Objective Abnormal QT prolongation associated with arrhythmias is considered the major cardiac electrical disorder and a significant predictor of mortality in diabetic patients. The precise ionic mechanisms for diabet...Objective Abnormal QT prolongation associated with arrhythmias is considered the major cardiac electrical disorder and a significant predictor of mortality in diabetic patients. The precise ionic mechanisms for diabetic QT prolongation remained unclear. The present study was designed to analyze the changes of ventricular repolarization and the underlying ionic mechanisms in diabetic rabbit hearts. Methods Diabetes was induced by a single injection ofalloxan （145mg/kg, Lv. ）. After the development of diabetes （10 weeks）, ECG was measured. Whole-cell patch-clamp technique was applied to record the action potential duration （APD50, APD90）, slowly activating outward rectifying potassium current （IKs）, L-type calcium current （ICa-L） and inward rectifying potassium current （IK1）. Results The action potential duration （APD50 and APD90） of ventricular myocytes was obviously prolonged from 271.5＋32.3 ms and 347.8＋36.3 ms to 556.6~72.5 ms and 647.9~72.2 ms respectively （P〈 0.05）. Meanwhile the normalized peak current densities of IKs in ventricular myocytes investigated by whole-cell patch clamp was smaller in diabetic rabbits than that in control group at test potential of＋50mV （1.27~0.20 pA/pF vs 3.08~0.67 pA/pF, P〈0.05）. And the density of the ICa-L was increased apparently at the test potential of 10 mV （-2.67~0.41 pA/pF vs -5.404-1.08 pA/pF, P〈0.05）. Conclusion Ventricular repolarization was prolonged in diabetic rabbits, it may be partly due to the increased L-type calcium current and reduced slow delayed rectifier K＋ current （IKs） （J Geriatr Cardio12010; 7：25-29）.展开更多
Objective Catecholamines antagonize the clinical efficacy of pure class Ⅲ antiarrhythmic agents in vivo. The antiarrhythmic agent d, l sotalol has β adrenergic blocking properties and class Ⅲ activity. However, ...Objective Catecholamines antagonize the clinical efficacy of pure class Ⅲ antiarrhythmic agents in vivo. The antiarrhythmic agent d, l sotalol has β adrenergic blocking properties and class Ⅲ activity. However, its d isomer without β blockade has been shown to exert significant proarrhythmia. To determine the role of β adrenergic blocking properties of d, l sotalol on its antiarrhythmic effect, we compared the effects of d, l sotalol and d sotalol on delayed rectifier K + outward current in the presence of isoproterenol at different concentrations. Methods Time dependent delayed rectifier K + outward currents, I K (I Kr and I Ks ) and tail current (I K tail ) were measured in isolated guinea pig myocytes using the whole cell configuration of the patch clamp technique. Currents were measured in response to 300 ms depolarizing pulses from a holding potential of Department of Cardiology, University Hospital Heidelberg, Germany (Yao XZ, Yannoulis NC, Kiehn J and Brachmann J) 40 mV in three experimental protocols [control, isoproterenol (10 9 -10 6 mol/L), and isoproterenol (10 9 -10 6 mol/L) plus either d, l sotalol (10 4 mol/L) or d sotalol (10 4 mol/L)]. I K tail currents were measured upon repolarization to 40 mV. Results Isoproterenol significantly inreased I K and I K tail in a concentration dependent manner. I K was significantly amplified in the presence of isoproterenol (10 9 -10 6 mol/L) plus d sotalol. At 10 8 mol/L isoproterenol, I K was increased by 92.3%±23.7% before and 54.3%±13.4% after d sotalol. In contrast, d, l sotalol strongly suppressed the effect of isoproterenol on I K, and compared to control, I K was decreased by 35.6%±8.1% at 10 8 mol/L isoproterenol. Conclusions The β adrenergic blocking property of d, l sotalol maintains delayed rectifier K + outward current block in the presence of isoproterenol in guinea pig myocytes. This may result in its supperior antiarrhythmic efficacy compared to d sotalol.展开更多
The family of voltage-gated （Shaker-like） potassium channels in plants includes both inward-rectifying （Kin） channels that allow plant cells to accumulate K＋ and outward-rectifying （Kout） channels that mediate ...The family of voltage-gated （Shaker-like） potassium channels in plants includes both inward-rectifying （Kin） channels that allow plant cells to accumulate K＋ and outward-rectifying （Kout） channels that mediate K＋ efflux. Despite their dose structural similarities, Kin and Kout channels differ in their gating sensitivity towards voltage and the extracellular K＋ concentration. We have carried out a systematic program of domain swapping between the Kout channel SKOR and the Kin channel KAT1 to examine the impacts on gating of the pore regions, the S4, S5, and the S6 helices. We found that, in particular, the N-terminal part of the S5 played a critical role in KAT1 and SKOR gating. Our findings were supported by molecular dynamics of KAT1 and SKOR homology models. In silico analysis revealed that during channel opening and closing, displacement of certain residues, especially in the S5 and S6 segments, is more pronounced in KAT1 than in SKOR. From our analysis of the S4-S6 region, we conclude that gating （and K＋-sensing in SKOR） depend on a number of structural elements that are dispersed over this -145-residue sequence and that these place additional constraints on configurational rearrangement of the channels during gating.展开更多
基金This work was supported by the National Natural Science Foundation of China （30600253）, Min＆try of Edu- cation Key Project （207031） and Scientific Research Fundation for the Returned Chinese Scholars of Heilongjiang Province of China （LC07C20）.
