THE SELECTIVE BRADYCARDIAC EFFECTS OF ZATEBRADINE (UL-FS 49) DO NOT ADVERSELY AFFECT LEFT-VENTRICULAR FUNCTION IN CONSCIOUS PIGS WITH CHRONIC CORONARY-ARTERY OCCLUSION

This study was designed to test whether the selective bradycardic effects of zatebradine (UL-FS 49) were altered in the setting of chronic mild left ventricular dysfunction secondary to a myocardial infarction. We therefore administered four doses of UL-FS 49 at 15-min intervals (cumulative doses of 10, 30, 100, and 300-mu-g/kg) to eight normal conscious pigs and to seven pigs in which the left circumflex coronary artery was occluded 3 weeks previously. Left ventricular dysfunction in this second group of animals was manifested by an increase in left ventricular end-diastolic pressure (LVEDP 11 +/- 2 mmHg vs. 7 +/- 1 mmHg, respectively; p < 0.05) and a decrease in LVdP/dt(max) (3020 +/- 210 mmHg vs. 3720 +/- 210 mmHg, respectively; p < 0.05). The results showed that UL-FS 49 was equally effective in reducing heart rate in both groups of animals [from 126 +/- 4 to 95 +/- 2 beats/min and from 140 +/- 5 to 98 +/- 6 beats/min for the normal animals and for the animals with a chronic myocardial infarction (MI), respectively]. The duration of left ventricular systole was not affected, but the duration of diastole was prolonged from 290 +/- 10 msec to 420 +/- 20 msec in the normal animals and from 250 +/- 10 msec to 430 +/- 30 msec in the animals with MI (both p < 0.05). Up to 100-mu-g/kg UL-FS 49 did not affect arterial blood pressure, whereas LVdP/dt(max) and cardiac output decreased by less than 10% in either group. With the highest dose there were decreases in cardiac output (20%) and LVdP/dt(max) (15%) and a 5-6 mmHg increase in left ventricular end-diastolic pressure in both groups. The data suggest that UL-FS 49 in doses up to 100-mu-g/kg may also, in the setting of chronic mild left ventricular dysfunction, be an attractive agent when heart rate has to be reduced selectively.