A comparison of four beta-adrenoceptor antagonists in patients with asthma.

1 Cardiovascular and airways response to two non-cardioselective beta-adrenoceptor blocking drugs, propranolol and pindolol (with partial agonist activity) and two cardioselective beta-adrenoceptor blocking drugs, acebutolol (with partial agonist activity) and atenolol, were compared in twelve patients with asthma. 2 All four drugs produced a significant reduction in resting pulse rate and prevented the increase in heart rate following inhaled isoprenaline (1,500 microgram). 3 Seven patients in clinical remission showed no significant bronchoconstrictor response to any of the drugs. In the remaining five patients, bronchoconstriction was greatest following propranolol (mean reduction in FEV1 26.6%) and least following atenolol (mean reduction in FEV1 6.5%). 4 The bronchodilator response to inhaled isoprenaline was blocked by propranolol and pindolol but not by acebutolol and atenolol. 5 Partial agonist activity did not appear to be clinically useful.     

Propranolol and metoprolol enhance the anticonvulsant action of valproate and diazepam against maximal electroshock.

The anticonvulsive potential of classical antiepileptics co-administered with beta-adrenergic receptor antagonists against generalized tonic-clonic seizures was evaluated in the model of maximal electroshock (MES)-induced convulsions. Propranolol, acebutolol, metoprolol and atenolol were tested in the doses not affecting the electroconvulsive threshold. Propranolol and metoprolol lowered the ED(50) of valproate and diazepam. Acebutolol reduced valproate's but not diazepam's ED(50) value. In contrast, hydrophilic atenolol, not penetrating via blood-brain barrier, affected neither the action of valproate nor diazepam. None of the studied drugs changed the protective activity of carbamazepine and phenytoin against MES. beta-blockers per se did not alter the motor performance of mice. Moreover, propranolol and metoprolol did not influence diazepam-evoked impairment of locomotor activity. The free plasma and brain levels of antiepileptic drugs were not affected by beta-blockers. In conclusion, the use of certain beta-adrenoceptor antagonists, such as propranolol and metoprolol, might improve the antiepileptic potential of valproate and diazepam.     

CARDIAC AND BRONCHIAL β-ADRENOCEPTOR ANTAGONISTIC POTENCIES OF ATENOLOL, METOPROLOL, ACEBUTOLOL, PRACTOLOL, PROPRANOLOL AND PINDOLOL IN THE ANAESTHETIZED DOG

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

Comparative beta-adrenoceptor blocking effects of propranolol, bisoprolol, atenolol, acebutolol and diacetolol on the human isolated bronchus.

Five beta-adrenoceptor blockers, propranolol, acebutolol, diacebutolol, atenolol and bisoprolol, were tested for their antagonistic effect against isoprenaline on human isolated bronchi. The results showed (1) that only propranolol exerted a competitive antagonistic effect against isoprenaline (pA2 = 9.40 +/- 0.22, n = 7) whereas the other drugs did not, and (2) that, in the presence of beta-adrenoceptor blockers in the plasma concentrations reported after a single usual therapeutic dose, the doses of isoprenaline giving the same bronchodilator effect must be multiplied by 32.6, 5.51, 4.63, 2.82 and 1.95 respectively with propranolol, diacetolol, acebutolol, atenolol, and bisoprolol. It was concluded that (1) atenolol and bisoprolol were the least potent drugs at bronchial level in therapeutic plasma concentrations and (2) that tests performed on the human isolated bronchus might be a useful screening procedure for new drugs with potential activity on the airways.     

Blockade of isoprenaline-induced changes in plasma free fatty acids, immunoreactive insulin levels and plasma renin activity in healthy human subjects, by propranolol, pindolol, practolol, atenolol, metoprolol and acebutolol

1 The effects of intravenously administered propranolol 0.01 and 0.03, pindolol 0.001 and 0.003, practolol 0.12 and 0.36, atenolol 0.03 and 0.09, metoprolol 0.045 and 0.135 and acebutolol 0.12 and 0.36 mg/kg, on isoprenaline-induced changes in heart rate, blood pressure, plasma free fatty acids, immunoreactive insulin plasma levels and plasma renin activity were determined in six healthy human subjects.

2 Propranolol, atenolol and metoprolol had a stronger effect on resting heart rate than practolol, acebutolol and pindolol, probably reflecting differences in intrinsic β-sympathomimetic activity. Antagonist potencies against isoprenaline-induced changes in heart rate and blood pressure suggested cardioselectivity for practolol, atenolol, metoprolol and the lower dose of acebutolol and non-cardioselectivity for propranolol, pindolol and the higher dose of acebutolol.

