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In this study I attempted to elucidate the depressant effects of volatile anesthetics on inositol trisphosphate (IP3)-mediated signal transduction pathway and to identify the site of action. For this purpose, we used Xenopus laevis oocytes which translated and expressed 5-HT receptors after injection of mRNA isolated from the rat brain. In this system, binding of the agonist to G-protein coupled receptors activates phospholipase C that produces IP3. Mobilization of Ca2+ by IP3 from the storage finally opens Ca2+ dependent Cl- channels. Halothane, isoflurane and methoxyflurane depressed Cl- current elicited by 5-HT. For the further quantitative study, methoxyflurane was used because of its better solubility and less vapor pressure that avoided evaporation of the agent. The 5-HT elicited Cl- current was depressed in a non-competitive fashion. Response were 75, 60, 20% of control in the presence of 0.5, 1 and 3 mM methoxyflurane, respectively. Responses elicited by a pressure-injection of Ca2+ or IP3 remained unchanged in the presence of high concentrations of either halothane, isoflurane or methoxyflurane. These results suggest that the depressant mechanism by volatile anesthetics on the signal transduction pathway involves neither Ca2+ dependent Cl- channel dynamics nor intracellular Ca2+ mobilization by IP3. Changes of microdomain characteristics of the membrane in the presence of anesthetic molecules including membrane-bound proteins and enzyme system may be a main mechanism of action of volatile anesthetics.

To evaluate the effects of halothane on central nervous function, preganglionic sympathetic and vagal tones (ST, VT), ganglionic transmission and somato-sympathetic reflex potential (SSRP) were studied under different concentrations of halothane in 17 cats and 6 dogs. Compound action potentials of the cervical sympathetic trunk and the vagus nerve were recorded simultaneously and analyzed quantitatively. Relative ganglion-blocking potencies of halothane, enflurane and methoxyflurane were examined by recording evoked potentials from the postganglionic nerve of the stellate ganglion. SSRP was recorded from the cervical sympathetic trunk followed by stimulation of the ipsilateral radial nerve. Mean arterial pressure was kept constant at 100 mmHg to eliminate barostatic response. Halothane affected sympathetic and parasympathetic outflows and moderately blocked ganglionic transmission compared with other inhalational anesthetics and markedly diminished SSRP. ST and VT levels were almost equally depressed and attenuated to about 70, 60, 50 and 30% of the control level (N2O 75% in oxygen) with additional halothane concentrations of 0.5, 1.0, 1.5 and 2.0 MAC, respectively. The magnitude of SSRP was decreased to 68, 34, 24 and 13% with the similar concentrations of halothane, respectively. Halothane moderately depressed ganglionic transmission to about 70% and enflurane markedly decreased it to about 20% at anesthetic depth of 2 MAC, respectively. Methoxyflurane, however, did not depress ganglionic transmission at anesthetic depth of 4 MAC. It was demonstrated that halothane markedly depressed the sympathetic and vagal outflows from the nervous system without changing the balance between the central sympathetic and vagal tones, and decreased ganglionic transmission and somato-sympathetic reflex.