The small intestine serves the functions of nutrition and maintenance of homeostasis via the absorption of water, electrolytes, nutrients and drugs. Intestinal transport is linked to intestinal blood flow and motility. We hypothesize that the regulation of intestinal transport and vascular resistance is dependent upon an interaction between autonomic neural, enteric neural, and hormonal inputs, and neurocrine and paracrine events acting directly upon the enterocyte. Further, we hypothesize that the regulation of intestinal transport and vascular resistance is mediated via membrane receptor systems which modulate cell membrane associated GTP dependent proteins (G-proteins) and subsequently alter either the adenylate cyclase or the phosphoinositide second messenger systems. We plan to test these hypotheses using an isolated, vascularly perfused, ex-vivo intestinal preparation. The advantages of this preparation compared to past models include: (a) proven intestinal viability, (b) total isolation from other organs, (c) complete control of the composition and flow of the vascular perfusate, (d) fully intact enteric nervous system, (e) sympathetic axonal innervation, (f) presence of intestinal motor activity, (g) lack of anesthetic agents and (h) single pass vascular perfusion which avoids recirculation of metabolic and hormonal products present in the venous effluent.
Five specific aims are to be addressed: Protocol I will test the hypothesis that endogenous norepinephrine alters intestinal vascular resistance of transport. Protocol II will test the the hypothesis that endogenous norepinephrine acts via alpha1 adrenoreceptors to modulate vascular resistance, and via alpha2 adrenoreceptors to modulate transport. Protocol iii will test the hypothesis that endogenous neuropeptide Y serves as a modulator of vascular resistance or transport. Protocol IV will address the function of cell membrane associated G- proteins as intermediaries between cell membrane receptor activation and adenylate cyclase. Protocol V will study the role of the intracellular second messenger phosphoinositol cycle in causing alterations of vascular resistance and transport. The results of these studies will provide information about the mechanisms that alter intestinal transport and vascular resistance, and may suggest neural or humoral manipulations which would favorably alter disease states such as secretory diarrhea (carcinoid, VIPoma) or diarrhea associated with autonomic dysfunction (diabetes, bowel transplantation).
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