Independent inhibition of calcineurin and K1 currents by the immunosuppressant FK-506 in rat ventricle

DuBell, W. H., S. T. Gaa, W. J. Lederer, and T. B. Rogers. Independent inhibition of calcineurin and K1 currents by the immunosuppressant FK-506 in rat ventricle. Am. J. Physiol. 275 (Heart Circ. Physiol. 44): H2041–H2052, 1998.—FK-506 increases the cytosolic Ca21 concentration transient in rat ventricular myocytes by prolonging the action potential through inhibition of the K1 currents Ito and IK [J. Physiol. (Lond.) 501: 509–516, 1997]. Physiological and biochemical techniques were used in parallel to examine the electrophysiological mechanisms and the role of calcineurin inhibition in these effects. FK-506 prolonged the recovery of Ito from inactivation. Thus Ito inhibition was frequency dependent, with no decrease at 0.2 Hz (recorded at 150 mV from 270 mV) but a 40% decrease at 2.0 Hz. In contrast, inhibition of IK (,60%) was time and voltage independent. At 25 μM, FK-506 (by 65%) and cyclosporinA(by 57%) inhibited calcineurin activity in myocyte extracts. However, only FK-506 increased the cytosolic Ca21 concentration transient in fieldstimulated myocytes. Furthermore, FK-506 was still active on K1 currents when cells were dialyzed with 10 mM EGTA. These results demonstrate that calcineurin inhibition is not responsible for the functional effects of FK-506 in heart and suggest that IK and Ito are modulated by FK-506-binding proteins or directly by FK-506.