Effects of
monatepil ([(+/-)-N-(6,11-dihydrodibenzo[b, e]thiepin-11-yl)-4-(p-fluorophenyl)-1-piperazinebutyramide]m aleate,
AJ-2615, CAS 103377-41-9), a novel
calcium antagonist, on the cardiac conduction system were compared by electrocardiography with those of the existing
calcium antagonists (
diltiazem,
verapamil and
nifedipine) in isolated rabbit heart preparations in vitro and in anesthetized and conscious dogs in vivo.
Monatepil (10(-7) mol/l) prolonged the atrio-His bundle conduction time (AH interval) in the Langendorff perfused rabbit heart, like
diltiazem,
verapamil and
nifedipine. This prolongation was decreased to 1/10 in the presence of 3.6%
bovine serum albumin. In anesthetized dogs,
monatepil (0.1-1.0 mg/kg i.v.), unlike
diltiazem and
verapamil, did not prolong AH interval. In conscious dogs,
monatepil even at 100 mg/kg p.o. did not affect electrocardiograms. At the high dose of 300 mg/kg p.o., only a slight prolongation of the QT interval was found, but the QTc interval was not affected.
Diltiazem at 10 mg/kg p.o. caused a prolongation of the PR interval and a disappearance of QRS waves. In conscious renal hypertensive dogs, repeated administration of
monatepil (10 mg/kg/d p.o. for 29 days) had little effect on the conduction system of the heart examined by electrocardiograms, albeit a persistent fall in blood pressure continued throughout the administration period. The above results suggest that
monatepil is a highly safe
drug in the treatment of
hypertension.