The relationship between changes in intracellular ion concentrations and the antiarrhythmic effects of stilbene derivatives

细胞内离子浓度变化与二苯乙烯衍生物抗心律失常作用的关系

• 批准号: 08672617
• 负责人: LAI Zhong-Fang
• 金额: $ 1.41万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672617/
• 关键词: Stilbene derivatives ;; DIDS ;; SITS ;; Intracellular pH ;; Intracellular chloride concentrations ;; Cardiac ischemia ;; Ionic selective microelectrodes ;; Action potentials.; スチルベン酸誘導体; 細胞内クロライド; 心筋細胞虚血; イオン選択性微小電極; 心筋細胞活動電位; DIDS; SITS; 細

We investigated the possible role of CI<@D1-@>D1-HCO<@D3-(/)3@>D3 exchanger on ischemia-induced intracellular acidosis in isolated guinea pig ventricular muscle by measuring intracellular pH (pHi) and intracellular chloride (aC<@D1i@>D1l) with ion-selective microelectrode techniques. Stilbene derivatives, SITS and DIDS,were used as probes to block the CI<@D1-@>D1-HCO<@D3-(/)3@>D3 exchanger and their effects on action potentials (APs) , pHi and aC<@D1i@>D1l in ventricular muscles subjected to simulated ischemia were examined. Simulated ischmia was produced by stopping flow of superfusing solution and preparations were covered with mineral oil. Ischemia induced a progressive decrease in the maximum upstroke rate and resting membrane potentials, and shortened action potential duration, resulting in cessation of APs. SITS (0.5mM) and DIDS (0.1mM) delayd the onset of ischemia-induced deterioration of APs and prolonged the time to cessation of APs. Ischemia induced marked intracellular acido … More sis (pHi of control : 7.023(]SY.+-。[)0.083 ; pHi at 15 min after ischemia : 6.64(]SY.+-。[)0.012, n=6), and SITS or DIDS suppressed the development of intracellular acidosis during ischemia. There were significant differences in pHi change of SITS or DIDS-treated group at 10 and 15 min after ischemia compared with that of control group (p<0.05> . Under an external CI<@D1-@>D1-free condition, the time to cessation of APs during ischemia significantly delayd, and the acidification was suppressed. Furthermore, ischemia induced a great increase in aC<@D1i@>D1l (control : 18.74(]SY.+-。[)9.28mM ; ischemia : 55.3(]SY.+-。[)6.11mM] and this increase was suppressed by the external CI<@D1-@>D1-free or by stilbene derivatives. Present results indicate that activation of CI<@D1-@>D1-HCO<@D3-(/)3@>D3 exchanger is involved in the development of intracellular acidosis occurring during ischemia and that manipulation of pHi and aC<@D1i@>D1l by blocking CI<@D1-@>D1-HCO<@D3-(/)3@>D3 exchange by stilbene derivatives can attenuate ischemia-induced intracellular acidosis, thereby having beneficial effects on ischemia-induced arrhythmias. Less

我们通过离子选择微电极技术测量细胞内pH （pHi）和细胞内氯离子（aC<@D1i@>D1l），研究了CI<@D1-@>D1-HCO<@D3-(/)3@>D3交换剂在离体豚鼠心室肌缺血诱导的细胞内酸中毒中的可能作用。采用芪类衍生物sit和DIDS作为探针阻断模拟缺血心室肌CI<@D1-@>D1-HCO<@D3-(/)3@>D3交换剂，观察其对动作电位（APs）、pHi和aC<@D1i@>D1l的影响。通过停止超液流动产生模拟缺血，并用矿物油覆盖制剂。缺血导致最大上搏率和静息膜电位进行性降低，动作电位持续时间缩短，导致ap停止。sit （0.5mM）和DIDS （0.1mM）延缓了APs缺血性恶化的发生，延长了APs停止的时间。缺血诱导细胞内明显的酸升高（p < 0.05） （p < 0.05），对照组：7.023(p < 0.05)；缺血后15 min pHi: 6.64([SY.+- .]] 0.012, n=6)，且sit或DIDS可抑制缺血时细胞内酸中毒的发生。缺血后10、15 min， sit组和dids组pHi变化与对照组比较差异有统计学意义（p<0.05）。体外CI<@D1-@>无d1条件下，缺血时APs的停止时间明显延迟，酸化受到抑制。此外，缺血导致aC<@D1i@>D1l显著升高(对照组：18.74(]SY.+- . [)9.28mM；缺血：55.3(]SY.+- . [)6.11mM]，体外CI<@D1-@>D1-free或苯乙烯衍生物抑制了这种增加。目前的研究结果表明，CI<@D1-@>D1-HCO<@D3-(/)3@>D3交换器的激活参与了缺血期间发生的细胞内酸中毒的发展，并且通过阻断CI<@D1-@>D1-HCO<@D3-(/)3@>D3交换来调节pHi和aC<@D1i@>D1l可以减轻缺血引起的细胞内酸中毒，从而对缺血引起的心律失常有有益的作用。少

项目成果

Lai ZF, et al.: "Modulation of ionic currents by stilbene derivatives in primary cultured neonatal mouse cardiac myocytes." Jap J Pharmacol. 71(Suppl I). 309 (1996)

Lai ZF 等人：“二苯乙烯衍生物在原代培养的新生小鼠心肌细胞中调节离子电流。”

Lai ZF, et al.: "Enhancement of spontaneous electrical activities and intracellular chloride concentrations induced by extracellular ATP and ADP in isolated guinea pig ventricular muscle." Jap J Pharmacol. 73(Suppl I). 240 (1997)

Lai ZF 等人：“在离体豚鼠心室肌​​中细胞外 ATP 和 ADP 诱导自发电活动和细胞内氯离子浓度的增强。”

Lai ZF,Wang X and Nishi K.: "Enhancement of spontaneous electrical activities and intracellular cholride concentrations induced by extracellular ATP and ADP in isolated guinea pig ventricular muscle." Jap J Pharmacol. 73 (Suppl I). 240 (1997)

Lai ZF、Wang X 和 Nishi K.：“细胞外 ATP 和 ADP 诱导离体豚鼠心室肌​​自发电活动和细胞内氯化物浓度的增强。”

LaiZF,et al.: "Enhancement of spontaneous electrical activities and intracellular chloride concentrations induced by extracellular ATP and ADP in isolated guinea・pig ventricular muscle." Jap J Pharmacol. 73(Suppl I). 240 (1997)

LaiZF 等人：“离体豚鼠心室肌​​中细胞外 ATP 和 ADP 诱导的自发电活动和细胞内氯浓度的增强”，Jap J Pharmacol 73（增刊 I）。

Liu J, Lai ZF, et al.: "Inhibition of sodium surrent by chloride cannel blocker 4,4′-diisothiocyanato stilbene-2,2′-disulfonic acid (DIDS) in guinea pig cardiac ventricular cells." J Cardiovasc Pharmacol.31(4)(in press). (1998)

Liu J、Lai ZF 等人：“氯通道阻滞剂 4,4-二异硫氰酸二苯乙烯-2,2-二磺酸 (DIDS) 对豚鼠心室细胞中钠流的抑制作用。J Cardiovasc Pharmacol.31” (4)（正在出版）（1998）。