Preventive effects of phenoxybenzamine on nitrous oxide‐induced reproductive toxicity in Sprague‐Dawley rats

In previous studies, we have shown that the reproductive toxicity of N2O in rats is prevented by the co‐administration of either halothane or isoflurane, whereas treatment with folinic acid, which should reverse the effects of N2O on DNA production, does not prevent toxicity. These results cast doubt on the commonly held theory that inactivation of methionine synthase is the sole cause of N2O‐induced reproductive toxicity, and suggest the need for other hypotheses. One such possibility is that N2O causes adverse reproductive toxicity secondary to its sympathomimetic effects. As a first step to test this theory, we studied the effects of phenoxybenzamine (PX), an alpha‐1 adrenergic antagonist, on N2O‐induced reproductive toxicity using a well‐established in vivo rat model. On day 8 of gestation (plug day = day 0), 130 timed‐pregnant Sprague‐Dawley rats were injected s.c. with either 0.5 ml of either 0.9% saline (control and N2O alone groups) or PX (0.5, 5, or 50 μg/kg) in 0.9% saline, the latter the maximum tolerated PX dose. They were then exposed to either air (control) or 60% N2O for 24 hours (all other groups). On day 20 of gestation, cesarean sections were performed and the fetuses were removed and examined for either visceral of skeletal abnormalities. Compared with control, treatment with N2O alone resulted in increased incidences of fetal resorptions, major and minor visceral abnormalities, and minor skeletal abnormalities. The most common major abnormalities were various forms of altered body laterality (20/72 fetuses; 28%). The two highest PX doses partially reduced the incidence of resorptions but none of the PX doses prevented major teratogenic effects. These results suggest that stimulation of alpha‐1 adrenergic receptors accounts for some of the adverse reproductive effects of N2O. It should be noted that although the concentration of N2O used in the present study is in the clinical range, N2O is rarely administered to surgical patients for more than a few hours. Our main aim was to study the mechanisms involved in the reproductive toxicity of longterm N2O exposure and not for any concerns that short‐term (a few hours) exposure represented a reproductive risk.