The effect of RO15-1788 on cardiovascular depression caused by fentanyl and diazepam

Cardiovascular depression occurring when diazepam is combined with fentanyl has been investigated using the benzodiazepine antagonist RO15-1788 in the dog. After the initial administration of fentanyl (40 mcg/kg), the mean arterial pressure (MAP) decreased to 89% of its control value. Following the administration of diazepam (1.2 mg/kg), the MAP and the total peripheral resistance (TPR) decreased significantly, to 75% and 83% of their control values respectively. After the administration of RO15-1788 (0.4 mg/kg), the MAP increased significantly to 90% and the TPR to 102% of their control values and, lastly, the administration of naloxone (40 mcg/kg) increased the MAP to 108% of its control value. No relationship was found between the changes in the catecholamines and the changes in the MAP after the administration of fentanyl, diazepam, and RO15-1788. The mechanism of circulatory depression when diazepam was used with fentanyl is interpreted as being a peripheral vasodilatory effect of diazepam acting by way of the benzodiazepine receptors since RO15-1788 was found to antagonize this effect.