Beta-adrenoceptor blockers in atrial fibrillation: the importance of partial agonist activity.

1. The ideal drug treatment for atrial fibrillation will control resting heart rate, blunt exercise induced tachycardia whilst not exacerbating nocturnal bradycardia. Monotherapy with digoxin may not be ideal. We have compared the effect of combining digoxin (0.25 mg daily) with atenolol 50 mg and 100 mg or pindolol 5 mg twice daily and 15 mg twice daily in a cross-over randomised single-blind trial in eight symptomatic patients (six male; mean age 62 years) with poorly controlled atrial fibrillation. 2. Heart rate control was measured by 24 h ECG at baseline on digoxin therapy and after 2 weeks with each treatment. Symptom scores for breathlessness and palpitation were measured using visual analogue scales. 3. The addition of both beta-adrenoceptor blockers significantly reduced mean diurnal maximum heart rate from baseline (all P < 0.001 ANOVA). Atenolol at both doses caused a greater reduction than either dose of pindolol (P < 0.001 ANOVA). Nocturnal maximum heart rate was not significantly reduced from baseline by either beta-adrenoceptor blocker, but both doses of pindolol caused increases in nocturnal maximum heart rate compared with atenolol (P < 0.001 ANOVA). 4. Atenolol caused a reduction in diurnal minimum heart rate compared with baseline and caused a reduction in nocturnal minimum heart rate whereas pindolol caused an increase (P < 0.001 ANOVA). 5. Atenolol 100 mg caused longer nocturnal pauses compared with baseline but pindolol 15 mg twice daily reduced the number of nocturnal pauses > 1.5 s (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine

Based on published reports of controlled double-blind studies, the efficacy of beta-receptor blockers and calcium antagonists in the prophylactic treatment of migraine is reviewed. Taking into consideration problems in trial design and evaluation of the effects of treatment, and the amount of documentation, it may be concluded that propranolol, metoprolol, timolol, nadolol and atenolol have been shown to reduce the frequency of migraine attacks in patients with common as well as classical migraine. The effect on duration and intensity of migraine attacks is less clear. Treatment effect is generally seen within 4 weeks, but seems to increase with time. Nonselective beta-receptor blockers as well as drugs selective for beta1-receptors may be effective, and their efficacy is comparable to that of other active antimigraine drugs. Available studies do not exclude the fact that beta-receptor blockers with partial agonist activity (intrinsic sympathomimetic activity) have an effect, but suggest that their efficacy is inferior to that of blockers lacking this property. Among the calcium antagonists tested for prophylactic effect in migraine, the effects of verapamil, nifedipine and diltiazem seem promising, but available documentation does not allow any definitive statements of efficacy to be made, particularly not for nifedipine and diltiazem. The ability of flunarizine to reduce the frequency of migraine attacks in patients with common and classical migraine is well documented; its effect on attack duration and intensity is less well established. The response rate is similar to that for beta-receptor blockers, and to that, for example, for pizotifen (pizotyline). Nimodipine also appears to reduce the frequency of migraine attacks, but the efficacy of this drug, compared with other alternatives, remains to be definitely established.     

Beta-adrenoceptor responses to inhaled salbutamol in the elderly.

The purpose of the present study was to evaluate and compare the responsiveness of beta 2-adrenoceptors in elderly and young subjects. Seven healthy elderly volunteers (72 +/- 3 years) were given cumulative doses of inhaled salbutamol (100 micrograms-4000 micrograms) or placebo, following pre-treatment with propranolol 40 mg or placebo. Finger tremor (Tr), plasma potassium (K), and heart rate (HR) were measured at each dose step. There were dose-dependent increases in Tr (P less than 0.001) and HR (P less than 0.001) and falls in K (P less than 0.001), which were completely attenuated by propranolol (P less than 0.001). Comparison with dose-response curves in a group of young (Y) subjects (24 +/- 3 years) given an identical dose protocol of salbutamol showed no evidence of subsensitivity of beta 2-adrenoceptor responses in the elderly (E) group (mean and 95% confidence intervals for maximum responses): delta K -0.90 (-1.1(-)-0.82) mmol l-1 Y, -0.82 (-1.04(-)-0.60) mmol l-1 E, delta Tr 274 (213-335)% Y, 269 (197-342)% E, delta HR 25 (21-28) beats min-1 Y, 26 (21-31) beats min-1 E.     

