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NK2 receptor-mediated spontaneous phasic contractions in normal and ulcerative colitis human sigmoid colon
Weibiao Cao1, Karen M Harnett, Victor E Pricolo
1Department of Medicine, Brown Medical School and Rhode Island Hospital, 55 Claverick Street, Room 337, Providence, RI 02903, USA. weibiao_cao@brown.edu
The Journal of Pharmacology and Experimental Therapeutics
|March 24, 2006
Summary
Spontaneous contractions in human colon muscle involve NK2 receptors and intracellular calcium release. In ulcerative colitis, these contractions decrease, potentially due to hydrogen peroxide, but neurokinin A release is unaffected.
Area of Science:
- Gastroenterology
- Neurogastroenterology
- Smooth Muscle Physiology
Background:
- Human colonic circular muscle exhibits spontaneous phasic contractions.
- These contractions are diminished in ulcerative colitis (UC).
- The mechanisms underlying contraction development and UC-related reduction remain unclear.
Purpose of the Study:
- To elucidate the mechanisms of spontaneous phasic contractions in human colonic smooth muscle.
- To investigate the role of neurokinin A (NKA) and NK2 receptors.
- To explore the signaling pathways involved, including intracellular calcium release, protein kinase C (PKC), and calmodulin.
- To understand the contribution of hydrogen peroxide (H2O2) in UC-associated reductions.
Main Methods:
- Isolated human sigmoid colon circular muscle strips were used.
- Pharmacological agents tested included tetrodotoxin, NK2 and NK1 receptor antagonists, thapsigargin, cyclopiazonic acid, chelerythrine, CGS9343B, and catalase.
- NKA release was measured under basal and stimulated conditions.
- Spontaneous phasic contractions were recorded in muscle strips from normal and UC patients.
Main Results:
- Tetrodotoxin reduced contractions and blocked NKA release.
- NK2 receptor antagonists (MEN10376, NK2ra) significantly decreased contractions, unlike NK1 antagonists or atropine.
- Thapsigargin, cyclopiazonic acid, chelerythrine, and CGS9343B abolished or reduced contractions, indicating roles for intracellular Ca2+ release, PKC, and calmodulin.
- In UC patients, contractions were reduced, and catalase partially restored them, suggesting H2O2 involvement.
- NKA release was not affected in UC patients.
Conclusions:
- Spontaneous phasic contractions in human sigmoid circular muscle are mediated by NK2 receptor activation, intracellular Ca2+ release, and PKC/calmodulin pathways.
- Reduced spontaneous contractions in UC may be partly due to H2O2 overproduction impacting smooth muscle.
- NKA release is not the primary factor explaining reduced contractions in UC.
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