TY - JOUR
T1 - 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 β3 subunit
AU - Liao, Mark
AU - Sonner, James M.
AU - Husain, S. Shaukat
AU - Miller, Keith W.
AU - Jurd, Rachel
AU - Rudolph, Uwe
AU - Eger, Edmond I.
PY - 2005/7
Y1 - 2005/7
N2 - 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 β3 subunit point mutation in GABAA 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 β3 subunit of the GABAA 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.
AB - 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 β3 subunit point mutation in GABAA 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 β3 subunit of the GABAA 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.
UR - http://www.scopus.com/inward/record.url?scp=20744432156&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20744432156&partnerID=8YFLogxK
U2 - 10.1213/01.ANE.0000153011.64764.6F
DO - 10.1213/01.ANE.0000153011.64764.6F
M3 - Article
C2 - 15976219
AN - SCOPUS:20744432156
SN - 0003-2999
VL - 101
SP - 131
EP - 135
JO - Anesthesia and Analgesia
JF - Anesthesia and Analgesia
IS - 1
ER -