Beta-adrenoceptor subtypes in the detrusor of guinea-pig urinary bladder.

beta-Adrenoceptors have been demonstrated in the urinary bladders of many animals including the guinea pig. However, there is little information on the subtypes involved in the antispasmodic activity of beta-adrenoceptor activation in the guinea-pig detrusor. The present study uses the non-selective beta-agonist isoproterenol, the antagonist nadolol, the beta 2-selective agonists salbutamol and terbutaline, the antagonist ICI 118551, and the beta 1-selective antagonist metoprolol, to demonstrate functionally the subtypes existing in the guinea-pig detrusor. Isoproterenol dose-dependently reduces the myogenic activity in the guinea-pig detrusor induced by mild depolarization with 20 mM potassium in the tissue bath. At the supramaximal concentration of 30 microM, isoproterenol achieves 73 +/- 2% of the reference maximal response. This activity of isoproterenol is reduced to 9 +/- 5, 24 +/- 6 and 54 +/- 1% in the total blockade of beta, beta 1 and beta 2 with nadolol, metoprolol and ICI 118551, respectively. Consistently, salbutamol and terbutaline at the same concentration produce only 35 +/- 1 and 38 +/- 4% of the response, respectively. Thus, both beta 1- and beta 2-adrenoceptors are present in the detrusor of the guinea-pig urinary bladder. Although activation of either subtype results in antispasmodic action, the larger portion of the antispasmodic activity appears to be associated with the activation of the beta 1-subtype.     

The implications of a growing evidence base for drug use in elderly patients. Part 3. Beta-adrenoceptor blockers in heart failure and thrombolytics in acute myocardial infarction

Beta-adrenoceptor blockers and thrombolytic agents are of established value in the pharmacological management of heart failure and ST-elevation myocardial infarction, respectively. However, there is uncertainty as to whether these therapeutic strategies can be safely and effectively adopted in elderly patients with comorbidities, particularly in old-old individuals. This review focuses on these trials and the age-related efficacy and safety of these drugs.     

Beta-adrenoceptor studies. III. On the beta-adrenoceptors in rat adipose tissue

A number of β-adrenoceptor blocking agents were tested for isoprenaline antogonism on rat adipose cells. The pA₂ values were compared to pA₂ values determined previously on guinea-pig atrial and tracheal preparations. Discrepancies between the results obtained and the hypothesis of Lands et al. (Nature, 214 (1967) 597) concenring the existence of two types of β-receptors are discussed. The classification of the lipolytic β-receptors as a β₁-receptor is questioned and another hypothesis is put forward.     

Beta-adrenoceptor blockade by atenolol, metoprolol and propranolol in the anaesthetized cat.

The inhibitory effects of atenolol, metoprolol and propranolol on isoprenaline-induced tachycardia, broncho-relaxation and vasodilatation were investigated in the reserpinized and anaesthetized cat. In low doses all three antagonists inhibited the heart rate response to isoprenaline, the order of potency being propranolol greater than metoprolol greater than atenolol. While propranolol inhibited the bronchodilation and vasodilation responses to isoprenaline in the same dose range as it blocked the heart rate response, atenolol and metoprolol had to be given in considerably higher doses to block these effects. The results indicate that both metoprolol and atenolol, in contrast to propranolol, are selective beta1-adrenoceptor antagonist. No statistically significant difference in the degree of selectivity was found between metoprolol and atenolol. The three compounds were devoid of intrinsic beta-mimetic activity.     

Beta-adrenoceptor distribution in murine lymphoid cell lines.

beta-Adrenergic receptors (R) on several tumor lymphoid cell lines were characterized both directly by beta radioligand binding of 125iodo-cyanopindolol (125I-CYP) to intact cells and membranes, and functionally by assessing hormone-dependent changes in cyclic 3',5' adenosine monophosphate (cAMP) levels on intact cells and measuring adenylate cyclase (a.c.) activity on membranes. Only two lymphoid cell types, BW 5147 (a T cell derived lymphoma cell line) and TIB 221 (a B cell derived line) displayed significant amounts of beta-adrenergic R by 125I-CYP specific binding. Despite this, no stimulation of the a.c. activity was found in the presence of beta-adrenergic agonists in these cells in comparison with native lymphocytes or cells of the well-known S49 cell line used as a positive control. beta-Adrenoceptor specific uncoupling was confirmed by aluminum tetrafluoride (AlFl4) direct activation of the a.c. system in the beta R-bearing cell membranes and by an increase in cAMP production induced by PGE1, another hormone that activates the a.c. Structural characterization of beta-adrenoceptors by photoaffinity-labeling demonstrates that uncoupling was not due to a structural alteration of the beta-adrenergic R expressed in these lymphoma cell lines, as these R gave similar results as native or S49 cells. It can be concluded that functional beta-adrenoceptors are absent in these lymphoma cells. The possible implication of alternative transmission pathways and original neuroendocrine control in tumor lymphoid cells is discussed.     

