Propranolol in cardiac arrhythmias: a comparative study of the conventional and long-acting formulations

The comparative anti-arrhythmic effect of equivalent daily doses of conventional propranolol ('Inderal') and long-acting propranolol ('Inderal' LA) was assessed in a double-blind, crossover study lasting 6 weeks in 13 patients with cardiac arrhythmias. Patients were investigated using 24-hour ambulatory monitoring. Both formulations of propranolol significantly reduced the heart rate, together with the number of ventricular premature beats and ventricular couplets, with no significant difference between treatments. The two formulations also produced similar plasma concentrations of propranolol. The long-acting formulation of propranolol proved an effective anti-arrhythmic treatment which, with once-daily dosage, may improve patient compliance with treatment.     

Protective effect of ST-93 against ouabain induced arrhythmias in guinea pigs

ST-93, a clonidine analog was studied for its antiarrhythmic activity in anaesthetised guinea pigs against ouabain induced arrhythmia. The amount of ouabain required (micrograms/kg) for the production of ventricular premature best. Ventricular fibrillation and cardiac arrest was recorded in control and drug treated group of animals. Both ST-93 and clonidine produced significant antiarrhythmic effect in guinea pigs. This protective effect was significantly blocked by yohimbine, suggesting that the antiarrhythmic effect is mediated through presynaptic alpha 2-adrenoceptors.     

Experimental study on arrhythmias induced by cerebral ischemia and ouabain in Mongolian gerbils]

Changes in the electrocardiogram following bilateral common carotid arteries ligation was observed during the awake state and pentobarbital anesthesia; and the influences of cerebral ischemia, pentobarbital or halothane anesthesia on the cardiotoxicity induced by continuous infusion of ouabain were also studied in Mongolian gerbils. Following ligation, all awake-animals died in about 60 min of ligation, all exhibiting severe neurological symptoms and ventricular arrhythmias. These changes did not appear in the animals under pentobarbital anesthesia. With regards to the amount of ouabain infusion needed to cause cardiotoxicity in pentobarbital-anesthetized animals, there were no significant differences between the vagus-intact group and the vagotomized group. However, the cardiotoxic dose of ouabain in the ligation group during pentobarbital anesthesia was larger than the cardiotoxic dose in the non-ligation group. In halothane anesthesia, the cardiotoxic dose of ouabain decreased more prominently than in pentobarbital anesthesia. The arrhythmias observed with isoproterenol were not enhanced by the halothane anesthesia and vagotomy. Therefore, these findings may indicate that during the cerebral ischemia, there is a heterotopic stimulus formation in the impulse conducting system of the heart; ouabain-induced cardiotoxicity appears to be enhancement via ouabain distribution into the cerebrum; and ventricular fibrillation had no definite effect for lowering sensitization of the myocardium to catecholamine by halothane in Mongolian gerbils.     

CPU 86017 suppression of arrhythmias induced by ischemia/reperfusion,ouabain, aconitine,and elevation of ventricular fibrillatory threshold

Protection by CPU 86017 against reperfusion-induced arrhythmias was studied in Langendorff perfused hearts and anesthetized rats. Inhibition of arrhythmias induced by ouabain and aconitine was observed, and the influence of CPU 86017 on ventricular fibrillation threshold (VFT) was determined. CPU 86017 exerted a dose-dependent antiarrhythmic effect in animal models. In Langendorff's perfused hearts, CPU 86017 significantly reduced the incidence and duration of ventricular fibrillation and ventricular tachycardia, as well as arrhythmic scores in a dose-dependent manner. The approximate ED₅₀ of CPU 86017 against ventricular fibrillation was 2.10 μM. The antiarrhythmic effect of CPU 86017 against arrhythmia persisted for more than 6 h. In anaesthetized rats, CPU 86017 provided potent antiarrhythmic and antifibrillatory effects by po or iv routes. CPU 86017 was similar in potency to propafenone by the po route, and 10 times more potent than lidocaine by the iv route. CPU 86017 significantly attenuated the exaggerated arrhythmia and ventricular fibrillation in hypertrophic hearts induced by 1-thyroxine. Against ouabain-induced arrhythmias CPU 86017 exerted a dose-dependent inhibitory effect, which was 6.5-fold more potent than berberine. CPU 86017 significantly reduced ventricular fibrillation incidence and prevented the further deterioration of ventricular arrhythmias induced by aconitine. In conclusion, CPU 86017 is a potent antiarrhythmic agent with multiple mechanisms of action. Drug Dev. Res. 39:184–190. © 1997 Wiley-Liss, Inc.     

