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ANESTHETIC PHARMACOLOGY

The Interaction of Isoflurane and Protein Kinase C-Activators on Sarcolemmal K_ATP Channels

Lawrence A. Turner, MD^*, Kazuhiro Fujimoto, MD, PhD^*, Akihiro Suzuki, MD^*, Anna Stadnicka, PhD^*, Zeljko J. Bosnjak, PhD^*, and Wai-Meng Kwok, PhD^*

Departments of *Anesthesiology, Physiology, and Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee

Address correspondence and reprint requests to Lawrence A. Turner, MD, Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Address e-mail to laturner{at}mcw.edu.

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 0.05) sarcolemmal K_ATP channel currents (I_KATP) 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 I_KATP by a second brief isoflurane exposure under these conditions. A diacylglycerol PKC activator applied via the pipette elicited concentration-related activation of I_KATP. The diacylglycerol alone (0.5 µM) 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 0.01) I_KATP, averaging 40 ± 9 pA/pF (10 cells), with an onset 48 ± 2 min after anesthetic pretreatment. Facilitation of I_KATP by isoflurane during the reduction of intracellular ATP is dependent on PKC, whereas "preconditioning" myocytes with isoflurane causes persistent changes in sarcolemmal K_ATP channel function, which enhance the induction of I_KATP by a diacylglycerol.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999