REGULATION OF COLONIC PROPULSION BY ENTERIC EXCITATORY AND INHIBITORYNEUROTRANSMITTERS

The contribution of excitatory and inhibitory motor neurotransmitters to colonic propulsion was examined in isolated segments of guinea pig colon. Synthetic fecal pellets were inserted at the proximal end of th e segment, and the velocity of pellet propulsion across a fixed distan ce was measured in the presence and absence of selective neurotransmit ter antagonists. The control velocity (0.97 +/- 0.02 mm/s) was inhibit ed in a concentration-dependent fashion by atropine and the neurokinin (NK)-2a antagonist MEN-10,376 [half-maximal inhibitory concentration (IC50), 1 mu M; maximal inhibition, 98 +/- 1%]. The NK-1 antagonist GR -82,334 (10 mu M) also inhibited velocity by 65 +/- 9%, consistent wit h involvement of acetylcholine, neurokinin A (NK-2 agonist), and subst ance P (NK-1 agonist) in the contractile components of the peristaltic reflex. Velocity was also inhibited in a concentration-dependent fash ion by the nitric oxide synthase inhibitor N-G-nitro-L-arginine (L-NNA ; IC50, 1 mu M; maximal inhibition, 96 +/- 2%) and by the vasoactive i ntestinal peptide (VIP) antagonist VIP-(10-28) (IC50, 30 nM; maximal i nhibition, 64 +/- 6%), consistent with involvement of both nitric oxid e and VIP in descending relaxation of circular muscle and contraction of longitudinal muscle. A combination of threshold concentrations of L -NNA and the NK-2a antagonist was synergistic (53 +/- 7% inhibition). The potentiation implied that the ascending and descending phases were functionally coupled in series. We conclude that blockade of neurotra nsmitters that mediate either phase of the peristaltic reflex inhibits colonic propulsive activity. Serial coupling of the phases leads to s ynergism between inhibitors, a condition of potential therapeutic impo rtance.