-4 weeks of treatment in patients with mild to moderate essential hypertension. Acebutolol (n = 12) significantly decreased conventionally measured blood pressure from 173/100 mmHg to 148/86 mmHg (p less than 0.005), and metoprolol (n = 11) decreased it from 164/106 mmHg to 138/87 mmHg (p less than 0.01). Based on data derived from automated 24-hour ambulatory blood pressure monitoring, both drugs significantly decreased the blood pressure in the early morning (5:00-10:00). Moreover, in the metoprolol group, there were significant falls in day-time blood pressure (7:30-19:30) and night-time blood pressure (23:00-7:00). In contrast, acebutolol showed significant antihypertensive effect on day-time blood pressure, but not effect on night-time blood pressure. The study confirmed the efficacy and character of metoprolol and acebutolol. We must choose an effective beta-blocker when using an automated 24-hour ambulatory blood pressure monitoring system to get adequate blood pressure reduction for the whole 24 hours.

A prospective study of the hemodynamic and renal changes was undertaken in 11 neonates whose mothers were treated with acebutolol for hypertension during pregnancy, compared with a control group of 11 infants born to normotensive mothers. Monitoring of the cardio-respiratory system was performed for a period of 4 days. Renal function was studied during 2 periods (12-36, 60-84 hours of life). Hemodynamic failure was observed in 5 of 11 children from treated mothers. The data concerning the renal function of treated group showed: 1) a diuresis significantly lower during the first period (p less than 0.05); 2) the absence of significant rise in the glomerular filtration rates during the second period; 3) a lower sodium balance during the 1st and 2nd periods (p less than 0.02 and p less than 0.05), a lower calcium balance during the 1st period (p less than 0.01). No relationship was found between the renal changes and the hemodynamic disturbances. The direct effect of the drug on the glomerular and tubular functions and/or the renal arteriolar vasomotricity could explain these changes in the renal function in the newborns prenatally exposed to acebutolol.

We have previously reported that the response of cultured chick cerebellar neurons to glutamate is enhanced by noradrenaline (NA) or isoproterenol and suppressed by clonidine. The present study was carried out to further specify the adrenergic receptor subtypes involved in the facilitatory effect of NA or isoproterenol and the suppressive effect of clonidine, and to examine the intracellular mechanisms underlying these modulatory effects of NA. The clonidine effect, which was mimicked by NA iontophoresed with large ejecting currents, was blocked by yohimbine and tolazoline (alpha 2 antagonists) and also by dibutyryl cyclic AMP or forskolin which augmented the glutamate response by itself. Prazosin, an alpha 1 receptor antagonist did not block the clonidine effect. NA- or isoproterenol-induced facilitation, which was mimicked by denopamine (beta 1 agonist), was antagonized by acebutolol (beta 1 antagonist) and not by ICI 118,551 (beta 2 antagonist). Pretreatment of neurons with pertussis toxin for more than 24 h blocked the suppressive action of clonidine without affecting the facilitatory action of isoproterenol. Furthermore, intracellular injection of GDP beta S inhibited the modulatory effects of either clonidine or isoproterenol. These results indicate that the facilitatory and inhibitory modulatory effects of NA may be mediated by beta 1 and alpha 2 receptors linked to cAMP systems, respectively, and the former is coupled with the stimulatory G protein (Gs) and the latter is with the inhibitory G protein (Gi).

Pharmacokinetics and the degree of beta-blockade of sustained release (SR) acebutolol (500 mg/day) and conventional acebutolol (200 mg tid) were examined after the first oral dose and after 10 days of treatment in ten healthy volunteers. After the first dose, acebutolol Cmax did not significantly differ between the two formulations; however, on day 10 acebutolol Cmax was significantly higher after SR formulation. Cmax of diacetolol, the major metabolite, did not differ between SR and conventional acebutolol neither on day 1 nor on day 10. The dose-corrected relative bio-availability of acebutolol was not different from 100% on day 1 and day 10; however the dose-corrected diacetolol AUC, SR/conventional ratio, was significantly lower than 100% on days 1 and 10. Both acebutolol preparations exerted a significant reduction in exercise tachycardia over 24 h on day 1 and day 10; however, conventional acebutolol exhibited a greater reduction 24 h after the first dose. Exercise-induced increase in systolic blood pressure was similarly inhibited by both treatments except for 24 h after the first dose when systolic blood pressure was significantly higher with SR than with conventional acebutolol. The percent reduction in heart rate during exercise was linearly correlated with log acebutolol plasma concentrations for each treatment regimen. These results suggest that beta-blockade exerted by SR acebutolol in healthy volunteers is equivalent to that of conventional acebutolol.

