Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes.

In a previous article (Escande et al. 1988a), we have shown that cromakalim (BRL 34915), a potassium channel opener (PCO), is a potent activator of ATP-sensitive K+ channels in cardiac cells. In the present article, the influence on K+ channels of two other potassium channel openers chemically unrelated to cromakalim, RP 49356 and pinacidil, has been investigated in patch-clamped isolated cardiac myocytes. In the whole-cell configuration, K+ currents were recorded in the presence of 50 microM TTX and 3 microM nitrendipine or 3 mM cobalt. Like cromakalim, RP 49356 or pinacidil activated a time-independent outward current at 33-35 degrees C but not at 19-21 degrees C, which showed little voltage-dependency in the potential range -60 to +60 mV. Its amplitude was a function of the agonist concentration, e.g. it was 2.1 +/- 0.4 nA at +60 mV with 30 microM RP 49356 and 4.3 +/- 0.8 nA with 300 microM. In control conditions, glibenclamide, a blocker of K+-ATP channels in pancreatic and heart cells, affected neither the inward rectifier, iK1, nor the delayed K+ current, iK. At 3 microM, glibenclamide fully prevented the effects of 300 microM RP 49356 or pinacidil. At lower concentrations, glibenclamide partially counteracted the activation by PCOs of a K+ current. In the cell-attached configuration, externally applied RP 49356 or pinacidil caused opening of large channels which reversed around O mV in a high K+ external medium. In inside-out patches, both RP 49356 or pinacidil activated K+-ATP channels by increasing the time period for which the channels remained in the open state. It is concluded that, like cromakalim, RP 49356 and pinacidil are potent activators of K+-ATP channels in cardiac myocytes.