Absence of agonistic or antagonistic effect of flumazenil (Ro 15-1788) in dogs anesthetized with enflurane, isoflurane, or fentanyl-enflurane

This study determined the effects of flumazenil on the anesthetic requirements (MAC) of the dog for isoflurane (group 1; n = 6), enflurane (group 2; n = 7), and a combination of fentanyl-enflurane (group 3; n = 6). Control MAC in each group was determined by the tail-clamp method. Each animal in groups 1 and 2 received four iv incremental doses of flumazenil: 0.5, 1.0, 1.5, and 4.5 mg/kg, and isoflurane MAC or enflurane MAC was determined after each dose. The animals in group 3 received a loading dose and a continuous infusion of fentanyl 0.8 micrograms.kg-1.min-1 over 8 h, and enflurane MAC was determined four times during this experimental period. After the fourth enflurane MAC determination in each animal of group 3, a single iv dose of flumazenil 1.5 mg/kg was injected and enflurane MAC was then determined for the last time. In the incremental doses administered, flumazenil did not demonstrate any agonistic or antagonistic interaction with isoflurane, enflurane, or the fentanyl-enflurane combination. In group 3, plasma fentanyl concentrations remained stable at 12.5 +/- 3.0 ng/ml (mean +/- SD) throughout the experiment and reduced enflurane MAC by 60 +/- 8%. The addition of flumazenil changed neither the fentanyl concentration in plasma (12.2 +/- 3.8 ng/ml) nor its reduction of enflurane MAC (61 +/- 7%). In conclusion, the absence of effect of flumazenil on the MAC of enflurane, isoflurane, or a fentanyl-enflurane combination suggests that they do not interact with the benzodiazepine receptor.