In elderly patients, nonsteroidal anti-inflammatory drugs (NSAIDs) are often used concomitantly with antihypertensive agents. It is therefore important to assess the potential for interactions between NSAIDs and these agents. In a double-blind, placebo-controlled study, 40 elderly hypertensive patients treated with acebutolol or atenolol, together with frusemide, were randomized to receive either ketoprofen, 200 mg/day (50 mg q.i.d.), or matching placebo for 7 days. Arterial blood pressure and heart rate were monitored for a 24-hour period at baseline and at the end of treatment. Standard sphygmomanometric measurements of blood pressure and heart rate were conducted twice a day during the study. No clinically significant side effects or blood pressure or heart rate alterations were observed during the trial. The results indicate that ketoprofen does not interfere with blood pressure control in elderly hypertensive patients being treated with a combination of beta-blockers and diuretics.

Strenuous physical exercise causes transient proteinuria and renal hemodynamic changes: decrease of renal blood flow and to a lesser extent of the glomerular filtration rate, and an increase of the filtration fraction. However, the mechanisms of these modifications are still poorly understood. In order to elucidate them we performed maximal exercise tests on 8 untrained healthy volunteers after inhibition of the renin-angiotensin system (RAS) by captopril, the sympathetic nervous system by a beta-blocking drug (acebutolol) or an alpha-blocking drug (prazosin) and the prostaglandin system by indomethacin. Urinary albumin excretion was measured in every subject first at rest (AB) and then after exercise (AA) performed successively without and with blockade by each of theses drugs. AA-AB difference in the captopril test (12.04 +/- 6.11 micrograms/min) compared to that in the control test (68.91 +/- 25.18 micrograms/min) was significantly reduced (p less than 0.02). This difference remained unchanged after acebutolol (59.87 +/- 21.91 micrograms/min, p = 0.62), prazosin (35.23 +/- 27.80 micrograms/min, p = 0.21) and indomethacin (55.21 +/- 28.43 micrograms/min, p = 0.35). There was a negative correlation between the lowering of AA elevation and the rise in plasma renin activity in the captopril test (r = 0.64; p less than 0.03). Only acebutolol decreased systolic blood pressure significantly. These results suggest that the RAS plays a major role in postexercise proteinuria. We hypothesize that stimulation of this system induces an increase of efferent glomerular artery constriction and consequently of glomerular transcapillary pressure and the filtration fraction. Captopril seems able to prevent these hemodynamic changes.

The influence of cardioselectivity and/or intrinsic sympathomimetic activity (ISA) of betablockers on hemodynamic antihypertensive effect and on left ventricular (LV) dimensions and function was studied by echocardiography in 72 hypertensive patients, mean age 43 years. After 15 days of placebo, active therapy was given for 1 month: acebutolol (ACEB, n: 16, 400-800 mg/day), atenolol (ATEN, n: 16, 50-100 mg/day), pindolol (PIND, n: 13, 15-30 mg/day), timolol (TIMO, n: 15, 10-20 mg/day) and nadolol (NADO, n: 12, 80-160 mg/day). All betablockers showed effective antihypertensive activity. Betablockers without ISA (ATEN, TIMO, NADO) reduced cardiac output (p less than 0.05), those with ISA (ACEB, PIND) decreased total peripheral resistance (p less than 0.01 and p less than 0.05 respectively). Independently from ISA, cardioselective betablockers (ATEN, ACEB) increased LV end diastolic dimension and stroke volume (p less than 0.05). LV mass was not changed, although interventricular septum thickness decreased after TIMO and NADO (p less than 0.05). LV function, as assessed by fractional shortening, was not impaired by any betablocker.

