The mediators of non‐adrenergic non‐cholinergic (NANC) relaxation of the longitudinal muscle of rat proximal, middle and distal colon were examined in vitro.
Electrical transmural stimulation (TMS) of proximal, middle and distal segments of rat colon induced NANC relaxations which were inhibited by tetrodotoxin (1 μm), but not by atropine (1 μm) or guanethidine (4 μm).
In the proximal colon, l‐nitro‐arginine (N5‐nitroamidino‐l‐2,5‐diaminopentanoic acid) inhibited the TMS‐induced NANC relaxation and l‐arginine (1 mm) reversed this inhibition. Nitric oxide (0.3–10 μm) induced relaxation of the proximal segment.
NANC relaxation of the proximal segments was still evident after desensitization to vasoactive intestinal peptide (VIP). A VIP antagonist (VIP 10–28, 10 μm) had no effect on the TMS‐induced NANC relaxation, which was also resistant to α‐chymotrypsin (2 units ml−1) and a substance P antagonist ([d‐Pro2, d‐Trp7,9]substance P, 1 μm).
In the middle colon, l‐nitro‐arginine did not inhibit the TMS‐induced NANC relaxation in 6 of 9 preparations tested and partially inhibited the relaxation in the other 3 preparations. l‐Arginine did not reverse the partial inhibition.
Complete desensitization to VIP was not achieved in the middle colon. The VIP antagonist had no effect on the TMS‐induced NANC relaxation. After α‐chymotrypsin treatment of the segment, desensitization of the segments to substance P, or in the presence of the substance P antagonist, the TMS‐induced NANC relaxation was augmented.
In the distal colon, l‐nitro‐arginine did not have any significant effect on the TMS‐induced relaxation and nitric oxide did not induce relaxation. The VIP antagonist significantly inhibited TMS‐induced NANC relaxation. α‐Chymotrypsin‐treatment of the distal segments resulted in significant inhibition of NANC relaxation. No desensitization to substance P was achieved. Treatment with the substance P antagonist had no effect.
These results suggest that nitric oxide is the mediator of the NANC inhibitory response in the proximal region of rat colon; in the middle colon, substance P acts as an excitatory neurotransmitter, antagonizing the NANC relaxation caused by the mediator of the response, which is still uncertain. Our results also suggest that VIP is the most likely candidate as a NANC transmitter in the distal colon.
1 Prostaglandin E (PGE) may be essential for maintaining the sensitivity of the myenteric plexus of guinea-pig ileum to nicotine. The contributions of prostaglandins to nervous activity evoked by different stimuli have now been investigated by measuring the amount of acetylcholine (ACh) released from the myenteric plexus of the guinea-pig ileum. 2 The amount of ACh released in response to dimethylphenylpiperazinium (DMPP) or substance P was depressed to about 40% of control by 2.8 pM indomethacin (Ind), whereas the release of ACh induced by 5-hydroxytryptamine (5-HT) was not affected. The inhibitory effects of Ind were oyercome by 14.3nm PGE2 .3 Mepacrine 5pgM, an inhibitor of phospholipase A2, depressed the release of ACh in response to DMPP and substance P to the same extent as Ind. These inhibitory effects of mepacrine were overcome by arachidonic acid (10pM), but not by arachidonic acid plus Ind. The release of ACh evoked by 5-HT or electrical field stimulation (EFS) was also inhibited to about 60% of control by mepacrine but these inhibitions were overcome by arachidonic acid (10pM) either in the absence or the presence of Ind. 4 The results suggest that endogenous prostaglandins and arachidonic acid contribute to the maintenance of the excitability of the myenteric plexus by DMPP and substance P. By contrast, the release of ACh induced by 5-HT and EFS may be regulated by arachidonic acid and not by prostaglandins.
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