3 All six β-adrenoceptor blocking agents were able, to a varying extent, to antagonize the isoprenaline-induced increases in plasma free fatty acids and plasma immunoreactive insulin levels. In general, the cardioselective agents were relatively less effective antagonists than the non-cardioselective agents.

4 Resting plasma renin activity was reduced by all six β-adrenoceptor blocking agents, suggestive of the presence of β₁-adrenoceptors mediating renin release, but the non-cardioselective agents propranolol and pindolol seemed relatively more effective in antagonizing isoprenaline-induced increases in plasma renin activity than the cardioselective agents, which indicates that β₂-adrenoceptors might also be involved.

5 The results are compatible with the hypothesis that both β₁- and β₂-adrenoceptors are involved in the regulation of lipolysis, insulin release and renin release.

     

High-pressure liquid chromatography of nadolol and other beta-adrenergic blocking drugs

A high-pressure liquid chromatographic assay was developed for the analysis of the beta-adrenergic blocking agent nadolol as a bulk material or formulated in a tablet. Other beta-adrenergic blocking drugs such as acebutolol, alprenolol, atenolol, metoprolol, oxprenolol, pindolol, practolol, propranolol, sotalol, and timolol can be chromatographed in this system. An ethylsilane column and a mobile phase consisting of 35% methanol-65% aqueous 0.0005 M hydrochloric acid-0.05 M sodium chloride are used. Detection is either at 254 nm with a variable-wavelength detector. As exemplified by nadolol, the drug content can be quantitated with or without atenolol as an internal standard.     

An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man.

1. The effects of single oral doses of three beta-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two beta-adrenoceptor antagonists (propranolol and atenolol), two beta-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2. Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3. None of the drugs studied affected quality of sleep. 4. Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5. Exercise heart rate was reduced by both beta-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6. Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7. Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8. Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol, and prenalterol. 9. beta-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to beta-adrenoceptor antagonists. 10. While Ro 31-1118 and flusoxolol are antagonists mainly at the beta 1-adrenoceptor they have agonist activity at both beta 1- and beta 2 adrenoceptors. 11. While pindolol is a non-selective antagonist its agonist activity is mainly at the beta 2-adrenoceptor.     

Evidence that reversal of mouse aggression is not related to beta blockade

The ED₅₀s for reversal of mouse aggression were determined for nine beta adrenergic receptor blockers: metoprolol, nadolol, pindolol, propranolol, acebutolol, penbutolol, labetalol, timolol, and atenolol. Propranolol and penbutolol generated linear doseresponse curves, suggesting easy access to brain. To determine if beta blockade was actually occurring at the receptor level, upregulation of beta receptors after 10 days of chronic treatment with the ED₅₀s was determined in the limbic system as well as other areas of brain. These areas included: olfactory bulbs, hypothalamus, septum, amygdala, cortex, midbrain, cerebellum, pons, and medulla. Upregulation occurred in all areas of the brain in animals treated with propranolol and penbutolol, suggesting that at the dose required to block aggressing in fighting mice, beta receptors were also effectively blocked. With other drugs (timolol, atenolol, pindolol, metoprolol, nadolol, and acebutolol) the ED₅₀s produced localized upregulation of beta receptors, but nothing consistent in the limbic areas. The beta blocker labetalol at the ED₅₀ for reversal of mouse aggression produced virtually no upregulation of brain receptors, suggesting no correlation between antiaggression and beta blockade.     

Effects of four beta-adrenergic receptor antagonists on male rat sexual behavior

Antihypertensive medication has been reported to cause serious sexual side effects in men. Frequently mentioned as causing sexual dysfunction are beta-adrenergic receptor antagonists. The purpose of this study was to examine in detail the effects of beta blockers on adult male rat sexual behavior. Thirty minutes following a single subcutaneous injection of propranolol, pindolol, atenolol or labetalol, mating tests were conducted. The mixed beta 1- and beta 2-adrenergic antagonists, propranolol and pindolol, profoundly inhibited male sexual behavior. At the 5 and 10 mg/kg doses, propranolol inhibited ejaculatory behavior to the extent that only 9.1 and 8.3% respectively showed the behavior while pindolol reduced this behavior to 36.4% (16 mg/kg). These drugs also adversely affected various parameters of behavior in a dose-dependent manner. The selective beta 1 antagonist, atenolol, had only minor effects and labetalol even less so at the doses tested. It was suggested that the strongly inhibitory effects of propranolol and pindolol on male rat sex behavior may well be due to their 5-HT1A antagonistic binding properties rather than their beta-antagonistic properties.     

