Effects of a novel smooth muscle relaxant, KT-362, on contraction and cytosolic Ca2+ level in the rat aorta.

1. Inhibitory effects of a novel smooth muscle relaxant, KT-362 (5-[3-([2-(3,4-dimethoxyphenyl)-ethyl]amino)-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate), on contraction and the cytosolic Ca2+ level ([Ca2+]cyt) in isolated vascular smooth muscle of rat aorta were examined. 2. KT-362 inhibited the contractions induced by high K+ and noradrenaline. The inhibitory effect was antagonized by an increase in external Ca2+ concentration. A Ca2+ channel activator, Bay K 8644, did not change the effect of KT-362 on high K+-induced contraction. 3. [Ca2+]cyt, measured with fura-2-Ca2+ fluorescence, increased during the contractions induced by high K+ or noradrenaline. KT-362 decreased [Ca2+]cyt and muscle tension stimulated by high K+ or noradrenaline. By contrast, a Ca2+ channel blocker, verapamil, inhibited the noradrenaline-induced increase in [Ca2+]cyt with only partial inhibition of the noradrenaline-induced contraction and KT-362 inhibited the verapamil-insensitive portion of the contraction without changing [Ca2+]cyt. 4. In a Ca2(+)-free solution, noradrenaline and caffeine induced a transient contraction following a transient increase in [Ca2+]cyt. KT-362 inhibited the increments due to noradrenaline but not those induced by caffeine. 5. These results suggest that KT-362 inhibits vascular smooth muscle contraction by inhibiting Ca2+ channels, receptor-mediated Ca2+ mobilization, and receptor-mediated Ca2+ sensitization of contractile elements.