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

G Rubanyi, A Iqbal, A Schwartz and PM Vanhoutte

Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota.

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 F2 alpha. 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.

Volume 259, Issue 2, pp. 639-642, 11/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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