Pharmacological mapping of regional effects in the rabbit heart of some new antiarrhythmic drugs.

Abstract

In vitro preparations of rabbit heart were made from which measurements of effective refractory period (ERP), atrio-Hisian (A-H) and His-Purkinje (H-P) conduction times could be obtained, analogous to electrophysiological measurements customarily carried out in vivo. Intracellular potentials also were recorded from the sino-atrial (SA) node, atrium, bundle of His, preterminal Purkinje fibres and papillary muscles. The effects of a range of concentrations of three new antiarrhythmic drugs, melperone, cibenzoline and alinidine were compared, the lower concentrations studied corresponding to clinical levels. At low concentrations the effects of melperone, inducing bradycardia and lengthening ERP, could be attributed to prolongation of action potential duration (APD) in the sinus node and atrial and ventricular tissues. The slope of slow diastolic depolarization was not altered, nor was there any change in A-H or H-P conduction time, or in maximum rate of depolarization (MRD). At higher concentrations melperone had a substantial class 1 action, but there was no negative inotropic effect, or other evidence of restriction of slow inward current. Cibenzoline was primarily a class 1 agent but also lengthened APD to some extent in the SA node and in atrial and ventricular muscle, but not in Purkinje fibres. APD thus became more uniform along the ventricular conducting pathway. Cibenzoline also depressed contractions and increased A-H conduction time, implying restriction of slow inward current. The bradycardia could thus be attributed to a slowing of both depolarization and repolarization in the SA node, without any change in slope of the slow diastolic depolarization. Conduction time was increased in all tissues. 8 Alinidine greatly reduced the slope of the slow diastolic depolarization and slightly lengthened APD in the SA node. MRD was also reduced in the SA node, and A-H conduction time was increased, implying some restriction of slow inward current. However, there was no negative inotropic effect. 9 Alinidine had no significant effect on MRD in atrium, ventricle or Purkinje cells, nor was H-P conduction time altered, implying absence of effect on fast inward current. APD was moderately lengthened in atrium and ventricle but not in Purkinje cells. 10 It was concluded that the effects of the drugs in the sinus node and on ERP and on A-H and H-P conduction times could be accounted for by their selective cellular actions in different regions of the heart.