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

Abstract

1 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. 2 Intracellular potentials also were recorded from the sino-atrial (SA) node, atrium, bundle of His, preterminal Purkinje fibres and papillary muscles. 3 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. 4 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). 5 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. 6 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. 7 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.

An investigation into the characteristics of reperfusion‐induced arrhythmias in the anaesthetized rat and their susceptibility to antiarrhythmic agents

“…Melperone and bepridil also share this property of reducing the fast inward sodium current in cardiac tissue (Kane & Winslow, 1980;Millar & Vaughan Williams, 1983) but they have other effects which might underly their antiarrhythmic actions. For instance, melperone is an a-adrenoceptor blocking agent (Peterson, 1981) and it prolongs the duration of the cardiac action potential (Arlock, 1978).…”

Profiles of Aprindine, Cibenzoline, Pilsicainide and Pirmenol in the Framework of the Sicilian Gambit

“…APD of atrial and ventricular muscles from rabbits or dogs were moderately prolonged, while the APD of dog Purkinje fibers was shortened. [47][48][49][50] APD in rabbit Purkinje fibers and guinea pig papillary muscles was unaffected by cibenzoline. 47,48,51 This discrepancy could be a result of differences in ionic currents responsible for repolarization of the action potential in different cardiac tissues and animal species.…”

“…[47][48][49][50] APD in rabbit Purkinje fibers and guinea pig papillary muscles was unaffected by cibenzoline. 47,48,51 This discrepancy could be a result of differences in ionic currents responsible for repolarization of the action potential in different cardiac tissues and animal species. 52 Only limited information is available regarding the effects of cibenzoline on cardiac tissues whose excitation depends on activation of slow calcium channels.…”

“…In atrial and ventricular muscles as well as in Purkinje fibers from rabbits and dogs, Millar and Vaughan Williams 47,48 and Dangman 49 demonstrated that cibenzoline (1-20 mol/L) decreased Vmax without affecting the resting membrane potential. Similar concentration-dependent Vmax inhibition by cibenzoline was observed in guinea pig ventricular muscle.…”

“…In SA node preparations isolated from rabbits, cibenzoline (1-30 mol/L) was shown to cause concentration-dependent decreases in Vmax, action potential amplitude, and rate of spontaneous excitation. 47,48,53 …”