MODE OF VASORELAXING ACTION OF 5-[3-[[2-(3,4-DIMETHOXYPHENYL)-ETHYL]AMINO]-1-OXOPROPYL]-2,3,4,5-TETRAHYDRO-1,5-BENZOTHIAZEPINE FUMARATE (KT-362), A NEW INTRACELLULAR CALCIUM-ANTAGONIST

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Abstract
In rabbit aorta, pretreatment with KT-362 (KT; 10-6 and 10-5 M) inhibited contractile responses to norepinephrine (NE; 3 .times. 10-9-10-5 M) and methoxamine (10-7-10-4M) but failed to affect responses to potassium (10-70 mM). KT (10-5 M) partially inhibited Ca2+-induced contractions in K+-depolarized aorta preequilibrated in a Ca2+-free medium. After incubation of tissues for 30 min in a Ca2+-free medium containing EDTA (0.2 mM), residual responses to NE and methoxamine were inhibited by KT (10-6-10-4M) and nitroglycerine (10-5 M), but not by nifedipine, verapamil or diltiazem (all 10-5 M). The inhibitory action of a combined treatment with KT and nitroglycerin (both 10-5 M) on the residual response to NE was also much greater than that of either agent alone. In a Ca2+-free medium, the residual caffeine-induced contraction of rabbit iliac artery was inhibited by KT (10-5-10-4 M) but not by nifedipine (10-5 M). The inhibitory action of KT on the residual responses to methoxamine and caffeine in a Ca2+-free medium was much greater than that of nitroglycerin. In a Ca2+-free medium with low EGTA (0.01 mM), D600 (10-5 M) and NE (3 .times. 10-7 M), the addition of Ca2+ (2 mM) resulted in a tonic contraction. This NE-induced Ca2+-dependent, D600-insensitive contraction was not affected by KT at 10-6 or 10-5 M and only slightly depressed by 10-4 M, suggesting that the inhibitory action of KT may not be primarily related to Ca2+ entry through specific receptor-activated pathways. La3+-resistant Ca2+ uptake at 60 min was decreased in a concentration-dependent manner by KT. KT eliminated the La3+-resistant bound Ca2+ that is normally released by NE. La3+-resistant Ca2+ influx (3 min) was unchanged by KT and increased by NE. This NE-induced increase was prevented by KT. These results suggest that the primary inhibitory action of KT on vascular smooth muscle is due to the interference with the release of intracellular Ca2+ from NE- and caffeine-sensitive Ca2+ stores.