The effects of the propranolol enantiomers on the intracardiac electrophysiological activities of Langendorff perfused hearts

Abstract

The optical isomers of the beta blocking agent propranolol exert beta receptor blocking as well as membrane stabilizing effects. The latter is thought to be responsible for the antiarrhythmic effect of the drug. In this study we quantified the electrophysiological effects of both isomers of propranolol on the conduction and pacemaker system of the heart. The experiments were performed on isolated hearts using a special ECG recording and stimulation technique. To abolish isoproterenol's beta adrenergic stimulatory effect on heart rate, 30-times higher concentrations of (+)propranolol were necessary than of (-)propranolol in order to be consistent. Both isomers caused a similar and marked slowing of conduction velocity through the bundle of His and ventricular myocardium. Also, heart rate, as well as atrio-ventricular conduction velocity were significantly slowed by a concentration of 10 microM of either drug, (-)propranolol being slightly more effective. Only in the presence of (-)propranolol did significant changes of atrio-ventricular and His-bundle conduction occur at a concentration of 1 microM. During programmed stimulation sinus node recovery time was more prolonged by (-)propranolol than during perfusion with (+)propranolol. The highest rate of pacing with 1:1 conduction of the sino-atrial conduction, the atrial and ventricular myocardium was significantly depressed to a comparable degree by either isomers of propranolol. These effects appear to be primarily responsible for the antiarrhythmic effects of both isomers. Because of the minor effects of (+)propranolol on sinus- and AV-node activity, as well as on beta adrenergic receptors, this isomer may have potential clinical importance in the treatment of arrhythmias.

Additional Features of Beta-Blockers

“…Bare of ß-blocking effects that reside stereoselectively in the l-enantiomer, optically pure d-sotalol increased mortality by 65% compared to placebo [19]. According to our present knowledge, not only d-sotalol but also d-propranolol might potentially put patients at risk since it possesses antiarrhythmic class I effects [22] similar to those of encainide and flecainide which increased mortality in the Cardiac Arrhythmia Suppression Trial [29]. This might also be true for other ß-blockers that are used as racemates since their d-enantiomers have never been shown not to cause harm similar to that of d-sotalol.…”

“…Thus, a major part of the efficacy of propranolol in patients suffering from hyperthyroidism resides exclusively in the non-ß-blocking d-(+)-enantiomer. On the other hand, propranolol has been shown to exert additional antiarrhythmic class I effects which reside equally in both the d-(+)-and l-(-)-enantiomers [22].…”

“…Indeed, specific effects of the non-ß-blocking d-enantiomers of ß-blockers were unknown 20 years ago. However, during the last years a number of studies reported highly specific effects of the d-enantiomers of different ß-blockers such as antiarrhythmic class-1 effects [22] and inhibition of the conversion of thyroxine to triiodothyronine by d-propranolol [23,24,26], antiarrhythmic class III effects of d-sotalol [27], and pure ·-blockade of d-carvedilol [28]. In addition, it was shown that the co-administration of d-propranolol together with the l-enantiomer influences the pharmacokinetics of l-propranolol indicating drug interactions between the two enantiomers when the racemic mixture is administered [26].…”

Propranolol stereoisomer plasma concentrations and portal haemodynamic response in patients with liver cirrhosis

“…Propranolol is administered as a racemic mixture. However, the R‐enantiomer is haemodynamically inactive 15 –17 . Thus, a considerable proportion of the total plasma propranolol has no haemodynamic effect and may obscure the relationship between plasma concentrations and haemodynamic response because a linear correlation between the plasma concentrations of the active isomer (S‐propranolol) and total propranolol has not been established.…”

Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

“…Spropranolol has up to 100x greater binding affinity than R-propranolol for β-adrenergic receptors, and due to stereoselective hepatic clearance more of the R-propranolol is eliminated (Gilmore et al, 1992;Overman et al, 2019). Due to this difference in activity, S-propranolol is more effective for alleviating hypertension; however, R-propranolol is better suited to treating arrhythmia (Stark et al, 1989;Yang et al, 2015). It is unproven whether the different enantiomers of propranolol would affect cancer in different ways.…”