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]-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.
Lamperti
G
G
Research and Development Department, Mediolanum Farmaceutici, Via S. G. Cottolengo 15, 20143, Milan, Italy. g.lamperti@mediolanum-farma.com
Champeroux
P
P
Martel
E
E
Colibretti
M L
ML
Santoro
L
L
Imbimbo
B P
BP
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002940:Circadian Rhythm; D003243:Consciousness; D003971:Diastole; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects; D013599:Systole; D013997:Time Factors
C416546:5-(4-(4-(diethylamino)butyl)-1-piperidinyl)acetyl-5H-dibenz(b,f)azepine; D001381:Azepines; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic