Alphaxalone, a Neurosteroid Anesthetic, Inhibits Norepinephrine Transporter Function in Cultured Bovine Adrenal Medullary Cells

• Published in: Anesthesia and analgesia Vol. 95; no. 6; pp. 1661 - 1666
• Main Authors: Horishita, Takafumi, Minami, Kouichiro, Yanagihara, Nobuyuki, Shiraishi, Munehiro, Okamoto, Takashi, Shiga, Yousuke, Ueno, Susumu, Shigematsu, Akio
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD International Anesthesia Research Society 01.12.2002; Lippincott
• Subjects: Adrenal Medulla - cytology; Adrenal Medulla - drug effects; Anesthetics - pharmacology; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Blood Pressure - drug effects; Cattle; Cells, Cultured; Desipramine - metabolism; Medical sciences; Neuropharmacology; Norepinephrine - metabolism; Norepinephrine Plasma Membrane Transport Proteins; Pharmacology. Drug treatments; Pregnanediones - pharmacology; Symporters - drug effects; Symporters - physiology; Steroid; Alfaxalone; Cell culture; Bovine; Rat; Adrenal medulla; Rodentia; General anesthesia; Catecholamine; Sympathetic nervous system; In vitro; Conveyor; In vivo; Vertebrata; Mammalia; General anesthetic; Autonomic nervous system; Animal; Arterial pressure; Norepinephrine; Artiodactyla; Mechanism of action; Ungulata
• ISSN: 0003-2999; 1526-7598
• DOI: 10.1097/00000539-200212000-00034

We studied the effects of alphaxalone, a neurosteroid anesthetic, on norepinephrine transporter (NET) function in cultured bovine adrenal medullary cells and the effect of a bolus injection of alphaxalone on blood pressure and serum norepinephrine (NE) levels in anesthetized rats. Alphaxalone (10–100 μM) inhibited the desipramine-sensitive uptake of [H]-NE by bovine adrenal medullary cells in a concentration-dependent manner. Eadie-Hofstee analysis of [H]-NE uptake showed that alphaxalone increased the apparent Michaelis constant without altering the maximal velocity, indicating that inhibition occurred via competition for the NET. Alphaxalone inhibited the specific binding of [H]-desipramine to plasma membranes isolated from bovine adrenal medulla. Scatchard analysis of [H]-desipramine binding revealed that alphaxalone increased the apparent dissociation constant for binding without altering maximal binding, indicating competitive inhibition. Bolus IV administration of alphaxalone had little effect on blood pressure but slightly, and significantly, increased the serum NE levels in anesthetized rats. These findings suggest that alphaxalone competitively inhibits NET function by interfering with both desipramine binding and NE recognition on the NET in adrenal medullary cells and probably in sympathetic neurons.