The interaction of isoflurane and protein kinase C-activators on sarcolemmal KATP channels.
Protein kinase C (PKC)-dependent signaling pathways may be involved in the "memory" effect of anesthetic and ischemic preconditioning, which facilitates activation of cardioprotective adenosine triphosphate (ATP)-sensitive potassium channels during later ischemic challenge and ATP depletion. Using patch-clamp techniques, we found that exposure of isolated guinea pig cardiomyocytes to 1 mM of isoflurane after phorbol ester stimulation of PKC facilitates the induction of larger (P < or = 0.05) sarcolemmal K(ATP) channel currents (IKATP) during cell dialysis with 0.5, compared to 1.0, mM of ATP in the pipette (10 +/- 5 versus 2 +/- 1 pA/pF in five and six cells, respectively). A PKC inhibitor, bisindolylmaleimide, abolished the induction of IKATP by a second brief isoflurane exposure under these conditions. A diacylglycerol PKC activator applied via the pipette elicited concentration-related activation of IKATP. The diacylglycerol alone (0.5 microM) elicited I(KATP), averaging 5 +/- 3 pA/pF in nine cells. Briefly treating myocytes on the microscope stage with isoflurane, followed by washout and patching with the same diacylglycerol solution, elicited larger (P < or = 0.01) IKATP, averaging 40 +/- 9 pA/pF (10 cells), with an onset 48 +/- 2 min after anesthetic pretreatment. Facilitation of IKATP by isoflurane during the reduction of intracellular ATP is dependent on PKC, whereas "preconditioning" myocytes with isoflurane causes persistent changes in sarcolemmal KATP channel function, which enhance the induction of IKATP by a diacylglycerol.
Turner
Lawrence A
LA
Departments of *Anesthesiology, †Physiology, and ‡Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee.
Fujimoto
Kazuhiro
K
Suzuki
Akihiro
A
Stadnicka
Anna
A
Bosnjak
Zeljko J
ZJ
Kwok
Wai-Meng
WM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D053119:Benzophenanthridines; D003956:Dialysis; D004075:Diglycerides / Q000494:pharmacology; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D015221:Potassium Channels; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D018685:Anesthetics, Inhalation; D053119:Benzophenanthridines; D004075:Diglycerides; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008565:Membrane Proteins; D010617:Phenanthridines; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate; D007530:Isoflurane; C016299:chelerythrine; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D013755:Tetradecanoylphorbol Acetate