Contrasting effects of pseudoephedrine and papaverine in dextran sodium sulfate-induced colitis.

BACKGROUND: Dextran sodium sulfate (DSS) induces submucosal arteriolar constriction that reduces blood flow to the intestine, and the relevance of this decrease in flow needs further investigation. In the present study we examined the effects of a vasoconstrictor (pseudoephedrine) and a vasodilator (papaverine) on the outcome of DSS-induced colitis. METHODS: Mice were given DSS in drinking water for 6 days, with enemas on days 0, 1, 3, and 5 containing pseudoephedrine, papaverine, or no drug. At the conclusion of the 6-day protocol a disease activity index comprising weight loss, stool consistency, and rectal bleeding was evaluated, along with intravital microscopy observations of submucosal venular leukocyte and platelet adherence in the proximal colon and terminal ileum. RESULTS: Pseudoephedrine and papaverine had several contrasting effects on the outcome of DSS ingestion: pseudoephedrine induced the highest levels of weight loss, loose stools, venular platelet adherence, and overall disease activity index, while papaverine induced the highest levels of venular leukocyte adherence, but the lowest levels of rectal bleeding, loose stools, and overall disease activity index. CONCLUSIONS: The results suggest that vasoconstriction worsens the pathological consequences of DSS in the mouse model of colitis.

Ozagrel reverses streptozotocin-induced constriction of arterioles in rat retina.

Retinal blood flow decreases early in the progression of diabetic retinopathy; however, the mediators and mechanisms responsible for this decrease have yet to be determined. In this study, diabetes was induced by streptozotocin in rats, and retinal blood flow was measured via intravital microscopy 1 or 3 weeks following the induction of hyperglycemia. Additionally, retinal arteriolar diameters and flow were measured prior to and following acute administration of the thromboxane synthase inhibitor ozagrel to investigate the potential role of thromboxane in the observed constriction. Minimal changes in the retinal diameters and flow were observed at 1 week of diabetes; however, at 3 weeks of diabetes, arteriolar constriction and decreases in blood flow were significant. Notably, the constriction occurred only in the arterioles that were in closer proximity to the venules draining the retina. Acute administration of ozagrel reversed the constriction of the closely venule-paired arterioles. In summary, the results suggest that thromboxane mediates localized, venule-dependent arteriolar constriction induced by streptozotocin-induced diabetes in rats.

Altered microvascular hemodynamics during the induction and perpetuation of chronic gut inflammation.

Adoptive transfer of naïve CD4+ T cells into lymphopenic mice induces chronic small and large bowel inflammation similar to Crohn's disease. Although much is now known regarding the immunopathology in this model of inflammatory bowel disease, virtually nothing is known about the microvascular hemodynamic changes during the induction and perpetuation of chronic gut inflammation. In this study, CD4+CD45RBhigh T cells obtained from healthy C57BL/6 donor mice were transferred into lymphopenic recombinase-activating gene-1-deficient (RAG knockout) mice, which induced small and large bowel inflammation. At various time points following reconstitution (3 days-9 wk), intravital microscopy was used to examine the microvessels in the submucosa of the ileum and proximal colon following infusion of fluorescently labeled platelets and injection of rhodamine 6G (to label leukocytes). Hemodynamic measurements and the extent of blood cell adhesion to the venular wall were compared with measurements in unreconstituted RAG knockout controls. In <1 wk following reconstitution, velocity and wall shear rate of the arterioles decreased by >50% compared with controls, with this decrease also observed at 4-5 and 7-9 wk postreconstitution. At 7-9 wk, arteriolar diameters were found to be approximately 15% larger than in controls, but, despite this dilation, flow rates in the individual vessels were decreased by approximately 30%. Venular platelet and leukocyte adherence were not significantly elevated above controls; however, an association was found between platelet adherence and venular shear rate. In summary, significant decreases in arteriolar velocity and shear rates are observed in this model of chronic gut inflammation.