Antagonism of nitrous oxide induced anxiolytic-like behavior by sildenafil (Viagra)

Erectile dysfunction affects a large segment of the male population, more than 100 million worldwide. The recent introduction of sildenafil, a relatively specific vasodilator of the penile circulation, has revolutionized the treatment of impotence. Sildenafil (Viagra) inhibits phosphodiesterase type 5 (PDE5), the enzyme that catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP). Subanesthetic concentrations of N2O are routinely used in clinical dentistry to produce conscious sedation. N2O stimulates production of NO, which activates soluble guanylyl cyclase to produce cGMP leading to the anxiolytic effect of N2O. Objectives: The aim of present study was to investigate the possible interaction of N2O and sildenafil since they both influence cGMP and behavior. Methods: We characterized the effects of N2O and sildenafil alone and in combination in the mouse light-dark compartment test. Results: Exposure of male NIH Swiss mice (18-25 g) to 70% N2O/30% O2 increased the time spent in the light compartment as well as the number of transitions in the light-dark exploration test. In contrast, i.p. administration of 1.0 mg/kg sildenafil decreased the amount of time spent in the light compartment and the number of attempts to enter the illuminated side compared to the saline/room air-treated group. Treatment with 1.0 mg/kg sildenafil followed by exposure to 70% N2O/30% O2 further decreased the time spent in the light side of the compartment as well as the number of transitions. Conclusion: Sildenafil appeared to induce an anxiogenic-like profile in the mouse light-dark compartment test. Sildenafil also antagonized the anxiolytic-like behavioral effect of N2O. This may be of clinical significance in the use of N2O in patients receiving sildenafil. Further investigation in the influence of N2O and sildenafil on brain cyclic GMP systems and their relationship to anxiety needs to be carried out.

This research was supported by NIH Grant DA-10343.