Toxicity of β-blockers in a rat whole embryo culture: concentration-response relationships and tissue concentrations

Beta-adrenoceptor blockers are widely used drugs for the treatment of cardiovascular diseases. Since β-blockers cross the placenta, it is essential to consider possible adverse effects on the embryo. Six β-adrenoceptor blockers were tested at various concentrations (10 – 5000 μM) in a rat whole embryo culture. Although inducing a very similar pattern of dysmorphogenetic effects (incomplete flexure, disturbed development of the neural tube, the head, the heart and the tail bud), the compounds exhibited a wide range of embryotoxic potency. Estimation of the EC₅₀ (median-concentration producing dysmorphogenesis in 50% of the embryos) for the six compounds revealed differences of more than two orders of magnitude: propranolol 25 μM, alprenolol 30 μM, metoprolol 100 μM, pindolol 150 μM, acebutolol 500 μM, atenolol 4000 μM. Measurements of the concentrations of the various drugs in the cultured embryos at corresponding EC₅₀ levels showed differing values: metoprolol 4.5 μM, propranolol 5.2 μM, alprenolol 8.4 μM, pindolol 9.0 μM, acebutolol 12.5 μM and atenolol 77.0 μM. With regard to the EC₅₀ and the degree of substance transfer to the embryo it can be stated that propranolol and metoprolol show a much higher intrinsic potency to interfere with normal in vitro embryonic development than, e.g. atenolol. Received: 1 September 1993 / Accepted: 16 February 1994     

Comparison of four different beta-adrenoceptor blocking drugs on lymphocyte isoprenaline-stimulated cyclic AMP production.

1 The influence of acebutolol, atenolol, pindolol and timolol on human lymphocyte cyclic AMP (cAMP) and its stimulation by isoprenaline in vitro has been studied. 2 Acebutolol and atenolol (10(-8)-10(-6)M) had no significant influence on lymphocyte cAMP levels or on isoprenaline-stimulated increase in cAMP. 3 Pindolol and timolol significantly antagonised the effect of isoprenaline, and pA2 values were calculated to be 8.12 and 8.04 respectively. This suggests that beta 2-adrenoceptors are involved in this phenomenon. 4 Only pindolol produced a significant increase in lymphocyte cAMP, which is consistent with its partial agonist activity.     

The distribution of propranolol, pindolol and atenolol between human erythrocytes and plasma.

1 This study aimed (1) to measure the whole blood to plasma (WB:P) and red blood cell to plasma (RBC:P) concentration ratios of propranolol in healthy volunteers and two types of patients, and (2) to compare the concentration ratios of the lipophilic drug propranolol with moderately lipophilic pindolol and hydrophilic atenolol. 2 There was no significant difference between the WB:P and RBC:P ratios of propranolol concentration in healthy volunteers and neurological patients compared with hypertensive patients. The mean +/- s.d. WB:P ratios of propranolol concentration in the three groups were 0.74 +/- 0.03, 0.71 +/- 0.05, and 0.76 +/- 0.08 respectively. The mean RBC:P ratios were 0.39 +/- 0.08, 0.36 +/- 0.11, and 0.47 +/- 0.15 respectively. WB:P and RBC:P concentration ratios of propranolol were linearly correlated with the free fraction of drug in plasma. Propranolol was 90% bound in plasma. 3 The mean WB:P and RBC:P ratios of pindolol in seven volunteers were 0.69 +/- 0.08 and 0.37 +/- 0.14 respectively. Pindolol was 71.4 +/- 8.6% bound to plasma proteins. The concentration of pindolol in the RBC was linearly correlated with that unbound in plasma. 4 In four healthy volunteers, the mean WB:P concentration ratio of atenolol was 1.07 +/- 0.25 and the mean RBC:P ratio was 1.15 +/- 0.55. 5 The similarity of the RBC:free plasma drug concentration ratios for all three drugs suggests that the use of organic solvent partition coefficients for the prediction of in vivo distribution may be unreliable.     