文摘Objective Abnormal QT prolongation associated with arrhythmias is considered the major cardiac electrical disorder and a significant predictor of mortality in diabetic patients. The precise ionic mechanisms for diabetic QT prolongation remained unclear. The present study was designed to analyze the changes of ventricular repolarization and the underlying ionic mechanisms in diabetic rabbit hearts. Methods Diabetes was induced by a single injection ofalloxan （145mg/kg, Lv. ）. After the development of diabetes （10 weeks）, ECG was measured. Whole-cell patch-clamp technique was applied to record the action potential duration （APD50, APD90）, slowly activating outward rectifying potassium current （IKs）, L-type calcium current （ICa-L） and inward rectifying potassium current （IK1）. Results The action potential duration （APD50 and APD90） of ventricular myocytes was obviously prolonged from 271.5＋32.3 ms and 347.8＋36.3 ms to 556.6~72.5 ms and 647.9~72.2 ms respectively （P〈 0.05）. Meanwhile the normalized peak current densities of IKs in ventricular myocytes investigated by whole-cell patch clamp was smaller in diabetic rabbits than that in control group at test potential of＋50mV （1.27~0.20 pA/pF vs 3.08~0.67 pA/pF, P〈0.05）. And the density of the ICa-L was increased apparently at the test potential of 10 mV （-2.67~0.41 pA/pF vs -5.404-1.08 pA/pF, P〈0.05）. Conclusion Ventricular repolarization was prolonged in diabetic rabbits, it may be partly due to the increased L-type calcium current and reduced slow delayed rectifier K＋ current （IKs） （J Geriatr Cardio12010; 7：25-29）.
文摘Objective Catecholamines antagonize the clinical efficacy of pure class Ⅲ antiarrhythmic agents in vivo. The antiarrhythmic agent d, l sotalol has β adrenergic blocking properties and class Ⅲ activity. However, its d isomer without β blockade has been shown to exert significant proarrhythmia. To determine the role of β adrenergic blocking properties of d, l sotalol on its antiarrhythmic effect, we compared the effects of d, l sotalol and d sotalol on delayed rectifier K + outward current in the presence of isoproterenol at different concentrations. Methods Time dependent delayed rectifier K + outward currents, I K (I Kr and I Ks ) and tail current (I K tail ) were measured in isolated guinea pig myocytes using the whole cell configuration of the patch clamp technique. Currents were measured in response to 300 ms depolarizing pulses from a holding potential of Department of Cardiology, University Hospital Heidelberg, Germany (Yao XZ, Yannoulis NC, Kiehn J and Brachmann J) 40 mV in three experimental protocols [control, isoproterenol (10 9 -10 6 mol/L), and isoproterenol (10 9 -10 6 mol/L) plus either d, l sotalol (10 4 mol/L) or d sotalol (10 4 mol/L)]. I K tail currents were measured upon repolarization to 40 mV. Results Isoproterenol significantly inreased I K and I K tail in a concentration dependent manner. I K was significantly amplified in the presence of isoproterenol (10 9 -10 6 mol/L) plus d sotalol. At 10 8 mol/L isoproterenol, I K was increased by 92.3%±23.7% before and 54.3%±13.4% after d sotalol. In contrast, d, l sotalol strongly suppressed the effect of isoproterenol on I K, and compared to control, I K was decreased by 35.6%±8.1% at 10 8 mol/L isoproterenol. Conclusions The β adrenergic blocking property of d, l sotalol maintains delayed rectifier K + outward current block in the presence of isoproterenol in guinea pig myocytes. This may result in its supperior antiarrhythmic efficacy compared to d sotalol.
文摘The family of voltage-gated （Shaker-like） potassium channels in plants includes both inward-rectifying （Kin） channels that allow plant cells to accumulate K＋ and outward-rectifying （Kout） channels that mediate K＋ efflux. Despite their dose structural similarities, Kin and Kout channels differ in their gating sensitivity towards voltage and the extracellular K＋ concentration. We have carried out a systematic program of domain swapping between the Kout channel SKOR and the Kin channel KAT1 to examine the impacts on gating of the pore regions, the S4, S5, and the S6 helices. We found that, in particular, the N-terminal part of the S5 played a critical role in KAT1 and SKOR gating. Our findings were supported by molecular dynamics of KAT1 and SKOR homology models. In silico analysis revealed that during channel opening and closing, displacement of certain residues, especially in the S5 and S6 segments, is more pronounced in KAT1 than in SKOR. From our analysis of the S4-S6 region, we conclude that gating （and K＋-sensing in SKOR） depend on a number of structural elements that are dispersed over this -145-residue sequence and that these place additional constraints on configurational rearrangement of the channels during gating.
