Paris Andrea, Philipp Melanie, Tonner Peter H, Steinfath Markus, Lohse Martin, Scholz Jens, Hein Lutz
Department of Anaesthesiology, University of Kiel, Kiel, Germany.
Anesthesiology. 2003 Oct;99(4):889-95. doi: 10.1097/00000542-200310000-00022.
The intravenous anesthetic etomidate exhibits structural similarities to specific alpha2-adrenoceptor agonists of the type such as dexmedetomidine. The current study was performed to elucidate the possible interaction of etomidate with alpha2-adrenoceptors in mice lacking individual alpha2-adrenoceptor subtypes (alpha2-KO).
Sedative and cardiovascular responses to etomidate and the alpha2-agonist, dexmedetomidine, were determined in mice deficient in alpha2-receptor subtypes. Inhibition of binding of the alpha2-receptor antagonist [3H]RX821002 to recombinant alpha2-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro.
In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha2A-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha2A-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 alpha2B-KO or alpha2AB-KO mice. In membranes from HEK293 cells transfected with alpha2-receptors, etomidate inhibited binding of the alpha2-antagonist, [3H]RX821002, with higher potency from alpha2B- and alpha2C-receptors than from alpha2A-receptors (Ki alpha2A 208 microm, alpha2B 26 microm, alpha2C 56 microm). In alpha2B-receptor-expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2.
These results indicate that etomidate acts as an agonist at alpha2-adrenoceptors, which appears in vivo primarily as an alpha2B-receptor-mediated increase in blood pressure. This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.
静脉麻醉药依托咪酯与右美托咪定等特定类型的α2肾上腺素能受体激动剂在结构上有相似之处。本研究旨在阐明依托咪酯与缺乏单个α2肾上腺素能受体亚型（α2-KO）的小鼠体内α2肾上腺素能受体之间可能存在的相互作用。
在缺乏α2受体亚型的小鼠中测定对依托咪酯和α2激动剂右美托咪定的镇静和心血管反应。在体外人胚肾（HEK293）细胞中测试依托咪酯对α2受体拮抗剂[3H]RX821002与重组α2受体结合的抑制作用。
在体内，野生型和α2A受体缺陷型小鼠腹腔注射依托咪酯后翻正反射的消失和恢复所需时间相似，表明依托咪酯在小鼠体内的催眠作用不需要α2A受体亚型。静脉注射依托咪酯导致野生型小鼠动脉血压短暂升高（持续时间2.4±0.2分钟）（升高17±3 mmHg）。依托咪酯对α2B-KO或α2AB-KO小鼠的血压无影响。在用α2受体转染的HEK293细胞膜中，依托咪酯抑制α2拮抗剂[3H]RX821002与α2B和α2C受体结合的效力高于α2A受体（Kiα2A为208微摩尔，α2B为26微摩尔，α2C为56微摩尔）。在表达α2B受体的HEK293细胞中，依托咪酯迅速增加细胞外信号调节激酶ERK1/2的磷酸化。
这些结果表明依托咪酯作为α2肾上腺素能受体的激动剂起作用，在体内主要表现为α2B受体介导的血压升高。依托咪酯的这种作用可能有助于依托咪酯诱导麻醉后患者的心血管稳定性。