Influence of some beta-adrenoceptor antagonists on the anticonvulsant potency of antiepileptic drugs against audiogenic seizures in DBA/2 mice

The two enantiomers of propranolol antagonize generalized tonic-clonic seizures in DBA/2 mice with the (-)-enantiomer being about 1.5 times more potent than the (+)-enantiomer. Metoprolol was less active and atenolol was unable to affect audiogenic seizures. In combination with conventional antiepileptic drugs, both propranolol enantiomers tested in doses not affecting the occurrence of audiogenic seizures increased the anticonvulsant activity of diazepam, phenobarbital, valproate and lamotrigine and tended to increase that of carbamazepine and phenytoin. The effect was more pronounced with the (-)-enantiomer. This increase was associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of the antiepileptic drugs with both propranolol enantiomers was more favourable than the combination with saline alone. Metoprolol was also able to decrease the ED(50) values of the antiepileptic drugs, whereas atenolol showed no effects. Since neither enantiomer of propranolol significantly influenced the total and free plasma levels of the antiepileptics, pharmacokinetic interactions are not likely. In addition, (+)- and (-)-propranolol did not significantly affect the hypothermic effects of the antiepileptics tested. In conclusion, both enantiomers of propranolol and metoprolol showed an additive anticonvulsant effect when co-administered with some conventional antiepileptic drugs, most notably diazepam, phenobarbital, lamotrigine and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Use of cyclic boronates for GC/MS screening and quantitation of beta-adrenergic blockers and some bronchodilators

Gas chromatographic and mass spectrometric properties of cyclic methyl and n-butyl boronates of 13 beta blockers and bronchodilators were investigated for potential use in screening and quantitation in biological materials of interest. The tested compounds included acebutolol, atenolol, labetalol, levobunolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, sotalol, albuterol, and isoproterenol. The cyclic methyl boronates were superior in gas chromatographic properties to the corresponding n-butylboronates of these compounds. Higher weights of fragments obtained with n-butyl boronation may be advantageous for analyses of complex biological matrices. Mass spectra and retention times relative to SKF-525A are provided.     

Determination of some beta-blockers as dabsyl derivatives by HPLC

A HPLC method has been developed that permits the sensitive determination of beta adrenergic blocking drugs, including acebutolol, metoprolol, oxprenolol, pindolol, and propranolol. These compounds were converted to their chromophoric dabsyl derivatives and were separated by a reversed phase chromatographic column (mu-Bondapak C18) with methanol-water (75:25) as isocratic mobile phase. The derivatives were detected by a variable wavelength detector operating at 430 nm. The method was applied to commercial pharmaceutical preparations and the results were statistically compared with those obtained by official methods using t- and F-tests.     

Stability of atenolol, acebutolol and propranolol in acidic environment depending on its diversified polarity

The main objective of this research was to investigate the relationship between the polarity of atenolol, acebutolol, and propranolol described by logP and kinetic and thermodynamic parameters characterizing their degradation process in acidic solution. Hydrolysis was carried out in hydrochloric acid at molal concentrations of 0.1 mol/L, 0.5 mol/L, and 1 mol/L for 2 hr at 40 degrees C, 60 degrees C, and 90 degrees C. Chromatographic-densitometric method was used for the determination of drugs under investigation. The identification of degradation products was carried out by using 1H NMR. The degradation processes that occurred in drugs under investigation are described with kinetic parameters (k, t0.1, and t0.5) and energy of activation (Ea). It has been found that the stability of drugs increases toward lipophilic propranolol in the assumed experimental model. The rate constants k decrease, contrary to t0.1, t0.5, and Ea, which vary comparably to logP, thus increasing from the most hydrophilic atenolol, through acebutolol, of lower polarity, to the most lipophilic propranolol. This study demonstrated that the stability of chosen beta-adrenergic blocking agents increases with their lipophilicity.     

Inhibition of nicotine-induced relaxation of the bovine retractor penis muscle by beta-adrenoceptor antagonists.

The relative potency in inhibiting nicotine-induced relaxation of the bovine retractor penis muscle (BRP) was estimated for the racemates of seven beta-adrenoceptor antagonists, both of the optical isomers of propranolol, and lidocaine. The order of potency of the drugs studied was (+)-propranolol greater than (-)-propranolol greater than propranolol greater than alprenolol greater than metoprolol greater than lidocaine greater than acebutolol greater than pindolol greater than sotalol greater than atenolol. It is concluded that the inhibition of the relaxation was not due to blockade of beta-adrenoceptors but to the nonspecific effects of the beta-adrenoceptor antagonists. It is also concluded that the neurotransmitter(s) which was (were) released from the non-adrenergic non-cholinergic inhibitory nerves in the BRP did not relax the muscle by activating the beta-adrenoceptors. It is suggested that the beta-adrenoceptor antagonists inhibited the release of the inhibitory neurotransmitter(s) by a mechanism which is significantly correlated to their lipophilicity.     

