Cyclooxygenase-dependent alterations in substance P-mediated contractility and tachykinin NK1 receptor expression in the colonic circular muscle of patients with slow transit constipation.
Tachykinins are important neurotransmitters regulating intestinal motility. Slow transit constipation (STC) represents an extreme colonic dysmotility with unknown etiology that predominantly affects women. We examined whether the tachykinin system is involved in the pathogenesis of STC. Isolated sigmoid colon circular muscle from female STC and control patients was studied using functional and quantitative reverse transcriptase-polymerase chain reaction methods. A possible alteration of neurotransmission was investigated by electrical field stimulation (EFS) and ganglionic stimulation by dimethylphenylpiperazinium (DMPP). Substance P (SP)-mediated contractions in circular muscle strips were significantly diminished in STC compared with age-matched control (P < 0.001). In contrast, contractile responses to neurokinin A, the selective tachykinin NK(2) receptor agonist, [Lys(5),MeLeu(9),Nle(10)]NKA(4-10), and acetylcholine were unaltered in STC. The reduced responses to SP in STC were fully restored by indomethacin, partially reversed by tetrodotoxin (TTX), but unaffected by atropine or hexamethonium. The restoration by indomethacin was blocked by the NK(1) receptor antagonist CP99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and TTX. In STC colonic muscle, there was a significant increase of NK(1) receptor mRNA expression, but no difference in NK(2) mRNA level. DMPP generated biphasic responses, relaxation at lower and contraction at higher concentrations. Although the responses to DMPP were similar in STC and control, an altered contractile pattern in response to EFS was observed in STC circular muscle. In conclusion, we postulate that the diminished contractile response to SP in STC is due to an increased release of inhibitory prostaglandins through activation of up-regulated NK(1) receptors. Our results also indicate some malfunction of the enteric nervous system in STC.
Liu
Lu
L
Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney 2052, Australia. lu.liu@unsw.edu.au
Shang
Fei
F
Morgan
Matthew J
MJ
King
Denis W
DW
Lubowski
David Z
DZ
Burcher
Elizabeth
E
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D001285:Atropine / Q000494:pharmacology; D012809:Colon, Sigmoid / Q000201:enzymology / Q000378:metabolism*; D003248:Constipation / Q000378:metabolism* / Q000503:physiopathology; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004558:Electric Stimulation; D017615:Enteric Nervous System / Q000187:drug effects; D005260:Female; D005731:Ganglionic Stimulants / Q000494:pharmacology; D005772:Gastrointestinal Transit / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000201:enzymology / Q000378:metabolism*; D015288:Neurokinin A / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis* / Q000235:genetics; D011978:Receptors, Nicotinic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D055815:Young Adult
D005731:Ganglionic Stimulants; D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D018040:Receptors, Neurokinin-1; D011978:Receptors, Nicotinic; D013373:Substance P; D013779:Tetrodotoxin; D004246:Dimethylphenylpiperazinium Iodide; D001285:Atropine; D015288:Neurokinin A; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine