Ketamine and Etomidate Down-regulate the Hypothalamic-Pituitary-Adrenal Axis in an Endotoxemic Mouse Model.

Abstract

We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis. Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3β-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11β-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD). At 12 h, lipopolysaccharide induced an overexpression of corticotropin-releasing hormone (32 ± 5 vs. 18 ± 6, P < 0.01), proopiomelanocortin (21 ± 3 vs. 8 ± 0.9, P < 0.0001), P450 side-chain cleavage (32 ± 4 vs. 23 ± 10, P < 0.05), 21-hydroxylase (17 ± 5 vs. 12 ± 2, P < 0.05), and 11β-hydroxylase (11 ± 4 vs. 6 ± 0.5, P = 0.001), and an elevation of corticosterone (642 ± 165 vs. 98.3 ± 63 ng/ml, P < 0.0001). Etomidate and ketamine reduced P450 side-chain cleavage (19 ± 7 and 19 ± 3 vs. 32 ± 4, P < 0.01), 21-hydroxylase (8 ± 0.8 and 8 ± 1 vs. 17 ± 5, P < 0.001), 11β-hydroxylase (4 ± 0.5 and 7 ± 1 vs. 11 ± 4, P < 0.001 and P < 0.05), and corticosterone (413 ± 189 and 260 ± 161 vs. 642 ± 165 ng/ml, P < 0.05 and P < 0.01). Ketamine also inhibited adrenocorticotropin hormone production (2.5 ± 3.6 vs. 36 ± 15 pg/ml, P < 0.05). At 48 h, all four adrenal enzymes were down-regulated by lipopolysaccharide administration with corticosterone levels similar to the control group. Ketamine and etomidate did not modify corticosterone plasma levels. Our endotoxemic model induces an initial activation of the hypothalamic-pituitary-adrenal axis, followed by a secondary inhibition of adrenal steroidogenesis processes. Ketamine and etomidate inhibit the enzyme expression and activity of the adrenal gland at the early stage.