The nonadrenergic noncholinergic system can modulate the effect of prokinetic agents on contractile response of isolated guinea-pig trachea segments to electrical field stimulation.
OBJECTIVE
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 microM N(G)-nitro-L-arginine-methyl ester (L-NAME, a nitric oxide synthetase inhibitor) and 2 U/mL alpha-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 (< or = 1 microM), metoclopramide reduced the contractile response to EFS, but cisapride did not have a significant effect. At concentrations greater than 1 microM, 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 alpha-chymotrypsin, cisapride caused augmentation and metoclopramide did not have a significant effect on the contractile response to EFS at concentrations of 1 microM or less.


CONCLUSIONS
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.
Yau
Kuo-Inn
KI
College of Medicine, Fu-Jen Catholic University, Department of Pediatrics, Cardinal Tien Hospital, Hsintien, Taipei Hsien, Taiwan.
Hwang
Tsong-Long
TL
D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D002918:Chymotrypsin / Q000494:pharmacology; D020117:Cisapride / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D014132:Trachea / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors
D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D014660:Vasoactive Intestinal Peptide; D019001:Nitric Oxide Synthase; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D008787:Metoclopramide; D020117:Cisapride; D019331:NG-Nitroarginine Methyl Ester