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  • Title: Pharmacologically induced long QT type 2 can be rescued by activation of IKs with benzodiazepine R-L3 in isolated guinea pig cardiomyocytes.
    Author: Nissen JD, Diness JG, Diness TG, Hansen RS, Grunnet M, Jespersen T.
    Journal: J Cardiovasc Pharmacol; 2009 Aug; 54(2):169-77. PubMed ID: 19568177.
    Abstract:
    The ionic current responsible for terminating the action potential (AP), and thereby in part determining the AP duration (APD), is the potassium current (IK), consisting of primarily two components: a rapidly (IKr) and a slowly (IKs) activating delayed rectifier potassium current. The aim of this study was to evaluate potential antiarrhythmic effects of compound induced IKs activation using the benzodiazepine L-364,373 (R-L3). Ventricular myocytes from guinea pigs were isolated and whole-cell current clamping was performed at 35 degrees C. It was found that 1 microM R-L3 significantly reduced the APD90 at pacing frequencies of 1, 2, and 4 Hz when compared to control (40 +/- 6%, 22 +/- 2%, and 32 +/- 2%, respectively). The reduction of APD90 was accompanied by a reduced triangulation (given as APD30-90) when compared to control at all pacing frequencies (62 +/- 7 ms vs. 41 +/- 3 ms, 55 +/- 5 ms vs. 35 +/- 6 ms, and 45 +/- 4 ms vs. 32 +/- 2 ms, at 1 Hz, 2 Hz, and 4 Hz, respectively). The abbreviated APDs also resulted in a reduction in the relative refractory period, and no direct protection against pacing induced early after-depolarizations (EAD) could be observed. However, an increase in repolarizing capacity was seen with 1 microM R-L3, as more complete repolarization of the AP was achieved before EADs could be elicited. Finally, a functional demonstration of the repolarization reserve revealed that increased IKs can counteract a pharmacologically reduced IKr. In conclusion, pharmacological activation of IKs possesses both pro- and antiarrhythmic characters. The most prominent antiarrhythmic propensity is the ability for IKs activation to rescue a cellular model of long QT type 2.
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