Effects of novel pyridothiazepines and pyridothiazines on contractility of isolated guinea-pig heart muscle and vascular smooth muscle preparations

Abstract

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4- dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4-tetrahydro-pyrido[2,3- b][1,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N- methylaminopropionyl]-1,2,3,4-tetrahydro-pyrido[2,3-b][1,4] thiazepine fumarate) and the novel pyridothiazines MM 10 (2,3-dihydro-1-[N-[2-(3,4- dimethoxyphenyl)ethyl]-N-methylaminoacetyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N- methylaminopropionyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolated papillary muscles and aortic preparations of guinea pigs were studied using isometric contraction force measurements. The EC50 values for the negative inotropic effect were 27 μmol/l (MM 4), 19 μmol/l (MM 6), 32 μmol/l (MM 10) and 24 μmol/l (MM 11). In K+-precontracted aortic rings ([K+](o) 60 mmol/l), the compounds induced relaxation with EC50 values of 27 μmol/l (MM 4), 24 μmol/l (MM 6), 84 μmol/l (MM 10) and 68 μmol/l (MM 11). Pyridothiazepines as well as pyridothiazines (100 μmol/l) were able to depress norepinephrine bitartrate (NE 10 μmol/l)- induced contraction of aortic rings in a calcium-free solution. It was concluded that the investigated compounds exert calcium antagonistic properties in both cardiac and smooth muscle. This antagonistic effect might be due to the inhibition of transmembrane calcium influx and/or intracellular calcium release.