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ANESTHETIC PHARMACOLOGY

A Neurosteroid Anesthetic, Alphaxalone, Inhibits Nicotinic Acetylcholine Receptors in Cultured Bovine Adrenal Chromaffin Cells

Munehiro Shiraishi, MD^*, Izumi Shibuya, PhD, Kouichiro Minami, MD PhD^*, Yasuhito Uezono, MD PhD, Takashi Okamoto, MD^*, Nobuyuki Yanagihara, PhD, Susumu Ueno, MD PhD, Yoichi Ueta, MD PhD, and Akio Shigematsu, MD PhD^*

Departments of *Anesthesiology, Physiology, and Pharmacology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu; and Department of Second Pharmacology, Nagasaki University, School of Medicine, Nagasaki, Japan

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

Several lines of evidence suggest that nicotinic acetylcholine receptors (nAChRs) are a target of general anesthetics. Alphaxalone (5-pregnan-3-ol-11, 20-dion) is a neurosteroid, which was used clinically for anesthesia, but its effects on the function of nAChRs have not been well investigated. We examined the effects of alphaxalone on nAChRs in cultured bovine adrenal chromaffin cells. We studied the effects of alphaxalone on nicotine-induced increases in the cytosolic Ca²⁺ concentration ([Ca²⁺]_i) and on membrane currents using Ca²⁺-imaging and whole-cell patch-clamp techniques, respectively, in these cells. We also examined the effects of alphaxalone on -aminobutyric acid A receptors in the same cells and compared them with the effects on nAChRs. Alphaxalone (0.1–100 µM) inhibited nicotine-induced [Ca²⁺]_i increases in a concentration-dependent manner. Alphaxalone inhibited high K⁺-induced [Ca²⁺]_i increases, but the inhibition was observed only at 100 µM. In voltage-clamp experiments using negative holding potentials, alphaxalone (0.1–100 µM) itself induced inward currents, which were abolished by the -aminobutyric acid A receptor antagonist picrotoxin. Alphaxalone also inhibited nicotine-induced inward currents, and the inhibition was unaffected by picrotoxin. We conclude that alphaxalone, at anesthetic concentrations, inhibits nAChRs in adrenal chromaffin cells. Alphaxalone may affect the sympathetic and other nervous systems via inhibition of nAChRs.

IMPLICATIONS: Alphaxalone inhibits the function of nAChRs at clinically relevant concentrations in adrenal chromaffin cells. Thus, the present findings may provide some information for understanding the anesthetic mechanism of alphaxalone.

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