Effect of longitudinal muscle-myenteric plexus removal and indomethacin on the response to tachykinin NK-2 and NK-3 receptor agonists in the circular muscle of the guinea-pig ileum.
1. The effect of removal of the longitudinal muscle-myenteric plexus (LM-MP) and/or indomethacin (10 microM) on the response to the tachykinin NK-2 receptor selective agonist, [beta Ala8]NKA(4-10), or to the NK-3 receptor selective agonist, senktide, was investigated by measuring mechanical activity (isotonic recording) of circular muscle (ring preparation) of the guinea-pig ileum. 2. Indomethacin (10 microM) increased the percentage of ileal rings displaying spontaneous activity, either intact or LM-MP-free. The response to senktide (10 nM and 1 microM) was lower in LM-MP-free than in intact ileal rings, either in the absence or presence of indomethacin. The response to a low concentration (10 nM) of [beta Ala8] NKA (4-10) was enhanced in LM-MP-free rings and by indomethacin. 3. In intact ileal rings, the response to senktide was unaffected by atropine (3 microM) alone or by the tachykinin NK-2 receptor antagonist MEN 10,376 (10 microM) alone while it was reduced by the combined administration of the two antagonists. The response to senktide was greatly reduced by tetrodotoxin (TTX, 1 microM). Senktide-induced contractions (10 nM) were also reduced by the blocker of N-type voltage-sensitive calcium channels, omega-contoxin (CTX, 0.1 microM). 4. In about 30% of preparations tested, an inhibitory response (decrease in spontaneous activity) to 10 nM senktide, was disclosed in CTX-treated intact ileal rings. This inhibitory effect was TTX-sensitive. 5. In LM-MP-free ileal rings, the response to senktide was abolished or reduced by atropine and MEN 10,376, alone or in combination, and was also reduced or abolished by TTX and CTX. 6. The response to [beta Ala8]NKA (4-10) was inhibited by MEN 10,376, in both intact and LM-MP-free ileal rings while it was unaffected by atropine, TTX or CTX. 7. These results indicate that indomethacin pretreatment induces a regular background activity for studying the motor response to tachykinins in the circular muscle of the ileum, probably by blocking the formation of relaxant prostanoids. A further increase in sensitivity to direct smooth muscle stimulation (NK-2 receptor agonist) can be obtained by removal of the LM-MP. The response to NK-3 receptor stimulation is diminished but not abolished by removal of the LM-MP, suggesting that NK-3 receptors are located on neuronal bodies of myenteric neurons, but possibly also at other sites (possibly, nerve terminals).(ABSTRACT TRUNCATED AT 400 WORDS)
Maggi
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Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Patacchini
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Meini
S
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Giuliani
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S
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009197:Myenteric Plexus / Q000502:physiology*; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000502:physiology*; D018042:Receptors, Neurokinin-3 / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D010446:Peptide Fragments; D010455:Peptides; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C054724:senktide; C064218:neurokinin A (4-10), beta-Ala(8)-; C069192:neurokinin A(4-10), Tyr(5)-Trp(6,8,9)-Lys(10)-; D013373:Substance P; D013779:Tetrodotoxin; D001285:Atropine; D015288:Neurokinin A; D020866:omega-Conotoxin GVIA; D007213:Indomethacin