Effect of beta-carboline-3-carboxoylate-t-butyl ester on ventilatory control.
beta-carboline-3-carboxylate-t-butyl ester (beta CCT) is the most selective antagonist for the alpha 1 beta 2 gamma 2 benzodiazepine (BZ) receptor subtype which blocks anticonvulsant and antipunishment (anxiolytic) but not sedative and myorelaxant effects of diazepam. We sought to determine whether the alpha 1 beta 2 gamma 2 BZ receptor subtype modulates ventilation and whether beta CCT antagonizes respiratory depressant effects of BZ's. Room air (RA) ventilation and the ventilatory response to 6% & 12% CO2 were non-invasively assessed by barometric plethysmography in 30 gm mice, n = 11. Plethysmograph signal amplitude (AMP), respiratory rate (RR) and minute ventilatory effort (MVE = AMP*RR), were measured. Runs were performed pre-drug & after IP injection of saline, vehicle for beta CCT, beta CCT (60mg/kg), midazolam (10mg/kg), and midazolam followed by beta CCT. Compared with pre-drug value, midazolam depressed MVE during RA and CO2 stimulation (% of pre-drug value: RA:57.7 +/- 17.4%, 6% CO2:53.73 +/- 14.3%, 12% CO2:69.1 +/- 26.1%, p < .0001, ANOVA). Subsequent beta CCT partially reversed this depression during RA conditions (72.8 +/- 25.7% of pre-drug value, p < .03 compared with midazolam) and 6% CO2 stimulation (67.1 +/- 10.7% of pre-drug value, p < .006 compared with midazolam) but not with 12% CO2. Thus, the alpha 1 beta 2 gamma 2 BZ receptor subtype modulates ventilation and beta CCT partially antagonizes respiratory depressant effects of BZ's.
Greenberg
H E
HE
Division of Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York, 11042, USA.
Scharf
M
M
Mendelson
W
W
Cook
J M
JM
Cox
E
E
Scharf
S M
SM
D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008874:Midazolam / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D012119:Respiration / Q000187:drug effects*
D002243:Carbolines; D018756:GABA Antagonists; D014677:Pharmaceutical Vehicles; C043232:tert-butyl beta-carboline-3-carboxylate; D008874:Midazolam