Different effects of various beta-adrenoceptor antagonists on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase in heart

A series of six beta-adrenergic blocking drugs including propranolol, bufetolol, bunitrolol, pindolol, labetalol and acebutolol were examined for effects on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase from heart. The adrenergic blocking agents had no apparent effects on basal activities of adenylate cyclase, guanylate cyclase and phosphodiesterase. The drugs blocked the enhancement of adenylate cyclase activity by isoproterenol, but not by guanine nucleotide or fluoride. The inhibitory effects of beta-antagonists were overcome by sufficiently large doses of isoproterenol. Sodium azide specifically required catalase whereas NaNO2 required cysteine to activate myocardial guanylate cyclase. Among beta-adrenergic blocking drugs tested, both pindolol and acebutolol inhibited the stimulation of guanylate cyclase by NaNo2 or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). However, other beta-blocking drugs did not significantly affect the activation by NaN3, NaNO2 and MNNG. Several beta-antagonists, such as labetalol, bunitrolol, pindolol and acebutolol were also effective in blocking the activation of phosphodiesterase by calmodulin. The inhibitory effects of beta-adrenergic blocking drugs, i.e. pindolol and acebutolol upon either nitroso compound-stimulated guanylate cyclase or calmodulin-activated phosphodiesterase display little correlation with their potency as beta-adrenergic blocking agents. These data suggest that beta-antagonists may have another site of action which is not directly related to the control of catecholamine metabolism.     

Estimation of the nonspecific cardiovascular toxicity of beta-adrenoceptor blocking drugs with different hydrophobic properties in the cat

The structure-activity relationship between the acute nonspecific cardiovascular depressant effects of the beta-adrenoceptor blocking drugs and their hydrophobic properties was evaluated experimentally for propranolol, pindolol, practolol, and atenolol, in the anaesthetized cat after preceding beta-adrenoceptor blockade. The LD50 values (geometric mean and range in mumol/kg i.v., each drug n = 5) for the nonspecific depression of max dp/dt were: 7.5 (5.6-9.1) for propranolol, 21 (15.5-28) for pindolol, 190 (115-290) for practolol, and 230 (170-400) for atenolol. The respective partition coefficients in octanol buffer (pH 7.0) as a measure of hydrophobicity were: propranolol 5.4, pindolol 0.20, practolol 0.025, and atenolol 0.0032. These experimental data showed a good fit into the regression equation obtained previously [18]. Practolol, in contrast, had a lower toxicity than calculated because of a pronounced intrinsic sympathomimetic activity (ISA), even after catecholamine depletion. The nonspecific cardiovascular toxicity of 15 other clinically used beta-adrenoceptor blocking drugs were estimated from their respective octanol buffer partition coefficients. The fall of the diastolic blood pressure was representative of the toxicity of the compounds. It is concluded that the cardiovascular toxicity is lowest in compounds with low hydrophobicity and with distinct ISA.     

Differential effect of selective beta 1 and nonselective beta-adrenoceptor blockade on epinephrine and atropine response in normal humans.

Sympathetic stimulation with epinephrine (EPI) combined with parasympathetic blockade with atropine was studied in 10 healthy volunteers premedicated with placebo or three different beta-adrenoceptor blockers: atenolol (62.5 micrograms/kg, beta 1-selective), propranolol (62.5 micrograms/kg, nonselective), and pindolol (7.5 micrograms/kg, nonselective with intrinsic sympathomimetic activity, ISA). EPI infusion (0.06 microgram/kg/min) after placebo increased heart rate (HR) and systolic blood pressure (SBP) and decreased diastolic BP (DBP). Pretreatment with atenolol reduced the HR increase, and caused similar changes in BP. In contrast, pretreatment with propranolol and pindolol decreased HR and increased BP. Combined EPI and atropine (15 micrograms/kg) after placebo increased HR by 40% without causing BP changes. Similar HR changes were observed after administration of all beta-adrenoceptor blockers, but whereas a marked pressor response was observed after propranolol and pindolol a blunted response was observed after atenolol. Propranolol and pindolol reduced myocardial oxygen demand estimated by the HR x BP product after EPI, but this response was abolished by atropine. Serum potassium decreased from 3.9 +/- 0.2 to 3.2 +/- 0.3 mM after EPi and atropine. This effect was less after atenolol, and potassium increased after premedication with propranolol and pindolol. Our results show that nonselective beta-adrenoceptor blockade has a favorable effect on potassium homeostasis and oxygen demand parameters during EPI infusion but causes a marked pressor response, contrary to a beta 1-selective agent, during combined sympathetic stimulation and parasympathetic blockade. They also highlight the importance of the vasodilator cholinergic system as a defense mechanism in such situations.