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Molecular Pharmacology, Vol 14, 950-959, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Pressure Resolves Two Sites of Action of Inert Gases

KEITH W. MILLER 1, MICHAEL W. WILSON 1, and RAYMOND A. SMITH 1

1 Departments of Pharmacology and Anaesthesia, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114

The effect of pressure upon the potency of two pharmacological effects of inert gases has been studied in mice. In one series of experiments the effect of high pressures of helium on the anesthetic potency of nitrogen, argon, nitrous oxide, carbon tetrafluoride and sulfur hexafluoride was studied up to pressures of 183 atm. Pressure increased the ED50 for loss of righting reflexes by 36% at 100 atm on average. In the other experiments we measured the ability of these inert gases to raise the ED50 pressure at which pressure-induced hyperexcitability (spasms) was observed. Subanesthetic partial pressures of all the gases raised the ED50 pressure for spasms significantly. These data were used to test the two hypotheses that anesthesia results when anesthetics expand some hydrophobic phase by a critical amount, while the hyperexcitabiity occurs when pressure reduces the volume of some hydrophobic phase by a critical amount (the critical volume hypothesis). Theoretical calculations show that both sets of data are consistent with their respective hypotheses. The site at which the inert gases exert their anti-hyperexcitabiity effect is much more compressible and has a slightly lower solubility parameter than the site for anesthesia.

Submitted on January 27, 1978
Accepted on April 14, 1978




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