Inhibitory actions of diltiazem and its derivative, TA3090 on the Ba-current recorded from smooth muscle cells of the rabbit mesenteric artery.
The effects of diltiazem and its derivative, TA3090 on the Ba-induced inward current were investigated using dispersed smooth muscle cells of the rabbit mesenteric artery. Diltiazem and TA3090 inhibited the inward current, in a concentration-dependent manner, and TA3090 was more potent than diltiazem (IC50 for diltiazem was 300 mumol/l and for TA3090, 30 mumol/l). The inward current completely recovered from the inhibitory actions of diltiazem (100 mumol/l) after its removal at holding potentials of -60 and -40 mV, though complete recovery did not occur after TA3090 (1-100 mumol/l). The voltage-dependent inactivation curves were shifted to the left by both drugs. Judging from the amplitudes of shift of V-half, the dissociation constants of inhibition for both diltiazem and TA3090 in the inactivated state were 17 mumol/l and 2.6 mumol/l, respectively. At a holding potential of -60 mV, diltiazem and TA3090 reduced the peak amplitude of the inward current, and diltiazem, but not TA3090, accelerated the decay of the current (300 ms command pulse duration). However, TA3090 did accelerate the decay of the current when a longer pulse (1 s) was applied, or when a depolarizing pulse was applied from a holding potential of -80 mV. Changes in the pH (range 6.8-7.7) of the bathing solution did not influence the decay of the current. In conclusion, TA3090 inhibits the Ca-channels of smooth muscle cells of the rabbit mesenteric artery, in a voltage-dependent manner, and its inhibitory actions are similar to those of diltiazem. However, TA3090 has much longer and stronger inhibitory actions on the Ba-inward current than diltiazem.
Department of Pharmacology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Z
Z
Xiong
T
T
Sakai
Y
Y
Inoue
K
K
Kitamura
H
H
Kuriyama
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001464:Barium; D004110:Diltiazem / Q000494:pharmacology* / Q000031:analogs & derivatives; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D013841:Thiazepines / Q000494:pharmacology*
D000959:Antihypertensive Agents; D007473:Ion Channels; D013841:Thiazepines; D001464:Barium; C056595:clentiazem; D004110:Diltiazem