Abstract

The mechanism whereby RP 49356, a novel potassium channel opener, activates ATP-sensitive K+ channels (K+-ATP channels) in isolated cardiac cells was investigated with the patch-clamp technique. When directly applied onto the inner face of an inside-out membrane patch, RP 49356 (300 microM) had no effect on K+ channels opened in an ATP-free solution. In contrast, the same concentration of the drug reactivated K+-ATP channels that had experienced spontaneous "run-down" of their activity following long recording periods. In cell-attached experiments, externally applied RP 49356 (300 microM) opened K+-ATP channels at 35 degrees in spite of the high intracellular ATP concentration, which was sufficient to prevent channel openings in the absence of the drug. In control conditions, the dose-response relation for ATP closing the channels had a Hill coefficient of 2.37 and a half-inhibition concentration of 56 microM. With 30 microM RP 49356 present in the intracellular medium, the slope factor of this relation was unchanged but the curve was shifted to the right, with a half-inhibition concentration of 515 microM. Conversely, the dose-response relation of RP 49356 activating K+-ATP channels was shifted to the right in a parallel manner under the influence of increasing concentrations of ATP. It is concluded that RP 49356 acts on cardiac K+-ATP channels by decreasing their sensitivity to ATP. Our results are consistent with an apparent competition between ATP and RP 49356.