506 increases the cytosolic Ca 2ϩ concentration transient in rat ventricular myocytes by prolonging the action potential through inhibition of the K ϩ currents I to and I K [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 I to from inactivation. Thus I to inhibition was frequency dependent, with no

more »

... e at 0.2 Hz (recorded at ϩ50 mV from Ϫ70 mV) but a 40% decrease at 2.0 Hz. In contrast, inhibition of I K (ϳ60%) was time and voltage independent. At 25 µM, FK-506 (by 65%) and cyclosporin A (by 57%) inhibited calcineurin activity in myocyte extracts. However, only FK-506 increased the cytosolic Ca 2ϩ concentration transient in fieldstimulated myocytes. Furthermore, FK-506 was still active on K ϩ 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 I K and I to are modulated by FK-506-binding proteins or directly by FK-506. immunophilins; transient outward current; potassium current; excitation-contraction coupling The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.