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

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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.

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.

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.

[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.

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.

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.

DOI: 10.1111/j.1476-5381.1991.tb12149.x

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