Functional and electrophysiological effects of quinacrine on the response of ventricular tissues to hypoxia and reoxygenation.

ABSTRACT

This study examined the effects of quinacrine on the functional and electrophysiological responses of isolated guinea pig hearts and isolated canine papillary muscle and Purkinje fibre preparations. A dose-response relationship for quinacrine (0.01-10.0 micrograms/mL) was studied in isolated guinea pig hearts perfused for 40 min. Quinacrine was found to exert a concentration-dependent negative inotropic effect (1.0 and 10 micrograms/mL); in the presence of the 10 micrograms/mL of the drug, hearts developed contracture, atrioventricular conduction block, and ventricular asystole. In hearts exposed to hypoxia, lactate acidosis, and glucose deprivation and then reoxygenated for 30 min, pretreatment with quinacrine (0.1 microgram/mL) for 15 min prior to the initiation of hypoxia resulted in enhanced recovery of contractile function. Administration of the drug at any other time of the hypoxia-reoxygenation protocol was without effect. However, quinacrine reduced both the incidence and duration of reoxygenation arrhythmias. To examine the possible mechanistic basis for this antiarrhythmic action, isolated canine preparations were exposed to the same conditions and then reoxygenated. Quinacrine (1 microgram/mL) significantly reduced the reoxygenation-associated loss in membrane potential and prevented inexcitability and depolarization-induced automaticity in Purkinje fibres. These results suggest that quinacrine exerts an antiarrhythmic action during reoxygenation and may do so by modifying some potential mechanisms of arrhythmia that occur in the specialized conduction system.