哇巴因和乌头碱诱发豚鼠和大鼠心律失常的离子作用靶点哇巴因和乌头碱诱发豚鼠和大鼠心律失常的离子作用靶点

目的观察哇巴因和乌头碱对豚鼠和大鼠心肌单细胞离子通道的作用,确定两药诱发心律失常时离子靶点和最佳靶点,建立细胞水平的心律失常模型。方法用全细胞膜片钳技术记录哇巴因和乌头碱对酶解法分离的豚鼠和大鼠心肌细胞离子通道的作用。结果5 μmol·L^-1哇巴因使豚鼠心肌细胞APD延长、I_Ca-L增加、I_k减少、I_k1减少;1 μmol·L^-1乌头碱使大鼠心肌细胞APD延长、I_Ca-L增加、I_to减少、I_k1增加。结论哇巴因和乌头碱诱发心律失常的离子靶点有APD,I_Ca-L,I_k,I_to和I_k1,而最佳靶点应为APD,I_Ca-L,I_k 和I_to。在单细胞水平分别应用哇巴因和乌头碱诱发豚鼠和大鼠心律失常,具有稳定性高、条件可控、重复性好等优点,可用于药物筛选和机制研究。     

Comparison of the effects of propranolol and MJ 1999 on cardiac β-adrenoceptors in man

1. Propranolol, a beta-adrenoceptor blocking drug with local anaesthetic and a direct myocardial depressant action, and MJ 1999, a beta-adrenoceptor blocking drug which has no local anaesthetic or intrinsic sympathomimetic action, were compared for beta-adrenoceptor blocking activity in man.2. Propranolol was 2.67 times more active than MJ 1999 in reducing by 50% the tachycardia produced by the intravenous infusion of isoprenaline in healthy volunteers.3. Propranolol and MJ 1999 intravenously both reduced resting heart rate in the standing position and an exercise tachycardia, but there was no qualitative or quantitative difference between them.4. On oral administration, both propranolol and MJ 1999 reduced resting heart rate and an exercise induced tachycardia; propranolol was only slightly more active than MJ 1999.5. In patients with thyrotoxicosis propranolol was about twice as active as MJ 1999 in reducing the heart rate.     

Role of vagus in the antagonism of ouabain induced arrhythmias in dogs by beta-adrenoceptor antagonists and related drugs

The effects of propranolol and related drugs were investigated on ouabain-induced ventricular tachycardia (VT) in dogs with intact and ablated vagi. Propranolol and UM-272 completely antagonized the ouabain VT in dogs with intact vagi, whereas timolol was ineffective. Bilateral vagotomy completely abolished the effect of UM-272 and reduced the effect of propranolol. Diphenylhydantoin, however, reversed ouabain VT in dogs with both intact and ablated vagi. It is inferred that the vagus plays a significant role in the arrhythmolytic effect of propranolol and UM-272.     

胆碱对乌头碱和哇巴因所诱发的心律失常的保护作用

目的探讨胆碱对乌头碱和哇巴因所诱发的心律失常的保护作用。方法大鼠和豚鼠分别注射乌头碱或哇巴因制备心律失常模型,观察预先给予低剂量(5 mg.kg-1)和高剂量(20 mg.kg-1)的胆碱对心律失常的保护作用。结果给予胆碱可明显对抗乌头碱或哇巴因所诱发的心律失常,表现为明显延迟心律失常的出现,推迟动物死亡时间等。高剂量胆碱对心律失常的保护作用优于低剂量。结论胆碱对心律失常具有保护作用,高剂量的作用优于低剂量。     

Calcium in relation to the actions of ouabain and adrenaline on the heart

Isolated pairs of rabbit auricles have been observed in media containing 6, 24 or 75 mM-potassium, with corresponding reductions in sodium concentration. In 24 mM-potassium, adrenaline restored beating and excitability, as did calcium chloride, but ouabain had no effect. In 75 mM-potassium, adrenaline had no effect; calcium chloride caused a contracture; ouabain had no direct effect, but auricles which had been beating in the presence of ouabain contracted promptly on transfer to 75 mM-potassium. Left auricles, which do not beat spontaneously, were less sensitive to calcium and to ouabain. The results showed a membrane stabilizing action of calcium and an action on muscular contraction, and suggested that cardiac glycosides acted by causing accumulation of calcium at the activator site in the tissue.     

The haemodynamic effects of sotalol (MJ 1999) and propranolol in man

Summary In a dose of 40 mg, sotalol (MJ 1999) was more potent than 10 mg propranolol in blocking the cardiovascular effects of isoproterenol (5 healthy males, age 22–28 years). In a dose of 10 mg sotalol had weaker blocking properties. In a dose of 10 mg, propranolol under true basal conditions significantly decreased cardiac output (1.7 ± 0.34 1), stroke volume (31 ± 11 ml) and heart work (– 20 ± 7%), and increased the peripheral resistance (+35 ± 6%). Sotalol (10–40 mg i.v.) had no significant actions on cardiac output or any other cardiac function. There were statistically significant differences in the haemodynamic effects of sotalol and propranolol at doses producing a similar adrenergic -receptor blocking effect.This work was supported by grants from the Swedish State Medical Research Council (B69-14x-2546-01) and AB Bofors, Nobel-Pharma.For technical assistance we are indebted to Mrs. Anna-Greta Berggren and to Mrs. Anita Andersson.