Inhibition of fast sodium current in rabbit ventricular myocytes by protein tyrosine kinase inhibitors.
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 microM, respectively, without changing the voltage dependence of activation, while 100 microM AG957, 100 microM ST638, and 30 microM PP2 inhibited I(Na) by 38.7+/-2.4, 35.8+/-3.4, and 21.1+/-3.9%, respectively. Genistein (100 microM) and AG957 (100 microM) 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.
Todd Franklin Cardiac Research Laboratory, The Sibley Heart Center, Department of Pediatrics, Emory University, 2040 Ridgewood Dr. NE, Atlanta, GA 30322, USA.
Yanggan
Y
Wang
Mary B
MB
Wagner
Rajiv
R
Kumar
Jun
J
Cheng
Ronald W
RW
Joyner
D000818:Animals; D002934:Cinnamates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D013440:Sulfides / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
C412373:AG 1879; D002934:Cinnamates; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D015222:Sodium Channels; D013440:Sulfides; D020032:Tyrphostins; C104965:tyrphostin AG957; C060747:ST 638; D012964:Sodium; D019833:Genistein; D011505:Protein-Tyrosine Kinases