An Etomidate Analogue With Less Adrenocortical Suppression, Stable Hemodynamics, and Improved Behavioral Recovery in Rats

BACKGROUND: ET-26 hydrochloride (ET-26HCl) is a novel etomidate analogue designed to alleviate the adrenocortical suppression caused by etomidate while retaining the rapid sedative-hypnotic onset and stable hemodynamic features of etomidate. This study compared the anesthetic effect, hemodynamic stability, and recovery profiles of ET-26HCl, etomidate, and the sedative-hypnotic drug propofol in rats. METHODS: The metabolic half-life of ET-26HCl was determined in vitro using high performance liquid chromatography analysis of samples of rat plasma and liver homogenates taken from 3 animals. Hypnotic median effective doses (HD 50 ) of ET-26HCl, etomidate, and propofol were determined by up-and-down methods. Anesthesia effect and mean arterial pressure were estimated using equivalent intravenous (IV) doses of propofol, etomidate, and ET-26HCl in the rats. Serum concentrations of corticosterone were analyzed by enzyme-linked immunosorbent assay. The ability of rats to recover from the sedative-hypnotic effects of the drugs was evaluated using open field and Morris water maze tests at equipotent doses of propofol, etomidate, ET-26HCl, and normal saline. RESULTS: The metabolic half-life of ET-26HCl was 81 ± 6 minutes in rat plasma and 126 ± 12 minutes in incubation liver homogenate (mean ± standard deviation), respectively. In vivo experiments showed that the potency of ET-26HCl to cause a loss of righting reflex in rats was 3 times lower than that of etomidate in the rats. IV propofol caused a greater decrease in mean arterial pressure relative to the baseline (−27.9 mm Hg) than did ET-26HCl (−10.7 mm Hg) and etomidate (−19.4 mm Hg) at equipotent doses. Serum corticosterone levels after drug administration were significantly higher in the ET-26HCl group than in the etomidate group at equivalent doses when measured 15 ( P < .001), 30 ( P < .001), and 60 ( P = .002) minutes after stimulation with adrenocorticotropic hormone (ACTH 1–24 ). Recovery of spatial orientation from anesthesia induced by an IV bolus injection was faster with ET-26HCl than with propofol, but recovery of spontaneous activity was slower. CONCLUSIONS: ET-26HCl has anesthetic potency and hemodynamic stability similar to etomidate, but it caused less adrenocortical hormone synthesis suppression than etomidate and faster spatial orientation recovery from anesthesia than propofol, which was similar to etomidate.