Acebutolol is a beta blocking agent that induces in C57Bl/6 mice a polyclonal activation of lymphocytes (PAL). In this study, its effect on cellular parameters of spontaneous PAL and lupus disease in NZB x NZW female mice is investigated. A significant reduction of PAL is found in 10-week-old mice after only five injections of 50 mg/kg/day of acebutolol. This effect is also observed in 7- and 9-month-old mice after 12 weeks of treatment. In these chronically treated mice, a significant decrease in incidence and levels of proteinuria as compared with untreated mice is found. No statistically significant increase in survival is observed. In conclusion, acebutolol down modulates the spontaneous PAL which characterizes the NZB x NZW mouse lupus disease and might prevent to some extent the development of nephritis.

Intrinsic sympathomimetic activity (ISA) characterizes a group of beta blockers that are able to stimulate beta-adrenergic receptors (agonist effect) and to oppose the stimulating effects of catecholamines (antagonist effect) in a competitive way. Partial agonists are ligands that elicit a submaximal response when bound to beta receptors at maximal occupancy. In the isolated rat atrium, acebutolol produces a maximal stimulatory effect that is only 17 +/- 8% of the maximal effect induced by the full beta agonist isoproterenol. The presence of ISA results in less resting bradycardia and less of a reduction in cardiac output than is observed with beta blockers without ISA. In the long term, partial beta agonists may produce arterial vasodilation and increase arterial compliance, possibly leading to additional beneficial effects in the treatment of hypertension. beta blockers with ISA do not have adverse effects on plasma lipoproteins during long-term treatment; in addition, the presence of ISA could counteract the up-regulation of beta adrenoceptors often observed with beta blockers without ISA. Finally, the presence of ISA has been a conflicting issue for the use of such beta blockers in secondary prevention after myocardial infarction. However, the impressive results of the Acebutolol Prevention of Secondary Infarction trial in high-risk patients after myocardial infarction show that acebutolol, a beta blocker with moderate partial agonist activity, can be effective in decreasing the postinfarction mortality rate. By exhibiting a strikingly different hemodynamic profile from that of beta blockers without ISA, the partial beta agonists form an intriguing pharmacologic class of drugs for which prospective clinical trials should be extensively pursued.

Whole-day automated ambulatory blood pressure (BP) monitoring was used to assess the duration of the antihypertensive actions of the beta-blockers atenolol (50 to 100 mg; n = 20) and acebutolol (400 to 800 mg; n = 19) each given once daily at 9 AM. When compared with its pretreatment 24-hour average, atenolol decreased diastolic BP by 10 +/- 2 mm Hg (p less than 0.01) and systolic BP by 12 +/- 2 mm Hg (p less than 0.01). Acebutolol decreased the 24-hour diastolic BP by 11 +/- 1 mm Hg (p less than 0.01) and systolic BP by 13 +/- 2 mm Hg (p less than 0.01). More specifically, a comparison of the two drugs during the final 6 hours (3 AM to 9 AM) of the dosing interval showed that the mean decrease in diastolic BP of 10.2 +/- 1.5 mm Hg with acebutolol was greater (p less than 0.05) than the decrease of 6.2 +/- 1.3 mm Hg with atenolol. Moreover, this final 6-hour effect of atenolol was less (p less than 0.01) than that observed during the first 18 hours of the day. The late effects of acebutolol did not change significantly from its early effects. The two agents also differed in their trough (final 2-hour decrease in diastolic BP) and peak (maximum 2-hour decrease in diastolic BP) effects: for atenolol the peak-to-trough difference was 7.8 +/- 3.1 mm Hg (p less than 0.05), whereas for acebutolol it was 3.8 +/- 4.2 mm Hg (N.S.). This study confirms the efficacy of atenolol and acebutolol.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute (within hours) changes in the concentrations of T4, T3, reverse-T3 (rT3) and T3 resin uptake test (T3RU) were studied in 31 hyperthyroid patients for 4 h after po treatment with either acebutolol, oxprenolol, pindolol or timolol. In 21 of the patients, the changes were compared to changes in the serum concentrations of alpha 2-macroglobulin (a macromolecule) and two middle-sized molecules; thyroid hormone-binding globulin (TBG) and albumin in order to calculate the changes in extracellular distribution of the thyroid hormones and to distinguish between changes due to a changed metabolism and changes due to a changed distribution of the thyroid hormones. Acebutolol, oxprenolol and timolol caused a decrease in serum T3 after 1/2 h, and acebutolol and oxprenolol also a decrease in rT3 after 1/2 - 1 h, the changes reversed within 2 h. A concomitant decrease in serum albumin and TBG suggests a change in the extracellular distribution of middle-sized molecules to which thyroid hormones are attached, as an explanation of the acute decrease (1 h) of the thyroid hormones. The small and insignificant change in alpha 2-macroglobulin indicates that the changes are mainly extravascular, but the difference of alpha 2-macroglobulin changes between the drugs (acebutolol/timolol vs pindolol/oxprenolol) could depend on the intrinsic sympathomimetic activity of the drugs.

