Prophylactic effects of a new 1,5-benzothiazepine calcium antagonist on stroke in salt-loaded stroke-prone spontaneously hypertensive rats.

The influence of chronic treatment with clentiazem ((+)(2S,3S)-3-acetoxy-8-chloro-5-[2-(dimethylamino)ethyl]-2,3-dihydro- 2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one maleate, TA-3090), on blood pressure, incidence of stroke, stroke-related mortality and histological changes of the brain and other organs were examined in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP that were fed an 8% NaCl-containing diet began to die of a stroke 3 weeks after salt-loading, accompanied by decreases in body weight and food intake. Most of the rats (16 out of 18) died by the 8th week of salt-loading. Chronic treatment with clentiazem (300 or 1000 ppm) delayed the occurrence of stroke and death in a dose-related manner without any hypotensive action when measured by the tail-cuff method. However, examination of circadian changes in arterial blood pressure with implanted cannula under a freely-moving condition 3 weeks after salt-loading revealed that 1000 ppm clentiazem produced significant hypotension in the dark phase but not in the light phase. Histological studies (3 weeks after salt-loading) showed that 1000 ppm Clentiazem significantly suppressed the cerebral and renal damages, and vascular hypertrophy in all organs studied. Thus, clentiazem prevents stroke and also protects renal damage and vascular hypertrophy in salt-loaded SHRSP. The hypotensive effect and organ-protective action by clentiazem may be involved in its prophylactic action against stroke.