Makoto Kadoya

Electrophysiological effects of amiodarone on isolated rabbit heart muscles.

We studied the electrophysiological effects of amiodarone on isolated rabbit heart muscles by conventional microelectrode techniques. It significantly suppressed not only sinus node functions (basic cycle length, sinus recovery time, and corrected sinus recovery time) but also atrioventricular node functions (AH interval, effective refractory period, and functional refractory period) by both superfusion (10 μg/ml amiodarone in Tyrode solution) and long-term oral administration (50 mg/day for 2 weeks, then 25 mg/day for 4–6 weeks). On the other hand, oral administration significantly lengthened the action potential duration and effective refractory period of the left atrium and the right ventricle, while superfusion did not. The maximum rate of depolarization, action potential amplitude, and diastolic resting potential were not changed by either route of administration. It is thought that the action of amiodarone on the sinus node and on the atrioventricular node is mainly due to its noncompetitive sympathetic inhibition, and that its action on the left atrium and on the right ventricle is mainly due to reduction of serum triiodothyronine, which requires long-term administration of amiodarone.

Combined effect of disopyramide and bethanechol: use of bethanechol to prevent anticholinergic side effects of disopyramide without reduction of antiarrhythmic efficacy.

Because bethanechol chloride (B) relieves the anticholinergic side effects of disopyramide (D), we examined the combined effects of D and B on the heart and urinary bladder. B was confirmed to counteract dose dependently the effect of D on the dog bladder. In the ventricular muscle, the combined electrophysiological effects (D + B) were additive, with no reduction in the effect of D. With the control value set as 100%, the decrease in the maximum rate of depolarization with 5 × 10−6 g/ml D (90 ± 6%) was not affected by the same dose of B (D + B: 84 ± 14%). Moreover, the effective refractory period (ERP) was larger with D + B (128 ± 12%) than with either B (109 ± 9%, p < 0.01) or D (115 ± 11%, p < 0.05). In contrast, in the atrial muscle and AV and SA nodes, B had marked acetylcholine-like effects. These were completely suppressed by the addition of D except for the atrial ERP with the highest tested concentration of B (5 × 10−6 g/ml). In the latter case, the prolongation of ERP was minimal (B + D: 105 ± 14%) as compared with D alone (130 ± 15%). Since the plasma concentration of B after oral administration of a clinical dose is expected to be on the order of 10−7 g/ml, no practical effect is anticipated. We conclude that B can be expected to counteract urination disorders caused by D without reducing Ds antiarrhythmic efficacy.

Electrophysiological effects of melperone on isolated rabbit heart muscles

1 Electrophysiological effects of melperone on isolated atrial and ventricular muscle preparations of the rabbit were studied by a conventional microelectrode technique. 2 Melperone (3.3 μm) prolonged the action potential duration and effective refractory period of the atrial preparations without affecting the maximum rate of depolarization (). These effects of melperone on action potential duration and effective refractory period were inhibited by a low potassium perfusate (2.7 mm). 3 A high concentration of melperone (16.6 μm) decreased of atrial preparations. In ventricular muscles, melperone at either concentration decreased , although the increase in action potential duration was greater than in the atrium. 4 Depression of of ventricular muscles by melperone was found to be augmented by an increase of stimulation frequency and drug concentration. 5 The rate of onset of rate‐dependent block of in ventricle was increased with drug concentration and frequency of stimulation. However, the time constant of recovery from rate‐dependent block was almost constant. The kinetics of rate‐dependent block of by melperone were approximately similar to those of quinidine and disopyramide. Consequently it is concluded that melperone possesses class la antiarrhythmic activity as well as class 3 activity.