The anesthetic effects of etomidate: species-specific interaction with alpha 2-adrenoceptors.

Abstract

The IV anesthetic, etomidate, has structural and clinical similarities to specific alpha2-adrenoceptor agonists such as dexmedetomidine. We investigated whether the sedative effects of etomidate may be mediated by alpha2-adrenoceptors. The anesthetic potency of etomidate (1-20 microM) was determined in Xenopus laevis tadpoles in the absence and presence of the specific alpha2-adrenoceptor antagonist atipamezole (10 microM). Anesthesia was defined as loss of righting reflex. Nonlinear logistic regression curves were fitted to the data and half-maximal effective concentrations and the slopes of the curves were calculated. Additionally, sedative/ hypnotic effects of etomidate (8 mg/kg IP) were studied by rotarod test in wild-type (WT) mice and mice carrying targeted deletions of the alpha2A-adrenoceptor gene (alpha2A-KO). Data are presented as mean +/- sem. The fraction of anesthetized tadpoles increased with increasing concentrations of etomidate. Atipamezole significantly increased the half-maximal effective concentration of etomidate (4.5 +/- 0.2 microM; slope: 2.6 +/- 0.3) to 8.4 +/- 0.4 microM (slope: 2.3 +/- 0.3). Etomidate resulted in time-dependent sedative effects in all mice, as assessed by rotarod performance. In WT mice, the sedative effects of etomidate were not decreased by atipamezole (2 mg/kg). Consistently, etomidate-induced sedation was not reduced in alpha2A-KO animals compared with WT mice. The sedative effects of etomidate exhibit a species-specific interaction with alpha2-adrenoceptors. Although the decrease in potency of etomidate by atipamezole may be caused by an interaction with alpha2-adrenoceptors in X. laevis tadpoles, results in mice indicate that the hypnotic effect of etomidate does not require alpha2-adrenoceptors.