The shivering threshold in rabbits with JM-1232(-), a new benzodiazepine receptor agonist.
BACKGROUND
JM-1232(-) is a novel isoindoline derivative which shows sedative and hypnotic activities through the benzodiazepine site of gamma-aminobutyric acid type A (GABAA) receptors. Typical doses of midazolam, another GABAA receptor agonist, slightly reduce the shivering threshold in humans. We thus determined the extent to which JM-1232(-) decreases the shivering threshold.


METHODS
Eighteen rabbits, lightly anesthetized with isoflurane 0.2 minimum alveolar anesthetic concentration (MAC), were randomly assigned to infusions of 1) saline (control), 2) 0.01 mg x kg(-1) x min(-1) JM-1232(-), or 3) 0.1 mg x kg(-1) x min(-1) JM-1232(-). Body temperature was reduced at a rate of 2-3 degrees C/h by perfusing water at 10 degrees C though a U-shaped plastic tube positioned in the colon. Cooling continued until shivering was observed by an investigator blinded to treatment, or until core temperature reached 34 degrees C. Core temperatures were recorded from the distal esophagus, and core temperature at the onset of shivering defined the threshold. Data were analyzed by one-way analysis of variance with Student-Newman-Keuls tests. Results are presented as means +/- SD; P < 0.05 was considered statistically significant.


RESULTS
The rabbits given a saline infusion shivered at 36.5 +/- 0.3 degrees C. Five of the six rabbits given JM-1232(-) at a rate of 0.01 mg x kg(-1) x min(-1) shivered at 35.7 +/- 0.8 degrees C, and one of these rabbits failed to shiver at 34.0 degrees C. None of the rabbits given JM-1232(-) at a rate of 0.1 mg x kg(-1) x min(-1) shivered before reaching the 34.0 degrees C cutoff temperature.


CONCLUSIONS
A low dose of JM-1232(-) reduced the shivering threshold in rabbits approximately 0.8 degrees C which is similar to the effects in humans given premedication doses of midazolam. In contrast, a 10-fold larger dose reduced the threshold more than 2.5 degrees C. This is a substantial decrement and might facilitate induction of therapeutic hypothermia.
Operating Theatre, Yamanashi University Hospital, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. ezn00202@nifty.ne.jp
Taishi
T
Masamune
Hiroaki
H
Sato
Katsumi
K
Okuyama
Yusuke
Y
Imai
Hironobu
H
Iwashita
Tadahiko
T
Ishiyama
Takeshi
T
Oguchi
Daniel I
DI
Sessler
Takashi
T
Matsukawa
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D054833:Isoindoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D011897:Random Allocation; D011963:Receptors, GABA-A / Q000502:physiology; D012768:Shivering / Q000187:drug effects* / Q000502:physiology
C534223:3-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-2-phenyl-3,5,6,7-tetrahydrocyclopenta(f)isoindol-1(2H)-one; D058785:GABA-A Receptor Agonists; D054833:Isoindoles; D010879:Piperazines; D011963:Receptors, GABA-A