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

Abstract

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 μM TTX and 3 μM nitrendipine or 3 mM cobalt. Like cromakalim, RP 49356 or pinacidil activated a time-independent outward current at 33–35°C but not at 19–21°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 μM RP 49356 and 4.3±0.8 nA with 300 μM. In control conditions, glibenclamide, a blocker of K⁺-ATP channels in pancreatic and heart cells, affected neither the inward rectifier,i _K1, nor the delayed K⁺ current,i _K. At 3 μM, glibenclamide fully prevented the effects of 300 μM RP 49356 or pinacidil. At lower concentrations, glibenclamide partially counteracted the activation by PCOs of a K⁺ current. In the cell-attached contiguration, externally applied RP 49356 or pinacidil caused opening of large channels which reversed around 0 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.