Etomidate elevates intracellular calcium levels and promotes catecholamine secretion in bovine chromaffin cells.
Etomidate, an intravenous imidazole general anaesthetic, is thought to produce anaesthesia by modulating or activating ionotropic Cl(-)-permeable GABA(A) receptors. Chromaffin cells are known to express functional GABA(A) receptors with properties similar to their neuronal counterparts. We have shown that activation of the GABA(A) receptors, with specific GABA(A) agonists, leads to cellular excitation. Our goal was to determine whether etomidate mimicked this response and to explore the functional consequences of this activation. Imaging experiments with the Ca(2+)-indicator dye fura-2 were used to assay [Ca(2+)](i). Bovine adrenal chromaffin cells were superfused with a variety of GABA(A)-selective drugs to determine their effects on [Ca(2+)](i). Amperometric measurements were used to assay catecholamine release in real-time. We show that bovine adrenal chromaffin cells were excited by etomidate at clinically relevant concentrations. Etomidate directly activated GABA(A) receptors found in chromaffin cells thereby elevating [Ca(2+)](i). The effects of etomidate were mimicked by the specific GABA(A) agonist muscimol and blocked by the specific antagonist bicuculline. Our data show that low concentrations of etomidate modulated GABA(A) receptor activation by muscimol. Blockade of voltage-dependent Ca(2+) channels prevented the elevation of [Ca(2+)](i) by GABA. Application of etomidate directly to the chromaffin cells elicited robust catecholamine secretion from these cells. The data indicate that clinically relevant concentrations of etomidate can directly activate GABA(A) receptors, which, due to the positive anion equilibrium potential, depolarizes chromaffin cells. This depolarization activates voltage-dependent Ca(2+) channels thereby stimulating catecholamine release. Our data suggest that circulating catecholamine levels may be elevated after etomidate application.
University of Chicago, Department of Anesthesia and Critical Care, 5841 S. Maryland, MC 4028, Chicago, IL 60637, USA. jxie@airway.bsd.uchicago.edu
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism
D002395:Catecholamines; D002118:Calcium; D005045:Etomidate