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ANESTHETIC PHARMACOLOGY

Modulation of Noninactivating K⁺ Channels in Rat Cerebellar Granule Neurons by Halothane, Isoflurane, and Sevoflurane

Department of Anesthesia and Perioperative Care, University of California, San Francisco, California

Address correspondence and reprint requests to Bruce Winegar, Pherin Pharmaceuticals, 350 N. Bernardo Ave., Mountain View, CA 94043-5207. Address e-mail to bwinegar{at}pherin.com

Neuronal baseline K⁺ channels were activated by several volatile anesthetics. Whole-cell recordings from cultured cerebellar granule neurons of 7-day-old male Sprague-Dawley rats showed outward-rectifying K⁺ currents with a conductance of 1.1 ± 0.3 nS (n = 20) at positive potentials. The channel activity was noninactivating, exhibited no voltage gating, and was insensitive to conventional K⁺ channel blockers. Clinically relevant concentrations of halothane (112, 224, 336, and 448 µM) dissolved in Ringer’s solution increased outward currents by 29%, 50%, 63%, and 94%, respectively (n = 5; P < 0.05; analysis of variance [ANOVA]). Similar increases in currents were produced by isoflurane (274, 411, 548, and 822 µM), which increased outward currents by 22%, 47%, 52%, and 60%, respectively (n = 5; P < 0.05; ANOVA). Sevoflurane 518 µM increased outward currents by 225% (n = 10; P < 0.05; ANOVA). In all experiments, channel activity quickly returned to baseline levels during wash. The outward-rectifying whole-cell current-voltage curves were consistent with the properties of anesthetic-sensitive KCNK channels. These results support the idea that noninactivating baseline K⁺ channels are important target sites of volatile general anesthetics.

IMPLICATIONS: The volatile anesthetics halothane, isoflurane, and sevoflurane, reversibly enhanced a noninactivating outwardly rectifying K⁺ current in rat cerebellar granule neurons. These findings support a model of anesthesia that includes a site of action at baseline K⁺ channels.

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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