Beta-adrenoceptor stimulation enhances transmitter output from the rat phrenic nerve.

1. Neurally-evoked output of newly synthesized [3H]-acetylcholine from the rat phrenic nerve was measured in the absence of cholinesterase inhibitors. 2. Noradrenaline and isoprenaline enhanced neurally-evoked transmitter output markedly. Moreover, immediately after the application of noradrenaline the basal tritium efflux increased significantly. 3. Pretreatment with propranolol (0.1 mumol l-1) or atenolol (0.3 mumol l-1) completely prevented the stimulatory effect of noradrenaline and isoprenaline on evoked transmitter output. 4. The facilitatory effect of isoprenaline declined, when the exposure time was increased. This observation supports the assumption that beta-adrenoceptors can be desensitized or inactivated during continued exposure to agonists. 5. It was shown for the first time that stimulation of beta-adrenoceptors enhances transmitter output from the motor nerve. It is proposed that these beta-adrenoceptors are of the beta 1-subtype and are localized on the endings of motor nerves. Circulating catecholamines may facilitate neuromuscular transmission by stimulation of presynaptic beta-adrenoceptors.     

Beta-adrenoceptor blocking and electrophysiological effects of bufetolol in the guinea pig atria.

The potency of blockade of bufetolol, a beta-adrenoceptor blocking drug, and effects of bufetolol on the action potential, contractile force and various electrophysiological properties of the atrium were investigated in comparison with propranolol and quinidine. Bufetolol had a pA2 of 8.65 against the positive chronotropic action of isoproternol on the guinea pig sinus node. Bufetolol, 10(-7) g/ml, did not affect the action potential of the atrial muscle, while the drug, 3 X 10(-5) g/ml, significantly decreased the overshoot potential, the amplitude and the maximum rate of rise of the action potential and prolonged the times for 50% and 90% repolarization. The contractile force was reduced by bufetol, 3 X 10(-5) g/ml. The maximum responsive frequency to the driving stimulus was decreased by bufetol, 3 X 10(-5) g/ml. The excitability of the muscle membrane was suppressed by bufetolo, 3 X 10(-5) g/ml, as indicated by changes in membrane responsiveness, membrane reactivation and strength-duration curve. Propranolol, 10(-5) g/ml and quinidine, 10(-5) g/ml showed similar effects on excitability. The authors suggest that these effects of bufetolol are responsible for its antidyshythmic effects.     

Beta-adrenoceptor blocking effects and pharmacokinetics of pindolol

Summary The beta-adrenoceptor blocking effects of pindolol were compared with those of a placebo in a double-blind trial in twelve hypertensive Africans. Heart rate and arterial blood pressure were measured at rest and immediately after exercise, before and at intervals up to 8 h after oral administration of the drugs. Plasma levels of pindolol were also determined. Pindolol reduced systolic blood pressure and antagonised exercised-induced tachycardia. The mean time to peak level of pindolol was 1.9 h and the mean half-life was 4.2 h. Comparison of plasma levels of pindolol and beta-adrenoceptor blocking activity showed good correlation between them. It is concluded that the pharmacokinetics and beta-blocking effects of pindolol in Africans are not dissimilar from published data for other races.     

Beta-adrenoceptor stimulants and mesovarian leiomyomas in the rat

The experiment reported here shows that mesovarian leiomyomas may be induced in rats by the administration of 2 chemically distinct adrenergic stimulants, salbutamol or terbutaline. That the induction of these benign tumours is a function of adrenergic stimulation is shown by the fact that the concurrent administration of the adrenergic blocker propranolol prevented their development.     

Beta-adrenoceptor antagonists and human sperm motility

Several beta-adrenoceptor blocking agents have been evaluated for spermicidal activity using a transmembrane migration method. The rank order of potency of the active compounds was: penbutolol greater than (+)-propranolol greater than bufuralol greater than (-)-alprenolol greater than oxprenolol greater than metoprolol. Atenolol, pindolol, practolol, tolamolol were without activity. The observed potencies of spermicidal activity are believed to be unrelated to beta-blocking activities, and we have shown that whilst they are not predictable from lipid solubility or nonspecific membrane properties of the compound alone, both these aspects appear to play a role in this pharmacological activity.