Hemodynamic effects of MF 10058, a new cardioselective muscarinic M-2 receptor antagonist, in conscious dogs

The 5-{4-[4-(diethylamino)butyl]-1-piperidinyl}acetyl-5H-dibenz[b,f]-azepin e (MF 10058) is a new potent and selective muscarinic M-2 receptor antagoni st. The hemodynamic effects of MF 10058 were investigated in conscious free ly 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. H eart rate, cardiac conduction times, systolic and diastolic blood pressure were telemetrically recorded for 12-24 h after dosing. After placebo admini stration, a consistent reduction over time in heart rate was observed durin g the night-time period (-15%, P = 0.019). MF 10058 administration antagoni sed the nocturnal bradycardia and shortened QT interval. The effect of the drug reached statistically significance, compared to placebo, with the high est 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 w ere not significantly affected by MF 10058. No other signs of peripheral or central cholinergic block were observed at any dose. The results of this s tudy demonstrated that oral administration of MF 10058 produces long-lastin g hemodynamic effects in the conscious dog. The drug has a therapeutic pote ntial for the treatment of bradycardic disorders. (C) 2000 Elsevier Science B.V. All rights reserved.