B. Hegyi, Y. Chen-Izu, Zhong Jian
Feb 16, 2016
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Journal
Biophysical Journal
Abstract
Rationale: KN-93, an inhibitor of the calcium/calmodulin-dependent protein kinase II (CaMKII) is widely applied in cardiovascular research fields to study the mechanisms of cardiomyopathy and cardiac arrhythmias. Whereas KN-93 is a potent inhibitor of CaMKII, several off-target effects have also been reported in expression cell systems and smooth muscle cells, but there is a lack of information on the KN93 side effects in mammalian ventricular myocytes. Hence, the goal of this study was to examine the effect of KN-93 on IKr, the rapid component of delayed rectifier potassium current which significantly influences cardiac arrhythmogenesis.Method: IKr was recorded by using the action potential-clamp and conventional voltage-clamp techniques in the ventricular myocytes from rabbit and guinea pig hearts.RESULTS:(1)KN-93 inhibited IKr with an IC50 value of 102.57±9.28 nM, which is significantly lower than the previously reported IC50 value of KN-93 (>300 nM) for inhibiting CaMKII.(2)The inhibitory effect of KN-93 on IKr developed within 1 minute, a time period too short to be attributed to CaMKII inhibition.(3)The inhibitory effect of KN-93 was also present when cytosolic calcium was chelated by 10 mM BAPTA which should lower the CaMKII activity.(4)KN-92 also inhibited IKr, even though it does not inhibit CaMKII.Conclusion: Taken together, these data demonstrate for the first time that KN-93 exerts a direct inhibitory effect on IKr in cardiomyocytes, which is not mediated by CaMKII. This off-target effect of KN-93 should be taken into account when interpreting the data from using KN-93 to investigate the role of CaMKII in cardiac function.