The immune effects of acebutolol, a beta-blocker, are investigated in various strains of mice. In 6-12 weeks old C57Bl/6 female mice, an increase in the number of immunoglobulin secreting cells is observed only at the age of 9 weeks. At that age, such an effect is seen neither in C57Bl/6 male mice nor in female mice from 6 other strains including OF1 outbred mice. An increase in anti-trinitrophenol plaque forming cells is found in 9 week old C57Bl/6, Balb/c and CBA female mice.

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.

The bronchoconstrictor and beta-adrenoceptor blocking activity of (+/-)-propranolol, acebutolol and two of its analogues were compared in a group of littermate rats. Whilst the analogues of acebutolol had similar bronchoconstrictor potency to propranolol, acebutolol had considerably less activity. No correlation could be found between the degree of bronchoconstriction produced by the four drugs and their beta-adrenoceptor blocking activity in the airway smooth muscle. Acebutolol and its analogues show a wide properties could be related to the production of bronchospasm.

The effect of beta-blockade by acebutolol on global and regional myocardial perfusion (133Xenon wash-out) was studied in 10 patients with coronary artery disease. Another group of 10 similar patients was used to study the effect of acebutolol on left ventricular cavity size (metal markers--spot film camera). Global perfusion responses roughly paralleled the changes in rate-pressure variable which decreased in 8 patients and increased in 2 who had spontaneous angina pectoris. Regional perfusion decreased more in areas distal to less than 75% stenoses than in those distal to less than 75% stenoses (29 vs 12%; p = 0.10 less than 0.20). Left ventricular asynergy did not modify the response, nor did the presence or absence of collateral vessels. No evidence was found to support the thesis that beta-blockade may evoke a redistribution in perfusion which favours the potentially ischaemic areas of myocardium. Left ventricular cavity size remained unchanged after acebutolol, a cardioselective beta-blocking compound with some degree of agonist activity.

1 The effects of single evening doses of the beta-adrenoceptor blocking agents propranolol (80 mg orally) and acebutolol (200 mg orally) on plasma levels throughout the night of prolactin, growth hormone, luteinising hormone, follicle stimulating hormone, cortisol and testosterone have been studied in seven healthy male volunteers. 2 Three way analysis of variance showed that acebutolol significantly reduced circulating levels of prolactin and follicle stimulating hormone, but did not alter the levels of the other hormones studied. 3 Propranolol significantly reduced follicle stimulating hormone and testosterone, and significantly increased circulating levels of cortisol, but caused no change in the other hormones studied. 4 Prolactin, luteinising hormone, testosterone and cortisol showed a significant variation with time indicating the existence of a diurnal rhythm in the pattern of their secretion. 5 There was a significant inter-subject variability in all the hormones studied. 6 There was a significant between-subject variation in response to both propranolol and acebutolol. 7 Different subjects showed significant variations with respect to time in prolactin, growth hormone and cortisol levels. 8 Neither propranolol nor acebutolol significantly altered the time course of secretion of any of the hormones studied. 9 Possible relationships of these beta-adrenoceptor blocker-induced changes in anterior pituitary and related hormones to the antihypertensive mechanism of acebutolol and propranolol are discussed.