心脏复极储备电流IKs在糖尿病QT间期延长性别差异中的作用

目的: 观察不同性别糖尿病家兔QT间期延长病理条件下的缓慢延迟整流钾电流(I_Ks)以及蛋白变化,为探讨糖尿病性长QT综合征性别差异的离子机制做基础。方法: 取体重2-2.5 kg家兔,一次性注射预热(37 ℃)的四氧嘧啶(140 mg/kg),8周后造成1型糖尿病模型,测定血糖,记录标准II导联心电图,采用酶解法分离家兔单个心室肌细胞,应用全细胞膜片钳技术记录动作电位时程(APD)和I_Ks,并且运用Western blotting法检测KvLQT1和mink蛋白表达变化。结果: 雌雄糖尿病组QT间期和APD均较对照组延长,雄性延长明显,且延长百分比差异显著(P<0.05)。在+40 mV到+70 mV测试电压范围内,雄性糖尿病组I_Ks step电流密度均低于对照组(P<0.05),在+70 mV时,由对照组(3.08±0.67)pA/pF(n=17)降低到(1.27±0.20)pA/pF(n=16),在0 mV~+70 mV测试电压范围内,雌性糖尿病组I_Ks step电流密度均高于对照组(P<0.05),在+70 mV时,由对照组的(1.56±0.20)pA/pF(n=13)增加到(3.65±0.50)pA/pF(n=14)。Western blotting结果显示雄性糖尿病组KvLQT1和mink蛋白表达水平分别下 调21.6%和18.5%;雌性糖尿病组KvLQT1和mink蛋白表达水平分别上调42.3%和20.5%(P<0.05)。结论: I_Ks参与了糖尿病QT间期延长的发生,并且存在性别差异。在雌性家兔早期糖尿病模型中,作为一个复极储备,代偿性上调,限制了QT间期的过度延长。

Cardiac IKs as repolarization reserve plays a role in gender difference of diabetic QT prolongation

AIM: To explore the basic ionic mechanisms underlying long-QT syndrome by observing the changes of slowly activating outward rectifying potassium current (I_Ks) and its proteins in abnormal QT prolongation in different genders of diabetic rabbits.METHODS: A single injection of pre-warmed (37 ℃) alloxan (140 mg/kg) was used to establish a rabbit model of insulin-dependent diabetes mellitus. Eight weeks after alloxan injection, the levels of blood glucose in the rabbits were monitored and standard lead II electrocardiogram was recorded. The myocardial cells were isolated from the ventricle of the rabbits via enzymatic digestion. Whole-cell patch clamp technique was performed to study the action potential duration (APD) and I_Ks. The changes of both KvLQT1 and mink proteins were detected by Western blotting analysis.RESULTS: The QT interval and APD were prolonged apparently both in male and female diabetic rabbits. The increased APD/QT-I of the male diabetic rabbits is more remarkable than that of the female. The I_Ks step current density of the male diabetic rabbits was decreased at test potentials ranging from+40 mV to+70 mV compared with that of the control animals (P<0.05), which was lowered from (3.08±0.67) pA/pF (n=17) to (1.27±0.20) pA/pF (n=16) at+70 mV. However, the I_Ks step current density of the female diabetic rabbits was increased at test potentials ranging from 0 mV to+70 mV compared with that of control group (P<0.05), which was increased from (1.56±0.20) pA/pF (n=13) to (3.65±0.50) pA/PF (n=14) at+70 mV. The expression of KvLQT1 and mink in male diabetic group decreased by 21.6% and 18.5%, respectively. However, the expression of KvLQT1 and mink in female diabetic group were increased by 42.3% and 20.5%, respectively.CONCLUSION: The I_Ks may be a protective factor in the early period of diabetic development in female rabbits. As a repolarization reserve, cardiac I_Ks is likely to restrict the effects of excessively slowing repolarization.