[How do diazepam and flumazenil influence respiratory control by the activities of both hypoglossal and phrenic nerves in rabbits?].
BACKGROUND
Upper airway obstruction and inadequate ventilation often arise during sedation and anesthesia by benzodiazepines. To estimate the influence of benzodiazepines on the respiratory control, we studied the effect of diazepam and flumazenil on the neural activity and the respiratory response caused by a brief (60 sec) respiratory arrest (RA) observed in the hypoglossal nerve (HG) and phrenic nerve (PH) in rabbits.


METHODS
Experiments were preformed on adult rabbits vagotomized, paralyzed and ventilated artificially with 50% N2O, 50% oxygen and 0.3-0.5% sevoflurane. We evaluated and compared the effects of diazepam and flumazenil on the peak amplitude (AMP-HG&PH) and the root mean square (RMS-HG&PH) of HG and PH, and respiratory cycle (Tc).


RESULTS
Diazepam depressed HG activity more than PH activity with no influence on Tc. But it did not cause dose-related depression. Flumazenil 0.2 mg.kg-1 completely reversed the respiratory depressions caused by diazepam with the increased Tc. In addition to augmentation of the hypoglossal activity in inspiration, flumazenil caused a rise in its activity in pan-expiratory period in some cases. Additional administration of diazepam 6 mg.kg-1 following flumazenil depressed PH activity again, but did not affect HG activity any more. There was no significant depression in cardiovascular parameters with tested dosages of diazepam and flumazenil. RA response was characterized by raised AMPs and augmented RMSs (delta AMPs, delta RMSs) with marked prolongation in Tc (delta Tc). Diazepam depressed RA response dose dependently, but flumazenil did not seem to antagonize this depression.


CONCLUSIONS
These results suggest that 1) flumazenil is not only a specific antagonist of benzodiazepines but also a potential excitatory agent of hypoglossal nerve activity, and that 2) there is some functional diversity in disposition of benzodiazepine-receptor binding GABAA-receptor responsible for neural respiratory control system.
Hayashi
Takataro
T
Department of Anesthesiology, Saitama Medical School, Saitama 350-0495.
Nakamura
Shinichi
S
Ohno
Rie
R
Kusumoto
Go
G
Terayama
Kimie
K
Murakami
Yasuo
Y
Suzuki
Masahiko
M
Nagasaka
Hiroshi
H
Miyata
Yoshihiko
Y
Matsumoto
Isao
I
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003975:Diazepam / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology*; D007002:Hypoglossal Nerve / Q000187:drug effects*; D010791:Phrenic Nerve / Q000187:drug effects*; D011817:Rabbits; D011963:Receptors, GABA-A / Q000502:physiology; D012119:Respiration / Q000187:drug effects*
D011963:Receptors, GABA-A; D005442:Flumazenil; D003975:Diazepam