The 5-¿4-[4-(diethylamino)butyl]-1-piperidinyl¿acetyl-5H-dibenz[b, f]-azepine (
MF 10058) is a new potent and selective
muscarinic M(2) receptor antagonist. The hemodynamic effects of
MF 10058 were investigated in conscious freely moving dogs. Placebo and three doses of
MF 10058 (2, 4 and 8 mg/kg) were orally administered according to a randomised four-way crossover design. Heart rate, cardiac conduction times, systolic and diastolic blood pressure were telemetrically recorded for 12-24 h after dosing. After placebo administration, a consistent reduction over time in heart rate was observed during the night-time period (-15%, P=0.019).
MF 10058 administration antagonised the nocturnal
bradycardia and shortened QT interval. The effect of the
drug reached statistically significance, compared to placebo, with the highest dose of 8 mg/kg (+19% on heart rate, P=0.013; -4% on QT interval, P=0.049). The effect on heart rate lasted for the entire 24-h observation period (+16%, P=0.030). Nocturnal systolic and diastolic blood pressure were not significantly affected by
MF 10058. No other signs of peripheral or central
cholinergic block were observed at any dose. The results of this study demonstrated that
oral administration of
MF 10058 produces long-lasting hemodynamic effects in the conscious dog. The
drug has a therapeutic potential for the treatment of bradycardic disorders.