Activation of α2B-adrenoceptors mediates the cardiovascular effects of etomidate

Background: The intravenous anesthetic etomidate exhibits structural similarities to specific alpha(2)-adrenoceptor agonists of the type such as dexmedetomidine. The current study was performed to elucidate the possible interaction of etomidate with alpha(2)-adrenoceptors in mice lacking individual alpha(2)-adrenoceptor subtypes (alpha(2)-KO). Methods: Sedative and cardiovascular responses to etomidate and the alpha(2)-agonist, dexmedetomidine, were determined in mice deficient in alpha(2)-receptor subtypes. inhibition of binding of the alpha(2)-receptor antagonist [H-3]RX821002 to recombinant alpha(2)-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro. Results: In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha(2A)-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha(2A)-receptor subtype. intravenous injection of etomidate resulted in a transient increase (duration 2.4 +/- 0.2 min) in arterial blood pressure in wild-type mice (17 +/- 3 mmHg). Etomidate did not affect blood pressure in alpha(2B)-KO or alpha(2AB)-KO mice. in membranes from HEK293 cells transfected with alpha(2)-receptors, etomidate inhibited binding of the alpha(2)-antagonist, [H-3]RX821002, with higher potency from alpha(2B)- and alpha(2C)-receptors than from alpha(2A)-receptors (K-i alpha(2A) 208 mum, alpha(2B) 26 muM, alpha(2C) 56 muM). In alpha(2B)-receptor-expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2. Conclusions: These results indicate that etomidate acts as an agonist at a2-adrenoceptors, which appears in vivo primarily as an alpha(2B)-receptor-mediated increase in blood pressure. This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.