The selective bradycardic effects of zatebradine (UL-FS 49) do not adversely affect left ventricular function in conscious pigs with chronic coronary artery occlusion

Abstract

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 micrograms/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 less than 0.05) and a decrease in LVdP/dtmax (3020 +/- 210 mmHg vs. 3720 +/- 210 mmHg, respectively; p less than 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 less than 0.05). Up to 100 micrograms/kg UL-FS 49 did not affect arterial blood pressure, whereas LVdP/dtmax and cardiac output decreased by less than 10% in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of the novel potassium channel opener bimakalim in conscious pigs after myocardial infarction: A comparative study with nicorandil

“…To our knowledge, no such data are available for conscious pigs. We have shown, however, that in normal conscious pigs the specific bradycardic agent UL-FS 49, in the same heart rate range as in the present study, reduced heart rate by 25% and LVdP/dtm~ by 20%, while arterial blood pressure was not affected [22]. For animals with a permanently occluded left circumflex coronary artery, these data were 30% and 15%, respectively [22].…”

“…We have shown, however, that in normal conscious pigs the specific bradycardic agent UL-FS 49, in the same heart rate range as in the present study, reduced heart rate by 25% and LVdP/dtm~ by 20%, while arterial blood pressure was not affected [22]. For animals with a permanently occluded left circumflex coronary artery, these data were 30% and 15%, respectively [22]. In this respect it is also important that in the animals with the infarction, bimakalim at a dose of <-150 ng/ kg/min had no effect on heart rate and LVdP/dtma x but reduced systemic vascular resistance by 20% when the infusions occurred after beta-adrenoceptor blockade.…”

Acute Effects of Zatebradine on Cardiac Conduction and Repolarization

“…The potent bradycardiac effect of zatabradine has been observed in various animal models with the dose range of 0.05 mg/kg to 5 mg/kg administered by an IV bolus (12)(13)(14). The magnitude of the effect of the drug on heart rate has been found to be similar in normal…”

“…Zatebradine also exerted beneficial effects in a number of models of ischemic regional ventricular dysfunction (12)(13)(14). Although no proarrhythmic properties were observed in these studies, no observations have addressed the possibility of the differential actions of the drug on the various components of the conduction system as a function of dose.…”

Zatebradine: Pharmacological Activity and Potential Therapeutic Benefit of Sino‐atrial Node Modulators

“…Thus, depending on the intensity of the bradycardia produced by zatebradine, the increase in filling pressure in both ventricles could be detrimental in the presence of myocardial failure (26). Zatebradine reduces heart rate to a similar extent both in pigs with three weeks of left circumflex coronary artery occlusion and in normal animals without any deleterious effect on left ventricular function (51). More studies are required to clarify whether sino-atrial node modulators induce beneficial effects on cardiac function in both normal and pathological situations.…”