Sa2066 The Provocative Water Load Test Evokes Nausea and Gastric Dysrhythmias in Patients With Unexplained Chronic Nausea and Vomiting

Abstract

Previous studies found that mechanical stretch in bowel obstruction markedly induced gene expression of COX-2, but not COX-1, in colonic smooth muscle cells (SMCs). The aims of the present study were to determine whether genes encoding individual prostaglandin synthases are mechanically responsive, and whether the composition of prostaglandins resulting from obstruction differs from that in inflammation. Methods: Partial colon obstruction was induced with a silicon band implanted surgically in the distal colon of male SpragueDawley rats. Static mechanical stretch (18% elongation) was mimicked in vitro in the culture of rat colonic circular SMCs with a Flexercell FX-4000 System. Rat colon inflammation was induced by manipulation of the colonic surface with wet cotton applicators. Results: 1. Quantitative RT-PCR found that the expression of PGDS and PGIS genes was not significantly changed on day 3 of obstruction. However, the membrane bound PGES-1 (mPGES-1) mRNA was significantly up-regulated in the obstructed segment, whereas mRNAs for other two types of PGES, cytosolic PGES and mPGES-2, were not changed. On the contrary, the PGFS mRNA was down-regulated in the obstructed colon. 2. PGE2, but not PGF2 α, was significantly increased in the colonic muscularis externae in obstruction. The PGE2 level increased to 4577±1249 pg/mg at day 3 of obstruction, compared to 1264±259 in sham (n=6, p,0.05). The PGF2α level was 5718±910 pg /mg in obstruction compared to 6550±2178 pg/mg in the sham (n=5, p.0.05). 3. Direct stretch of rat colonic circular SMCs in vitro significantly up-regulated the mPGES-1 mRNA, but down-regulated that of PGFS. After stretch for 3 hrs, the mRNA levels of PGES and PGFS changed by 2.61±0.42 fold and 0.82±0.03 fold, respectively (n = 4 or 5, p,0.05). 4. In colonic inflammation, both PGE2 and PGF2α were significantly increased in the colonic smooth muscle (5.2(±1.5)-fold and 4.7(±1.3)-fold of control, respectively, p,0.05, n = 3). 5. Rat colonic circular muscle contractility was inhibited by exogenous PGE2 (10-9 ~10-6 M), but enhanced by PGF2 α (10-9 ~10-6 M) in a concentration-dependent manner (n = 4). Conclusions: Genes involved in the COX pathway of arachidonic acid metabolism are highly mechanosensitive in colonic SMCs, and play a critical role in motility function. Mechano-regulation of prostaglandin synthases accounts for increased PGE2 and unchanged PGF2 α in bowel obstruction, a pathological feature different from inflammation in which both PGE2 and PGF2 α are increased.