Effects of Dexmedetomidine, a Novel Imidazole Sedative-Anesthetic Agent, on Adrenal Steroidogenesis

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Abstract
Inhibition of steroidogenesis may be produced perioperatively by imidazole compounds, such as the hypnotic agent etomidate, with potentially serious consequences for patient morbidity and mortality. Dexmedetomidine, ({+}4−[l−{2,3-dimethylphenyl}-ethyl]-1H-imidazole), another imidazole compound with anestheticlike properties, is now being used perioperatively. Therefore, we investigated the effects of dexmedetomidine on steroidogenesis as well as on binding to glucocorticoid receptors in a series of in vitro and in vivo animal studies. The effect of dexmedetomidine, 10minus;8−10minus;3 M, on adrenocorticotrophic hormone (ACTH) stimulated release of corticosterone was assessed in isolated rat adrenal cells. To characterize dexmedetomidine interactions with the glucocorticoid receptor, dexmedetomidine's ability to compete for [3H]dexmethasone binding sites was studied in renal tubular cells. The effect of dexmedetomidine, 80 μg/kg subcutaneously, on ACTH-stimulated release of cortisol was studied in separate cohorts of dogs at various time intervals during and after anesthesia was given. To compare the inhibitory effects of etomidate and dexmedetomidine on steroidogenesis, ACTH-stimulated release of cortisol was studied in dogs treated with anesthetic doses of either dexmedetomidine (80 μg/kg IV) or etomidate (1 mg/kg IV). Finally, dogs were given dexmedetomidine by continuous subcutaneous infusion for 7 days at sedative doses after which their cortisol response to ACTH was determined. At dexmedetomidine concentrations greater than 10minus;7 M, a dose-dependent inhibition of corticosterone release was detected in response to ACTH stimulation in vitro. At these high dexmedetomidine concentrations, [3H]dexamethasone binding was not affected. In the in vivo dog experiments, basal cortisol levels decreased and the cortisol response to ACTH was blunted 3 h after dexmedetomidine administration. Continuously administered dexmedetomidine did result in decreased cortisol response to ACTH stimulation but was less than that observed after a single equianesthetic dose of etomidate. The authors conclude that dexmedetomidine inhibits steroid biosynthesis only in high concentrations. In the concentrations designed to provide either acute anesthesia or chronic sedation, dexmedetomidine does not cause the potent inhibitory effect on steroidogenesis seen after etomidate use. As this imidazole α2-adrenergic agonist is highly efficacious as a sedative/hypnotic agent in the low nanomolar range, an important biologic effect on steroidogenesis probably will not occur clinically.

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