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Inhibition of fast sodium current in rabbit ventricular myocytes by protein tyrosine kinase inhibitors

  • Ion Channels, Transporters
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Abstract

The present study investigated the effects of protein tyrosine kinase inhibitors on the fast sodium current (I Na) in rabbit ventricular myocytes. Single rabbit ventricular myocytes were isolated enzymatically using Langendorff perfusion. I Na was recorded using the whole-cell patch-clamp technique at room temperature. The protein tyrosine kinase inhibitors genistein, AG957, ST638, and PP2 reversibly inhibited I Na in a concentration-dependent manner. At a test pulse potential of −30 mV, genistein (n=7) inhibited I Na by 37.7±3.2%, 53.4±2.5%, and 71.8±2.7% at concentrations of 15, 50, and 100 µM, respectively, without changing the voltage dependence of activation, while 100 µM AG957, 100 µM ST638, and 30 µM PP2 inhibited I Na by 38.7±2.4, 35.8±3.4, and 21.1±3.9%, respectively. Genistein (100 µM) and AG957 (100 µM) shifted the voltage for half-maximal inactivation of I Na from −76.7±2.0 mV (n=10) in control to −88.37±2.6 mV (n=6, P<0.05), and −82.9±1.7 (n=4, P<0.05), respectively, without changing the slope factor. Genistein and AG957 also significantly prolonged the time course of I Na recovery from inactivation. Daidzein and PP3, inactive analogs of genistein and PP2, respectively, did not inhibit I Na significantly. We conclude that protein tyrosine kinase signaling pathways may play an important role in regulation of I Na in cardiac myocytes.

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Acknowledgements

This work was partially supported by NIH grant HL49438 (Dr. Ronald W. Joyner), NIH grant HL56787 (Dr. Rajiv Kumar), Children's Healthcare of Atlanta Sibley Heart Center, and the Emory Egleston Children's Research Center.

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Correspondence to Ronald W. Joyner.

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Wang, Y., Wagner, M.B., Kumar, R. et al. Inhibition of fast sodium current in rabbit ventricular myocytes by protein tyrosine kinase inhibitors. Pflugers Arch - Eur J Physiol 446, 485–491 (2003). https://doi.org/10.1007/s00424-003-1061-8

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  • DOI: https://doi.org/10.1007/s00424-003-1061-8

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