Effect of flumazenil on hypoglossal and phrenic nerves activities in rabbits

BACKGROUND: Upper airway obstruction and inadequate ventilation often arise during sedation and anesthesia by benzodiazepines (Bz). Flumazenil antagonizes these effects of active benzodiazepines on the central nervous system. To estimate the influence of flumazenil on the endogenous Bz system related respiratory control, we studied the effect of flumazenil and diazepam on the neural activity and the respiratory response caused by a brief (60 sec) respiratory arrest (RA) manifested in the hypoglossal nerve (HG) and the phrenic nerve (PH) activities in rabbits. METHODS: Experiments were performed on adult rabbits which were vagotomized, paralyzed and artificially ventilated with 50% N2O, 50% oxygen and 0.5% sevoflurane. We evaluated and compared the effects of the sequential administrations of flumazenil and diazepam on the peak amplitude (AMP) as well as the root mean square (RMS) of HG and PH, and respiratory cycle (Tc). RESULTS: Flumazenil by itself increased HG activity more than PH activity with no influence on Tc. But it was not dose-related. Previous administration of flumazenil in total dose of 0.25 mg x kg(-1) could not prevent the anticipated respiratory depression caused by diazepam 2.0 mg x kg(-1). These depressions are greater in HG activity than in PH activity. Additional flumazenil 0.15 mg x kg(-1) following the administration of diazepam promptly reversed these inhibitory effects on HG activity beyond the control level. The same dose of flumazenil, however, did not reverse PH activity sufficiently. RA response was characterized by raised AMPs and augmented RMSs (deltaAMPs, deltaRMSs) with marked prolongation in Tc (deltaTc). Flumazenil and diazepam did not seem to have any influence upon these RA responses. There was a significant change in cardiovascular parameters with the tested dosages of flumazenil and diazepam, but the change was in the normal physiological range. CONCLUSIONS: These results suggest the possibility that the endogenous benzodiazepine system is likely to play an inhibitory role in the regulation of respiration, especially in the maintenance of upper airway patency but the system is unrelated to the chemosensitive-respiratory control.