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 (K(ATP)) channels. The evidence is based largely on the ability of certain K(ATP) channel modulators to modify the protection in the various models of preconditioning. This study has investigated how two K(ATP) channel 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 (50 micromol/l) increased K(ATP) current approximately four-fold in isolated cardiomyocytes. This increase reversed rapidly after treatment with the K(ATP) channel blocker glibenclamide (200 nmol/l). After simulated ischemia, pinacidil protected cardiomyocytes (the area under cell-death curve was 29.5 +/- 1.1% x h) which was significantly less than that in control (46.9 +/- 2.0% x h). The protection from pinacidil could be completely eliminated by pretreatment with 10 microM glibenclamide (46.9 +/- 2.0% x h). In contrast, nicorandil (1 mmol/l), which opens K(ATP) channels in some tissues, caused no detectable effect on the K(ATP) current. Similarly, nicorandil did not produce cardioprotection. These results indicate that pinacidil and nicorandil have very different effects on rabbit cardiomyocyte K(ATP) channels. Furthermore, because protection correlated with the ability of the agent to open the channel, they support a role for K(ATP) channels in preconditioning.
Critz
S D
SD
Department of Structural and Cellular Biology, University of South Alabama, Mobile 36688, USA.
Liu
G S
GS
Chujo
M
M
Downey
J M
JM
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000517:prevention & control*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D020110:Pinacidil; D015221:Potassium Channels / Q000819:agonists*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology
D006146:Guanidines; D015221:Potassium Channels; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D020110:Pinacidil; D000255:Adenosine Triphosphate