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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Cyclooxygenase-Dependent Alterations in Substance P-Mediated Contractility and Tachykinin NK₁ Receptor Expression in the Colonic Circular Muscle of Patients with Slow Transit Constipation

Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia (L.L., F.S., E.B.); Fairfield Hospital, Sydney, Australia (M.J.M.); and St. George Hospital, Sydney, Australia (D.W.K., D.Z.L.)

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 NK₂ receptor agonist, [Lys⁵,MeLeu⁹,Nle¹⁰]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 NK₁ receptor antagonist CP99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and TTX. In STC colonic muscle, there was a significant increase of NK₁ receptor mRNA expression, but no difference in NK₂ 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 NK₁ receptors. Our results also indicate some malfunction of the enteric nervous system in STC.

Address correspondence to: Dr. Lu Liu, Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney 2052, Australia. E-mail: lu.liu{at}unsw.edu.au