Mechanisms involved in the loss of excitatory post-stimulus responses by inflammation.
OBJECTIVE
Electrical stimulation of colonic muscles elicits a response during the stimulation period, and a transient excitation after the stimulus. Post-stimulus or "rebound" excitation has been linked to pathways involving inhibitory neurotransmitters, prostaglandins and substance P but the mechanism is incompletely understood. Because rabbit colitis is characterized by a loss of inhibitory neurotransmission we hypothesized it might affect the rebound response. Therefore we characterized rebound responses in non-inflamed and inflamed tissue by comparing the effect of antagonists/blockers of putative (nitric oxide [NO], ATP, substance P, prostaglandins) and new (serotonin) neurotransmitters.


METHODS
Strips from rabbits with colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) were subjected to electrical field stimulation. Because rebound responses are more prominent under nonadrenergic noncholinergic (NANC) conditions, the effect of specific antagonists (N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin, SR140333, methiothepin) on the rebound response was compared under normal and NANC conditions.


RESULTS
NANC-conditions increased rebound responses in non-inflamed strips, but this effect was reduced or abolished in inflamed strips. Rebound responses were reduced by pretreatment with the NO-synthase inhibitor, L-NAME, under NANC conditions in non-inflamed strips but not affected in inflamed tissue. In contrast, the P(2) purine receptor antagonist, suramin, did not affect rebound responses in inflamed and non-inflamed strips. The effect of the cyclo-oxygenase inhibitor (COX), indomethacin, on rebound responses was reversed from excitatory to inhibitory by inflammation. Under NANC conditions rebound contractions were also reduced by the neurokinin-1 (NK(1)) antagonist, SR140333, both in normal and inflamed strips. The most pronounced reduction in rebound responses in inflamed and non-inflamed strips under normal conditions was observed with the 5-hydroxytryptamin (1,2) (5-HT(1,2)) antagonist, methiothepin.


CONCLUSIONS
Rebound responses are mainly non-cholinergic and involve NO, substance P, serotonin and inhibitory prostaglandins. In inflamed tissue the nitrergic pathway is absent, excitatory prostaglandins prevail and the cholinergic and tachykinergic components are relatively more important. However there remains an important serotonergic contribution. Our data suggest that inflammation damages different neural pathways to a different extent and is most selective for nitrergic pathways.
Depoortere
Inge
I
Department of Pathophysiology, Center for Gastroenterological Research, University of Leuven, Gasthuisberg O and N, 3000 Leuven, Belgium. inge.depoortere@med.kuleuven.ac.be
Thijs
Theo
T
Thielemans
Leen
L
Peeters
Theo L
TL
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D011812:Quinuclidines / Q000494:pharmacology; D011817:Rabbits; D012702:Serotonin Antagonists / Q000494:pharmacology; D013373:Substance P / Q000502:physiology; D013498:Suramin / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid
D016861:Cyclooxygenase Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D058919:Purinergic P2 Receptor Antagonists; D011812:Quinuclidines; D012702:Serotonin Antagonists; C085215:SR 140333; D013373:Substance P; D008719:Methiothepin; D013498:Suramin; D000255:Adenosine Triphosphate; D014302:Trinitrobenzenesulfonic Acid; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin