Electrophysiological effects of newly synthesized 1,4-pyridothiazepines on various guinea pig heart muscle preparations.

Slow channel blockers play a major role in the treatment of cardiovascular disease. The intention of this study was to investigate the electrophysiological properties of MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydropyrido[2,3-b][1,4]thiazepine fumarate) and MM 6 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydropyrido[2,3-b][1,4]thiazepine fumarate), two newly synthesized compounds structurally related to KT-362 (5-[3-[[2-(3,4-dimethoxy-phenyl)ethyl]-amino]-1-oxopropyl]-2,3,4,5-tetra -hydro-1,5-benzothiazepine fumarate), by means of the conventional intracellular microelectrode technique. In various guinea pig heart muscle preparations, MM 4 and MM 6 exerted very similar effects though the action of MM 6 was more pronounced. In a concentration range from 3 to 100 micromol/l the compounds did not produce any significant change in transmembrane action potential parameters of papillary muscle and left atria, whereas the action potential duration at 20% and 50% time to repolarization in spontaneously beating Purkinje fibers was significantly shortened. In sinoatrial nodes action potential amplitude, Vmax, rate of activity and slope of slow diastolic depolarization were decreased, whereas the time to 50% and 90% repolarization was significantly prolonged. A decrease in the slow calcium inward current may account for the observed effects. In contrast to KT-362, MM 4 and MM 6 do not seem to affect the fast sodium inward current. It was concluded that replacement of the 1,5-benzothiazepine nucleus by a 1,4-pyridothiazepine structure and/or methylation of the side chain may weaken or even eliminate sodium channel blocking ability while calcium antagonistic characteristics are preserved. Shortening of the side chain might result in a general loss of activity.