Abstract

Neurokinin A (NKA) is an important spasmogen in human colon. We examined inflammatory disease-related changes in the tachykinin NK₂ receptor system in human sigmoid colon circular muscle, using functional, radioligand binding, and quantitative reverse transcription-polymerase chain reaction methods. In circular muscle strips, indomethacin enhanced contractile responses to NKA (p < 0.01) and to the NK₂ receptor-selective agonist [Lys⁵,MeLeu⁹,Nle¹⁰]-NKA(4–10) (p < 0.05) in both normal and acute diverticular disease (DD) specimens, indicating NK₂ receptor-mediated release of relaxant prostanoids. Contractile responses to both tachykinins were reduced in strips from DD (p < 0.001) and ulcerative colitis (UC) (p < 0.05) specimens. Responses to acetylcholine were no different in other strips from the same disease patients, demonstrating that the change in responsiveness to tachykinins in disease is specifically mediated by the NK₂ receptor. In membranes from UC specimens, receptor affinity for ¹²⁵I-NKA (median K_D 0.91 nM, n = 16) was lower (p < 0.01) than that in age-matched control specimens (K_D 0.55 nM, n = 40), whereas K_D (0.65 nM, n = 28) in DD was no different from control. No disease-related changes in receptor number (B_max) were found (mean, 2.0–2.5 fmol/mg of wet weight tissue), suggesting that the reduced contractile responses in disease are not due to a loss of receptor number. Different mechanisms may account for the reduced contractility in DD compared with UC. A gender-related difference in receptor density was seen in controls, with B_max lower in females (1.77 fmol/mg, n = 15) than in males (2.60 fmol/mg, n = 25, p = 0.01). In contrast, no gender-related differences were seen in NK₂ receptor mRNA in control colonic muscle, indicating that the gender difference is a post-translational event.