R (+) etomidate and the photoactivable R (+) azietomidate have comparable anesthetic activity in wild-type mice and comparably decreased activity in mice with a N265M point mutation in the gamma-aminobutyric acid receptor beta3 subunit.
A photoactivable diazirine derivative of etomidate, azietomidate, shares many actions of etomidate, including a capacity to abolish the righting reflexes in tadpoles and enhance gamma-aminobutyric acid (GABA)-induced currents. Azietomidate's usefulness in studies of mechanisms of anesthesia depends on the assumption that it shares a site of action with etomidate. Mice bearing an N265M beta3 subunit point mutation in GABA(A) receptors have a markedly decreased sensitivity to loss of righting reflexes induced by etomidate over a range of doses. Accordingly, in the present study we measured the time to recovery of righting reflexes of wild type and mutant mice as a function of dose given as an IV bolus. Analysis of the data for azietomidate yielded mean times to recovery of righting reflexes at a dose of 7.5 mg/kg of 10.0 +/- 0.9 min and 3.0 +/- 1.6 min for wild type and mutant mice, respectively (mean +/- sd). A similar analysis for etomidate yielded mean times to recovery of righting reflexes at a dose of 7.5 mg/kg of 12.0 +/- 1.3 min and 4.0 +/- 0.7 min for wild type and mutant mice respectively. Thus, at this dose a single mutation, N265M on the beta3 subunit of the GABA(A) receptor, approximately halved the time to recovery of righting reflexes for both etomidate and azietomidate (by 7.6 +/- 1.5 min and 7.2 +/- 1.8 min, respectively), emphasizing the contribution of this residue as a determinant of a behavioral response of azietomidate in mice.
Liao
Mark
M
Department of Anesthesia and Perioperative Care, S-455, University of California, San Francisco, CA 94143-0464, USA.
Sonner
James M
JM
Husain
S Shaukat
SS
Miller
Keith W
KW
Jurd
Rachel
R
Rudolph
Uwe
U
Eger
Edmond I
EI
D018686:Anesthetics, Intravenous / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D010777:Photochemistry; D017354:Point Mutation; D011963:Receptors, GABA-A / Q000235:genetics*; D013237:Stereoisomerism
D018686:Anesthetics, Intravenous; C546270:Gabrb3 protein, mouse; D011963:Receptors, GABA-A; C473483:azietomidate; D005045:Etomidate