The nonadrenergic noncholinergic system can modulate the effect of prokinetic agents on contractile response of isolated guinea-pig trachea segments to electrical field stimulation

Background and Purpose: Prokinetic agents are frequently used in patients with bronchopulmonary dysplasia for the treatment of gastroesophageal reflux, but the effects of these agents on the airway remain unclear. This study investigated factors mediating the effects of two prokinetic agents, metoclopramide and cisapride, on contractile response to electrical field stimulation (EFS) in guinea-pig trachea segments. Methods: Trachea segments from male Dunkin-Hartley guinea pigs were used. Concentration-response curves of metoclopramide and cisapride to electrical stimulus of 50 V at 20 Hz were obtained as baseline values. A second concentration-response curve to each prokinetic drug was obtained after preincubation with 300 μM N^G-nitro-L-arginine-methyl ester (L-NAME, a nitric oxide synthetase inhibitor) and 2 U/mL α-chymotrypsin (a vasoactive intestinal peptide inhibitor). Parallel control studies were undertaken to correct for changes in the sensitivity of the tissue to EFS. Results: At lower concentrations (≤ 1 μM), metoclopramide reduced the contractile response to EFS, but cisapride did not have a significant effect. At concentrations greater than 1 μM, metoclopramide enhanced and cisapride suppressed the airway smooth muscle contraction evoked by EFS. However, when inhibitory nonadrenergic noncholinergic (NANC) innervations were pharmacologically abolished by L-NAME and α-chymotrypsin, cisapride caused augmentation and metoclopramide did not have a significant effect on the contractile response to EFS at concentrations of 1 μM or less. Conclusion: This study demonstrated that the effect of metoclopramide and cisapride on the contractile response to EFS can be influenced by inhibitory. NANC innervations in guinea-pig trachea.