NK2 Receptor-Mediated Spontaneous Phasic Contractions in Normal and Ulcerative Colitis Human Sigmoid Colon

Abstract

Human colonic circular muscle produces spontaneous phasic contractions that are reduced in ulcerative colitis. How the spontaneous phasic contractions develop and why they decrease in ulcerative colitis are not known. We found that spontaneous phasic contractions of normal sigmoid circular muscle strips were significantly reduced by 90-min incubation with tetrodotoxin (10 Ϫ5 M), which blocked neurokinin A release in basal conditions and in response to electrical stimulation. In addition, spontaneous contraction of human sigmoid colon was significantly decreased by the NK2 receptor antagonists, suggesting that NK2 receptors are involved in their development. The spontaneous phasic contractions were abolished by thapsigargin and cyclopiazonic acid and significantly decreased by the protein kinase C inhibitor chelerythrine and by the calmodulin inhibitor-piperidinyl]-2H-benzimidazol-2-one (1:1) maleate), suggesting that spontaneous phasic contractions may be mediated by Ca 2ϩ release from intracellular stores and by a protein kinase C-and calmodulindependent pathway. In strips from patients with ulcerative colitis, spontaneous contractions were significantly reduced, and this reduction was partially restored by the hydrogen peroxide scavenger catalase. Neurokinin A release, however, was not affected. We conclude that spontaneous phasic contractions of human sigmoid circular smooth muscle may be mediated by activation of NK2 receptors, calcium release from intracellular stores, and activation of calmodulin and protein kinase C. In ulcerative colitis patients, spontaneous phasic contractions are decreased, and this decrease may be in part due to overproduction of hydrogen peroxide affecting sigmoid circular muscle.

Multidrug Resistance Protein Transporter and Ins(1,4,5)P3-Sensitive Ca2+-Signaling Involved in Adenosine Triphosphate Export via Gq Protein–Coupled NK2-Receptor Stimulation With Neurokinin A

“…Besides, the evoked release was prevented by the PKC inhibitor staurosporine and the Ca 2+ /calmodulin inhibitor W-7, but not by the specific PI-3K inhibitor wortmannin (22). This is strengthened by the findings that spontaneous phasic contraction of human colonic circular muscles was reduced by NK 2 -receptor antagonists and thapsigargin and by CGS9343B, a Ca 2+ /calmodulin inhibitor, and chelerythrine, a PKC inhibitor (20). Accordingly, these findings indicate that the evoked release of ATP may also be mediated by a PKC-and Ca 2+ /calmodulindependent signal pathway.…”

“…However, somatostatin and neuropeptide Y did not elicit any release of ATP (unpublished observations). In the present study with the cultured SMCs, neurokinin A induced the substantial release of ATP, which was suppressed by L-659877, a NK 2 -receptor antagonist (19), but not by FK888, a NK 1 -receptor antagonist (20). Then, the cell signaling involved in the export of ATP was explored in this study.…”

Tachykinins in endocrine tumors and the carcinoid syndrome

“…P-TKs are involved in other diarrheic conditions such as the irritable bowel syndrome (37,38) and ulcerative colitis (39). In the normal gut, SP and NKA, via TK receptors on muscle cells and secretomotor neurons, have stimulatory effects on gut motility (37,40).…”

Pouch colon associated with anorectal malformations fails to show spontaneous contractions but responds to acetylcholine and histamine in vitro

“…The origin of spontaneous contraction is believed to be related to the activity of interstitial cells of Cajal [12]. These contractions have been found reduced in other pathologic conditions of colon including ulcerative colitis [11,13], and such reduction had Fig. 6 A, Bar diagram showing mean ± SEM values for ACh (100 μmol/L)-induced contraction (g/g wet tissue) from 7 CPC colonic strips.…”

“…Asterisks indicate significant difference (P b .05, Student's t test for paired observation). been attributed to the alteration of neurohumoral status or intracellular signaling pathways in the smooth muscle [11,13]. Therefore, it appears that the pathogenesis of CPC interferes with the pacemaker activity in pouch colon by altering the normal neurohumoral mechanisms.…”