论文部分内容阅读
目的 观察5-HT_4受体激动剂兼5-HT_3受体阻断剂2-[1-(4-piperonyl)piperazinyl]benzothiazole对大鼠离体心脏心律的影响,并探析其电生理学机制.方法 采用成年健康SD大鼠建立离体心脏Langendorff主动脉逆行灌流系统,观察0.1～10 μmol · L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole对离体心脏节律的影响,全程记录心电图的变化.应用全细胞膜片钳技术观察2-[1-(4-piperonyl)piperazinyl]benzothiazole对胶原酶分解的大鼠心室肌细胞膜内向整流钾电流(I_(K1))、瞬时外向钾电流(I_(to))、静息膜电位(RMP)及动作电位(AP)的影响.结果 在大鼠离体心脏,0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole可诱发明显的心律失常.给药15 min内,药物(10 μmol·L~(-1))诱发期前收缩(PVB)236±37个,室速(VT)和室颤(VF)发生率分别达到87.5%和62.5%(n=8,P<0.01).膜片钳记录结果显示,0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole可浓度依赖性抑制大鼠心室肌IK1(EC50=0.74 μmol·L~(-1))和I_(to)(EC_(50)=2.16 μmol·L~(-1)),降低膜电位,并明显延长动作电位时程(n=6,P<0.01).结论 作为5-HT_4受体激动剂和5-HT_3受体阻断剂2-[1-(4-pipero-nyl)piperazinyl]benzothiazole致大鼠心律失常风险的电生理学机制为抑制I_(K1)和I_(to),降低膜电位,延长动作电位时程.“,”Aim To investigate the effects of 5-HT_4 receptor agonist and 5-HT_3 receptor antagonist 2-[1-(4-piperonyl)piperazinyl]benzothiazole on rat heart rhythm and the involved ionic mechanisms.Methods Langendorff-perfused rat hearts were subjected to 0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)-piperazinyl]benzothiazole for 15 minutes with simultaneous ECGs recording.The whole-cell patch-clamp electrophysiology was used to record effects of 2-[1-(4-piperonyl)piperazinyl]benzothiazole on inward rectifier K~+ current(I_(K1)),transient outward K~+ current(I_(to)),resting membrane potential(RMP)and action potential(AP)in enzymatic dissociated rat ventricular myocytes.Results In ex vivo Langendorff-perfused hearts,0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole elicited singnificant rhythm disturbances.In the presence of 10 μmol·L~(-1) agent,the total of PVB were 236±37,87.5%(7/8)hearts exhibited VT,and 62.5%(5/8)hearts exhibited VF(P<0.01).At the concentration of 0.1～10 μmol·L~(-1),2-[1-(4-piperonyl)piperazinyl]benzothiazole could inhibit I_(K1)(EC50=0.74 μmol·L~(-1))and I_(to)(EC50=2.16 μmol·L~(-1)),decrease RMP and prolong action potential duration(APD)in concentration-dependent manners(n=6,P<0.01).Conclusion Inhibition of IK1,Ito and resultant prolongation of APD,depolarization of RMP might be the critical causes for induction of arrhythmias by 2-[1-(4-piperonyl)piperazinyl]benzothiazole in rat.