The electrophysiological effects of various concentrations of atenolol, metoprolol, nadolol, D-oxprenolol, L-oxprenolol, and D, L-oxprenolol and D-sotalol, L-sotalol, and D, L-sotalol were compared in rabbit right ventricular papillary muscle studied in vitro using intracellular microelectrodes. An assessment of the relative beta blocking effects of D-sotalol and D, L-sotalol against the inotropic action of isoprenaline was made in the same preparation. Of the drugs tested, only oxprenolol and sotalol showed prolongation of action potential duration and effective refractory period (class III action), with oxprenolol showing, in addition, depression of maximal upstroke velocity and the presence of post-repolarisation refractoriness (class I action). When contrasted at clinically relevant concentrations, only sotalol retained a class III effect, without any actions on variables related to fast inward current. The effects of oxprenolol and sotalol were not found to be stereospecific. The mechanical experiments indicate that, in this preparation, D-sotalol has approximately one-fourteenth of the beta blocking potency of the racemic compound. It therefore merits further consideration as a useful alternative class III antiarrhythmic agent, which would be free from the side effects of beta receptor blocking treatment.
The effects of acute myocardial ischaemia on the Class III antiarrhythmic properties of dl-sotalol 10(-4) mol . litre-1 were studied in the isolated arterially perfused interventricular septum of the rabbit heart. Before ischaemia, sotalol increased mean action potential duration (APD90) from 267 +/- 6 to 406 +/- 19 ms (p less than 0.001 mean +/- SEM, n = 7 septa), and mean effective refractory period (ERP) from 222 +/- 7 to 291 +/- 10 ms. During 30 min zero flow global ischaemia, mean APD90 in the control group fell from 264 +/- 7 to 128 +/- 13 ms (n = 7). APD90 fell more rapidly in the sotalol group, so that the initial difference between the sotalol and control groups was abolished after 24 min ischaemia. In the sotalol group, ERP shortened rapidly during ischaemia, and was significantly less than in the control group after 30 min. These changes were associated with the development of substantial post-repolarisation refractoriness in the control but not in the sotalol group. There was a greater fall in action potential upstroke velocity in the controls than in the sotalol group. The results indicate that the Class III effect of sotalol gradually disappears during ischaemia. The effects on post-repolarisation refractoriness and upstroke velocity are compatible with the hypothesis that sotalol slows the rate of rise of extracellular potassium concentration in acute ischaemia. This is a potentially antiarrhythmic property.
The effects of 30 min zero-flow ischaemia and reperfusion on the electrophysiological properties of amiodarone were studied in 11 rabbits treated with oral amiodarone (mean 117 mg kg-1, day-1) for 2-3 months, and 11 controls. Experiments were performed in vitro in the isolated perfused interventricular septum, and preischaemic values were compared with those obtained in right ventricular papillary muscles from the same hearts. Prior to ischaemia, mean values of action potential duration (APD90) and effective refractory period (ERP) were prolonged by 13% in the amiodarone-treated septa. Action potential upstroke velocity (Vmax) was reduced by 14% in the septa, but by 42% in papillary muscles. Ischaemia resulted in shortening of APD90 in both control and amiodarone-treated septa, with a loss of the ability of amiodarone to prolong APD90. In contrast, ischaemia resulted in a greater fall in Vmax, gross lengthening in conduction time and increase in stimulation threshold in the amiodarone-treated septa compared with controls. Reperfusion resulted in a restoration of the action of amiodarone on repolarization, and resolution of the marked effects on excitability and conduction. The electrophysiological properties of amiodarone are considerably altered in ischaemic myocardium, with a reversible loss of its ability to prolong repolarization, but evidence suggestive of a marked enhancement of its effect on the inward sodium current.
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