Ninomiya M, Tani T, Nakajima S, Ueda M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Jpn J Pharmacol. 1989 Oct;51(2):227-38. doi: 10.1254/jjp.51.227.
S-312, a new calcium antagonist with a bicyclic dihydrothienopyridine structure, potently relaxed the helical strips of various isolated rabbit arteries precontracted with high K+-depolarization, serotonin (5-HT) and U46619 (thromboxane A2 analogue), and it competitively inhibited Ca++-induced contractions in depolarized basilar and femoral arteries. These effects of S-312 were more potent than nifedipine and almost comparable to or slightly more potent than those of nicardipine. In comparison with nifedipine and nicardipine, the calcium antagonistic effect and the relaxant effect on 5-HT-induced contractions of S-312 were most prominent in the basilar artery. The potent vasodilating action of S-312 in the high K+-depolarized basilar artery was not easily reversed by washing. S-312 did not affect Ca++-induced contraction in the skinned fiber of guinea pig taenia caecum. The negative inotropic effect of S-312 in isolated guinea pig left atria was much less potent than those of nifedipine and nicardipine. S-312 above 10(-7) M preferentially increased AV nodal conduction time in Langendorff-perfused isolated rabbit hearts; and above 3 x 10(-8) M, it mainly decreased the maximum upstroke velocity of the action potential in isolated rabbit sinus node preparations. In summary, the present results indicate that S-312 is a potent new calcium antagonist possessing vasculoselectivity, especially for cerebral vessels.
S-312是一种具有双环二氢噻吩并吡啶结构的新型钙拮抗剂，它能有效舒张各种经高钾去极化、血清素（5-HT）和U46619（血栓素A2类似物）预收缩的离体兔动脉螺旋条，并且能竞争性抑制去极化的基底动脉和股动脉中钙离子诱导的收缩。S-312的这些作用比硝苯地平更强，与尼卡地平的作用几乎相当或略强。与硝苯地平和尼卡地平相比，S-312对基底动脉的钙拮抗作用和对5-HT诱导收缩的舒张作用最为显著。S-312在高钾去极化的基底动脉中的强效血管舒张作用不易通过冲洗逆转。S-312对豚鼠盲肠带皮纤维中钙离子诱导的收缩没有影响。S-312对离体豚鼠左心房的负性肌力作用比硝苯地平和尼卡地平弱得多。在Langendorff灌注的离体兔心脏中，浓度高于10^(-7) M的S-312优先增加房室结传导时间；在离体兔窦房结标本中，浓度高于3×10^(-8) M时，它主要降低动作电位的最大上升速度。总之，目前的结果表明S-312是一种具有血管选择性的强效新型钙拮抗剂，尤其对脑血管。
