L‐Citrulline Protects Against Hyperoxia‐Induced Increase in Airway Contractile Responses

Abstract

Neonatal hyperoxia increases contraction and decreases relaxation of airways in rat pups due to upregulation of arginase activity and decrease of L‐arginine bioavailability to nitric oxide synthase (NOS). Therefore, we tested the hypothesis that supplementation of L‐citrulline will overcome the increased contractile responses of tracheal smooth muscle (TSM) induced by hyperoxia. Tracheal cylinders were excised from rat pups 12 days old, exposed to hyperoxia or room air for seven days. To induce contraction of TSM, electrical field stimulation (EFS) was applied. Hyperoxia increased EFS‐induced contractile responses as compared to room air animals (1.29 ± 0.1 g vs. 0.83 ± 0.2 g). In vitro supplementation of L‐citrulline decreased the contractile responses in hyperoxic group, but did not show any effect in control group under basal conditions. Inhibition of enzymes involved in L‐citrulline recycling prevented this effect of L‐citrulline. Inhibition of NOS, increased airway contraction in control group but did not affect the responses in hyperoxic group. Incubation with exogenous L‐citrulline reversed the increased contractility.These data demonstrate that L‐citrulline/L‐arginine cycle is effective in TSM under conditions of reduced L‐arginine bioavailability to NOS. In vitro supplementation of L‐citrulline reverses the increased contractile responses in hyperoxic animals to control levels.