Inhibitory actions of a novel benzothiazepine derivative, TA3090, on the electrical and mechanical responses of the rabbit mesenteric artery.
Actions of diltiazem and TA3090 [(+)-(2S, 3S)-3-acetoxy-8-chloro-5-[(2-dimethylamino)ethyl]-2,3-dihydro-2- (4-methoxy-phenyl)-1,5-benzothiazepine-4-(5H)-one maleate] on smooth muscle cells of the rabbit mesenteric artery were investigated using the microelectrode and tension recording methods. Diltiazem (greater than or equal to 10 microM) but not TA3090 (less than or equal to 100 microM) depolarized the membrane of the rabbit mesenteric artery. TA3090 (greater than or equal to 3 microM) inhibited the action potential and K-induced contraction (128 mM) more than diltiazem (IC50 for action potential, 6.7 microM for TA3090 and 11 microM for diltiazem in the presence of 5 mM tetraethylammonium; IC50 for phasic and tonic K-induced contractions, 3.1 and 0.1 microM, respectively, for TA3090 and 10 and 1 microM for diltiazem). When the membrane was depolarized previously by high concentrations of K in Ca-free solution, TA3090 more potently inhibited the K-induced contraction (128 mM). As a consequence, the concentration-response curve shifted to the left, suggesting that this agent produces voltage-dependent inhibition. Recovery of the amplitudes of action potential and contraction evoked by 128 mM K required a much longer period with TA3090 than diltiazem after removal of these agents and the recovery of the K-induced contraction was also voltage-dependent. Repetitive application of short stimulating pulses (50 musec, 30 Hz) produced an action potential on the excitatory junction potentials. TA3090 inhibited the action potential without change in the amplitude of excitatory junction potentials.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
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E
Nishiye
K
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Nakao
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K
Kitamura
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Kuriyama
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology / Q000031:analogs & derivatives; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D013841:Thiazepines / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014666:Vasomotor System / Q000187:drug effects
D013841:Thiazepines; C056595:clentiazem; D004110:Diltiazem; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine