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Ketamine and Etomidate Down-regulate the Hypothalamic-Pituitary-Adrenal Axis in an Endotoxemic Mouse Model
Emmanuel Besnier1, Thomas Clavier, Marie-Christine Tonon
1From the Department of Anesthesia and Critical Care (E.B., T.C., J.S., A.L.-S., B.D., V.C.) and the Medical Critical Care Unit (F.T.), Normandy University, UNIROUEN (Rouen University), Rouen University Hospital, Rouen, France; Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Normandy University, UNIROUEN, INSERM (Institut National de la Santé Et de la Recherche Médicale) U982, Rouen, France (E.B., T.C., M.-C.T., A.L.-S., F.M., H.C., V.C.); Institute for Research and Innovation in Biomedicine, Rouen, France (E.B., T.C., M.-C.T., J.S., A.L.-S., F.M., F.T., H.C., V.C.); and the Department of Pharmacology, Normandy University, UNIROUEN, INSERM U1096, Rouen, France (J.S., F.T.).
Background:
We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis.
Methods:
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).
Results:
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.
Conclusions:
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.
