Vascular actions of TA 3090, a novel analog of diltiazem: Interaction with endothelium-dependent relaxation in canine femoral and coronary arteries

Abstract

The effects of a new 1,5-benzothiazepine calcium antagonist, TA 3090 (an analog of diltiazem), were analyzed in isolated canine femoral and coronary arteries suspended in organ chambers or studied in a bioassay system. TA 3090 (10 -9 to 10 -4 M) caused comparable relaxations in arterial rings with and without endothelium contracted by prostaglandin F(2α). Coronary arteries were more sensitive to the Ca ++ antagonist. In both preparations, TA 3090 was more potent than diltiazem. In femoral (but not coronary) artery rings with endothelium, acetylcholine (10 -8 M) inhibited relaxations to TA 3090. Previous treatment of femoral or coronary arteries with TA 3090 (10 -6 M) had no effect on endothelium-dependent relaxations to acetylcholine. In a bioassay system, TA 3090 (2 x 10 -7 M) caused partial reversal of acetylcholine-induced relaxation in perfused femoral arteries and superfused coronary arterial rings. The dihydropyridine enantiomer (-)-202,791 did not affect acetylcholine-induced relaxations and did not prevent the reversal by TA 3090. These data indicate that, in addition to a direct action on vascular smooth muscle, this novel benzothiazepine Ca ++-antagonist interferes with the synthesis/release of endothelium-derived relaxing factor stimulated by acetylcholine in canine femoral arteries. These findings, which are similar to those obtained with d-cis-diltiazem, support the hypothesis that a specific benzothiazepine-dependent mechanism(s) can suppress the production of endothelium-derived relaxing factor in endothelial cells.