EFFECTS OF ZENECA ZD7288 IN COMPARISON WITH ALINIDINE AND UL-FS-49 ONGUINEA-PIG SINOATRIAL NODE AND VENTRICULAR ACTION-POTENTIALS

ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1 ,2-dimethyl-6-(methylamino) pyrimidinium chloride) is a novel compound which we compared with ali nidine and UL-FS 49 (zatebradine) in guinea pig sinoatrial node (SAN) and papillary muscle preparations, using conventional microelectrode t echniques. At low concentrations (1 x 10(-8)-1 x 10(-6)M), ZD7288 caus ed slowing of the diastolic depolarisation rate of SAN pacemaker cells , thus prolonging the diastolic interval and slowing the beating rate. Alinidine and UL-FS 49 also had qualitatively similar effects on dias tolic depolarisation rate, but ZD7288 caused least prolongation of the action potential duration (APD) of SAN cells at the concentrations th at had ''selective bradycardic actions.'' ZD7288 affected the APs of v entricular cells in guinea pig papillary muscle only at relatively hig h concentrations (3 x 10(-6)M-1 x 10(-4)M), which reduced plateau pote ntial duration, although total APD was less affected. Reduced force of contraction (FOC) was also observed at these high concentrations; sig nificant effects on AP V-max were noted only at concentrations greater than or equal to 3 x 10(-5)M. Alinidine also had negative inotropic e ffects on papillary muscle, but its effects were noted at concentratio ns similar to those with bradycardic actions; in contrast, UL-FS 49 ha d marked positive inotropic actions and also increased ventricular APD within the bradycardic concentration range. These data provide a basi s for the selective actions of ZD7288 on heart rate (HR).