L-citrulline reverses the inhibition of nonadrenergic, noncholinergic relaxations produced by nitric oxide synthase inhibitors in guinea pig trachea and human bronchus.

Nonadrenergic, noncholinergic relaxations were elicited by field stimulation (8 Hz, 1 msec, 12 V for 15 sec) of guinea pig trachea desensitized with capsaicin (1 microM), pretreated with atropine (1 microM), propranolol (1 microM), indomethacin (3 microM) and alpha-chymotrypsin (2 U/ml) and contracted with 3 microM histamine. These relaxations averaged 60 to 80% of the contractions to histamine. The relaxations were inhibited markedly by the addition of the nitric oxide (NO) synthase inhibitor L-nitro-n-arginine (L-NNA)(30 microM), suggesting that these relaxations are due to the release of NO. The inhibition produced by L-NNA was reversed by either L-arginine or L-citrulline. L-Citrulline was both more potent and efficacious than L-arginine in this regard. The ability of L-citrulline to reverse the inhibition produced by L-NNA was not altered by L-glutamine (1 mM). The addition of L-citrulline (1 mM) added before L-NNA was without effect on the relaxant responses to field stimulation but was able to prevent the inhibition produced by L-NNA. L-Citrulline also reversed the inhibition produced by another NO synthase inhibitor, L-nitro monomethyl arginine. Relaxations to field stimulation (16 Hz, 1 msec, 12 V for 15 sec) of human bronchus also were inhibited by 30 microM L-NNA and, as in the guinea pig, this inhibition by L-NNA could be reversed by L-citrulline. These results suggest that L-citrulline is able to overcome the inhibition of NO synthase by NO synthase inhibitors in the guinea pig trachea and human bronchus.