Abstract

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.