It is well established that intestinal ischemia/reperfusion (I/R)leads to the generation of reactive oxygen species that produce dysfunction in both the vasculature and surrounding parenchyma. Yet, few studies have been designed to determine the extent to which I/R impairs intestinal blood flow regulation. Isolated reports suggest that vascular vasoconstrictor responsiveness is decreased by reactive oxygen metabolites that mediate reperfusion injury. However, the overall impact of reperfusion injury on intestinal blood flow control remains unclear. The purpose of the proposed studies is to employ intravital microscopic techniques to systematically analyze the intestinal microvascular response to I/R. Arteriolar diameter, erythrocyte velocity, intravascular pressure and blood flow are measured in sequentially branching arterioles. Tension generation by the individual arterioles is calculated from the pressure and diameter data.
The specific aims of the proposed research are: 1) To identify the site of altered vasoconstrictor sensitivity in the post-ischemic intestinal microcirculation. The responsiveness of arterioles in the intestinal submucosa and mucosa to cumulative doses of norepinephrine, vasopressin and angiotensin II will be studied in the post-ischemic intestine to determine if reperfusion injury alters vascular vasoconstrictor responsiveness uniformly in the intestinal microcirculation. 2) To determine the degree to which I/R alters endogenous neurohumoral blood flow control in the small intestine. The contribution of the alpha-adrenergic system, vasopressin and the renin-angiotensin system to arteriolar tone in the post-ischemic intestine will be determined by selectively removing the influence of these substances with specific receptor antagonists. 3) To assess the role of reactive oxygen metabolites and neutrophils in the altered vascular vasoconstrictor responsiveness in post-ischemic intestine. Studies will be conducted in the presence of superoxide dismutase or catalase to determine if the reduced vascular sensitivity is due to superoxide, H2O2 or reactive oxygen species produced by the interaction of superoxide with hydrogen peroxide. The role of xanthine oxidase derived oxidants will be tested in rats which xanthine oxidase has been inactivated or inhibited. Finally, we will examine the role of neutrophils by depleting the circulating pool of neutrophils with anti-serum. 4) To determine whether exogenously generated reactive oxygen metabolites alter intestinal vascular responsiveness to vasoconstrictor stimuli. The responsiveness of intestinal arteriolar to alpha-adrenergic agonists in normal animals will be studied before and after the introduction of reactive oxygen metabolites in the solution bathing the small intestine. By comparing the response to norepinephrine with less oxidizable agonists (phenylephrine), we will determine if reactive oxygen metabolites reduced alpha-adrenergic tone by oxidizing norepinephrine. The results of these studies will provide new information regarding the intestinal vascular response to I/R and may prove useful in developing treatment of ischemic disorders.
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