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

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4-dimet hoxy-phenyl)ethyl]-N-methyl-aminoacetyl]-1,2,3,4-tetrahydro-pyrido[2,3-b][1 ,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl aminopropionyl]-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-dimethoxyphen yl)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-methylaminopropio nyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolat ed papillary muscles and aortic preparations of guinea pigs were studied us ing isometric contraction force measurements. The EC50 values for the negat ive inotropic effect were 27 mu mol/l (MM 4), 19 mu mol/l (MM 6), 32 mu mol /l (MM 10) and 24 mu mol/l (MM 11). In K+-precontracted aortic rings ([K+]( o) 60 mmol/l), the compounds induced relaxation with EC50 values of 27 mu m ol/l (MM 4), 24 mu mol/l (MM 6), 84 mu mol/l (MM 10) and 68 mu mol/l (MM 11 ). Pyridothiazepines as well as pyridothiazines (100 mu mol/l) were able to depress norepinephrine bitartrate (NE 10 mu mol/l)-induced contraction of aortic rings in a calcium-free solution. It was concluded that the investig ated compounds exert calcium antagonistic properties in both cardiac and sm ooth muscle. This antagonistic effect might be due to the inhibition of tra nsmembrane calcium influx and/or intracellular calcium release.