5-HT4受体部分激动剂RS67506作为心肌IK1通道抑制剂的研究

Research of 5-H T 4 partial agonist RS67506 as a potential antagonist of cardiac IK1

目的验证5-HT4受体部分激动剂RS67506对心室肌内向整流钾通道(IK1)和动作电位(actionpotential,AP)的作用特征.方法取成年雄性SD大鼠心脏经Langendorff离体灌流、胶原酶法急性分离单个左心室肌细胞,采用膜片钳技术检测l^30μmol/LRS67506对心室肌静息电位(restingpotential,RP)、动作电位(actionpotential,AP)及Ix1通道电流的影响.结果1μmol/L、10μmol/L、30μmol/LRS67506可剂量依赖性降低静息电位[由(-75.2±0.4)mV分别降低至(-72.7±0.5)mV、(-70.1±0.4)mV和(-67.9±0.9)mV,P<0.01],延长动作电位复极时间(APD)[APD90由(31.1±1.1)ms分别延长至(34.7±0.6)ms、(40.4±1.2)ms和(45.0±0.5)ms,P<0.05或P<0.01].同时剂量依赖性抑制IK1,30μmol/LRS67506可使IK1外向电流密度(-60my)降低58.4%(P<0.05);内向电流密度(-100mV)降低53.2%(P<0.01).结论RS67506对大鼠心室肌IK1和AP的作用特征符合IK1抑制剂的特点,可能作为大鼠心肌IK1抑制剂,为临床防治心律失常提供新的药理学工具药.

Objective To testify the effect of 5-HT4partial agonist, RS67506, on inward rectifier potassium channel (IKi) and action potential (A P) in ventricular cardiomyocytes. Methods Langendorffperfusion and collagenase isolarion were used to acquire single left ventricular cardiomyocytes from adult male SD rats. The effects o f 1-30 ^m ol/L RS67506 on cardiac resting potential ( R P ), AP and Iki current were detected by the whole cell patch clamp technique. Results 1 (im ol/L, 10 fimol/L, 30 jxmol/L RS67506 dose-dependently reduced resting potential [from (-7 5 .2 ± 0 .4 ) mV to (-7 2 .7 ± 0 .5) mV,(-7 0 .1 土0.4) mV and (-6 7 .9 ± 0 .9 ) mV, respectively, P < 0 .0 1 ], prolonged action potential duration( A PD )[ APD90 from (31.1±1.1 )ms to (34.7±0.6) ms,(40.4土 1.2) ms and (4 5.0± 0.5) ms, respectively, or P<0.01] and simultaneously down-regulated Iki current. At 30 fxm ol/L,RS67506 made 58.4% decrease in outward component (- 6 0 mV) of Iki (尸<0.05) and 53.2% decrease in inward component (- 100 mV) of Iki (P < 0.01). Conclusion The effects of RS67506 on ventricular Iki and action potential in rats are consistent with the characteristics of IK! inhibitors, and might be used as I ki antagonist in the future. The study might provide a new pharmacological tool for clinical prevention and treatment o f arrhythmia.