TRIAMTERENE INHIBITS THE DELAYED RECTIFIER POTASSIUM CURRENT (I-K) IN GUINEA-PIG VENTRICULAR MYOCYTES

被引:23
作者
DALEAU, P
TURGEON, J
机构
[1] HOP LAVAL,RES CTR,QUEBEC HEART INST,ST FOY G1V 4G5,PQ,CANADA
[2] UNIV LAVAL,SCH PHARM,QUEBEC CITY G1K 7P4,PQ,CANADA
关键词
POTASSIUM CHANNELS; DIURETICS; CARDIAC REPOLARIZATION; DELAYED RECTIFIER;
D O I
10.1161/01.RES.74.6.1114
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
In humans, proarrhythmia during therapy with action potential-prolonging drugs can be associated with hypokalemia often provoked by concomitant administration of diuretic agents. Consequently, therapy with class III antiarrhythmics and K+-sparing diuretics, such as triamterene, may be indicated. Triamterene, along with its K+-sparing properties, exhibits other pharmacological effects. In the heart, it can increase action potential duration (guinea pig atria and papillary muscles), protect against reperfusion-induced arrhythmias (rat), and increase the QT interval (humans). Therefore, studies were undertaken to assess effects of triamterene on cardiac K+ repolarizing currents. Guinea pig Ventricular myocytes were superfused at 30 degrees C with Cd2+-containing solution to block I-si and held at -40 mV to inactivate I-Na. Currents were measured in the whole-cell configuration of the patch-clamp technique. The delayed rectifier outward current (I-K) was elicited by short (250-millisecond) and long (5000-millisecond) depolarizing pulses, and time-independent currents were assessed by a rapid ramp test protocol. After high-voltage long pulses (+50 mV; 5000 milliseconds), tail current amplitude of the slow component of I-K (I-Ks) was decreased 36+/-6% (n=6) and 51+/-8% (n=6) by triamterene 10(-5) and 10(-4) mol/L, respectively. After low-voltage short pulses (-20 mV; 250 milliseconds), tail current amplitude corresponding essentially to the rapid component of I-K (I-Kr) was decreased only 14+/-11% (n=9) and 19+/-10% (n=10) by triamterene 10(-5) and 10(-4) mol/L, respectively. These results were confirmed under conditions of pure I-Ks (block of I-si by E-4031) and pure I-Kr (block of I-si with nisoldipine, extracellular Ca2+ decreased to virtually 0 mmol/L, and 250-miIIisecond depolarizing pulse to -20 mV). In contrast, triamterene had no effects on time-independent currents. Thus, data obtained indicate that triamterene, at clinically relevant concentrations, inhibits I-Ks in a selective manner, although both components of I-K (I-Kr and I-Ks) were decreased. This block of I-K may explain triamterene-related prolongation of cardiac repolarization and warn about potential drug interaction with action potential-prolonging agents.
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页码:1114 / 1120
页数:7
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