Pinacidil but not Nicorandil Opens ATP-sensitive K+Channels and Protects Against Simulated Ischemia in Rabbit Myocytes

It has been proposed that ischemic preconditioning involves the regulation of ATP-sensitive potassium (KATP) channels. The evidence is based largely on the ability of certain KATPchannel modulators to modify the protection in the various models of preconditioning. This study has investigated how two KATPchannel openers, pinacidil and nicorandil, affect both membrane currents and viability in isolated and ischemic rabbit cardiomyocytes. We used the whole-cell recording technique and in separate experiments viability was assessed by exposure to these drugs during ischemia. Pinacidil (50μmol/l) increased KATPcurrent approximately four-fold in isolated cardiomyocytes. This increase reversed rapidly after treatment with the KATPchannel blocker glibenclamide (200 nmol/l). After simulated ischemia, pinacidil protected cardiomyocytes (the area under cell-death curve was 29.5±1.1% • h) which was significantly less than that in control (46.9±2.0% • h). The protection from pinacidil could be completely eliminated by pretreatment with 10μ glibenclamide (46.9±2.0% • h). In contrast, nicorandil (1 mmol/l), which opens KATPchannels in some tissues, caused no detectable effect on the KATPcurrent. Similarly, nicorandil did not produce cardioprotection. These results indicate that pinacidil and nicorandil have very different effects on rabbit cardiomyocyte KATPchannels. Furthermore, because protection correlated with the ability of the agent to open the channel, they support a role for KATPchannels in preconditioning.