Distinct molecular targets for the central respiratory and cardiac actions of the general anesthetics etomidate and propofol

General anesthetics are among the most widely used and important therapeutic agents. The molecular targets mediating different endpoints of the anesthetic state in vivo are currently largely unknown. The analysis of mice carrying point mutations in neurotransmitter receptor subunits is a powerful tool to assess the contribution of the respective receptor subtype to the pharmacological actions of clinically used general anesthetics. We examined the involvement of beta 3-containing GABA(A) receptors in the respiratory, cardiovascular, hypothermic, and sedative actions of etomidate and propofol using beta 3(N265M) knock-in mice carrying etomidate- and propofol-insensitive beta 3-containing GABA(A) receptors. Although the respiratory depressant action of etomidate and propofol, as determined by blood gas analysis, was almost absent in beta 3(N265M) mice, the cardiac depressant and hypothermic effects, as determined by radiotelemetry, and the sedative effect, as determined by decrease of motor activity, were still present. Taken together with previous findings, our results show that both immobilization and respiratory depression are mediated by beta 3-containing GABA(A) receptors, hypnosis by both beta 3 and beta 2-containing GABA(A) receptors, while the hypothermic, cardiac depressant, and sedative actions are largely independent of beta 3-containing GABA(A) receptors.