Modulation of ATP-sensitive K⁺ channel activity and contractile behavior in mammalian ventricle by the potassium channel openers cromakalim and RP49356

We have investigated the effects of potassium channel opening drugs on the ATP-dependence of ATP-sensitive K⁺ channel activity and on the contractile activity in rat and guinea pig ventricular myocytes. The results show that cromakalim (BRL34915), and RP49356, agents reported to open ATP-sensitive K⁺ channels, do so by shifting the intracellular [ATP] required to cause half-maximal inhibition of channel activity (k(i)) to higher [ATP]. In guinea pig ventricular myocytes at 37°C, the k(i) was shifted from 79 to 152 μM by 40 μM cromakalim and, in rat myocytes at room temperature, the k(i) was also shifted to higher [ATP] by 50 μM R49356. The effect of externally applied RP49356 on the contractile activity of intact rat ventricular myocytes was investigated. At 100 μM the drug was without effect in the presence of normal bathing solution containing 10 mM glucose. When glucose in the bathing medium had been replaced by 2-deoxyglucose for 84 ± 2 min, 100 μM RP49356 decreased the twitch amplitude to 23 ± 4% of control. The negative inotropic effect of 100 μM RP49356 increased with time after perfusion with 2-deoxyglucose, and the negative inotropic effect diminished on reperfusing with glucose; 83 ± 3 min after reperfusing with glucose, twitch amplitude was decreased by only 52 ± 6% on exposure to 100 μM RP49356. These results suggest that the effect of the potassium channel opening drugs on contractility and electrical behavior will depend critically on the intracellular [ATP]. The results provide an explanation of how potassium channel openers may become clinically useful as cardioprotective agents without interfering with normal function.