The Nitric Oxide Donor LA-419 [S-(6-Nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate] Prevents Intestinal Dysmotility, Bacterial Translocation, and Inflammation in a Rat Model of Enteritis

Abstract

Indomethacin induces a chronic model of inflammatory bowel disease (IBD) characterized by spontaneous relapses of inflammation, bacterial translocation, and long-lasting motor disturbances derived from cyclical up-regulated inducible nitricoxide synthase (iNOS) and sustained down-regulated neuronal NOS (nNOS). The aims of this study were to evaluate whether LA-419 [S-(6-nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate], a NO-donor drug, could re-establish the normal expression of NOS and, hence, prevent the development of intestinal dysmotility, bacterial translocation, and relapses of inflammation associated to this model. Enteritis was induced in rats by administration of indomethacin with and without treatment with a novel NO-donor: LA-419 (0.5 mg/ml in the drinking water). Inflammatory reaction was evaluated by measuring blood leukocytes, serum tumor necrosis factor, and tissue myeloperoxidase. Intestinal motor activity was evaluated using strain-gauges. Ileal expression of iNOS and nNOS mRNA was determined by reverse transcription-polymerase chain reaction. Bacterial translocation was evaluated in cultures from mesenteric lymph nodes. The indomethacin-induced acute inflammatory reaction was associated with a rise in blood leukocytes and tumor necrosis factor. In the chronic stage, blood leukocyte monitoring allowed the selection of animals in active and inactive phases. Active phase was associated with iNOS up-regulation, high myeloperoxidase levels, hypomotility, and bacterial translocation. In contrast, inactive phase was associated with hypermotility and absence of bacterial translocation. LA-419 treatment restored nitric-oxide synthase isoenzyme expression and prevented the oscillation of both inflammatory and motor parameters that could be cyclically observed in inflamed rats. LA-419 also prevented intestinal dysmotility, bacterial translocation, and relapses of intestinal inflammation. LA-419 might be a novel therapeutic approach to prevent acute inflammatory relapses in patients with IBD.

Bacterial translocation in critical illness

“…Intestinal inflammation leads to hypomotility and BT through dysregulation of inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Porras et al . ). Maintenance of physiologic levels of nitric oxide (NO) by administration of a novel NO‐donor can recover intestinal motility thus preventing bacteria overgrowth and BT (Porras et al .…”

“…Maintenance of physiologic levels of nitric oxide (NO) by administration of a novel NO‐donor can recover intestinal motility thus preventing bacteria overgrowth and BT (Porras et al . ). Small intestinal bacterial overgrowth (SIBO) can result secondary to decreased gastric acid secretion, reduced intestinal motility and dysregulated mucosal and systemic immunity (Koutsounas et al .…”

“…Recognition of bacteria or endotoxin and the resulting proinflammatory response directly affect intestinal motility and host microflora. Intestinal inflammation leads to hypomotility and BT through dysregulation of inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Porras et al . 2008 ).…”

“…2008 ). Maintenance of physiologic levels of nitric oxide (NO) by administration of a novel NO-donor can recover intestinal motility thus preventing bacteria overgrowth and BT (Porras et al . 2008 ).…”

Faces of ghrelin – research for the 21st century

“…One of the key events for the disturbed GI motility in IBD is the loss of neuronal nitric oxide synthase in the myenteric plexus. 24,25 This renders the intestine more sensitive to stimulating agents where ghrelin might find a place for its action. Since ghrelin was not shown to be involved in the reduction of the reduced motility responses in experimental colitis this opens up for other theories on stimulation of colonic motility such as neurokinin receptors.…”