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ANESTHETIC PHARMACOLOGY

The Inhibitory Effects of Alphaxalone on M₁ and M₃ Muscarinic Receptors Expressed in Xenopus Oocytes

Munehiro Shiraishi, MD^*, Kouichiro Minami, MD PhD^*, Izumi Shibuya, PhD, Yasuhito Uezono, MD PhD, Junichi Ogata, MD^*, Takashi Okamoto, MD^*, Osamu Murasaki, MD PhD, Muneshige Kaibara, MD PhD, Yoichi Ueta, MD PhD, and Akio Shigematsu, MD PhD^*

Department of *Anesthesiology and Physiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu; and Department of Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, Japan

Address correspondence and reprint requests to Munehiro Shiraishi, MD, Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan. Address e-mail to mshira{at}med.uoeh-u.ac.jp

Alphaxalone is a neurosteroid anesthetic, but its mechanisms of action are not completely understood. Muscarinic receptors are involved in a variety of neuronal functions in the brain and autonomic nervous system, and much attention has been paid to them as targets of anesthetics. In this study, we investigated the effects of alphaxalone on M₁ and M₃ muscarinic receptors using the Xenopus oocyte expression system. Alphaxalone inhibited acetylcholine-induced currents in oocytes expressing M₁ receptors at clinically relevant concentrations. Alphaxalone also suppressed acetylcholine-induced currents in oocytes expressing M₃ receptors. The half-maximal inhibitory concentration values for the inhibition of M₁- and M₃-mediated currents were 1.8 ± 0.6 µM and 5.3 ± 1.0 µM, respectively. GF109203X, a selective protein kinase C inhibitor, had little effect on the inhibition of acetylcholine-induced currents by alphaxalone in oocytes expressing these receptors. Alphaxalone inhibited the specific binding of [³H]quinuclidinyl benzilate to oocytes expressing M₁ or M₃ receptors. These findings suggest that alphaxalone at clinically relevant concentrations inhibits the function of M₁ and M₃ receptors through a protein kinase C-independent mechanism by interfering with the [³H]quinuclidinyl benzilate binding sites on the receptors.

IMPLICATIONS: Alphaxalone, a neurosteroid anesthetic, inhibited the function of muscarinic M₁ and M₃ receptors and the specific binding of [³H]quinuclidinyl benzilate ([³H]QNB) to oocytes expressing these receptors. These findings suggest that alphaxalone inhibits these receptors by interfering with the QNB binding sites.

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