Vascular actions of TA 3090, a novel analog of diltiazem: interaction with endothelium-dependent relaxation in canine femoral and coronary arteries.
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.
Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota.
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Rubanyi
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Schwartz
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Vanhoutte
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D005263:Femoral Artery / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*
D002121:Calcium Channel Blockers; D009569:Nitric Oxide; C056595:clentiazem; D004110:Diltiazem; D000109:Acetylcholine