Angiotensin II (AII) is a physiologically important mediator of jejunal absorption. However, the mechanism or mechanisms by which AII produces changes in absorption from the small intestine are poorly understood. Therefore, experiments in this proposal will define further the interaction of AII with the small intestine. Initial experiments will determine whether AII stimulates jejunal transport processes directly or indirectly via the release of norepinephrine (NE) from enteric sympathetic nerve endings. Additional experiments will determine whether part of the jejunal response to AII is mediated by changes in jejunal hemodynamics. The intestinal cell types that have specific Alpha1- adrenergic receptors and binding sites for AII will be determined. Finally, the function and relative contribution of AII formed locally in the jejunum to the overall changes in jejunal absorption observed following volume depletion will be assessed. Four general protocols will be employed to accomplish these aims. First, the effect of AII on NE release from field stimulated rings of jejunal mucosa will be studied. Ion and water absorption in response to AII will be determined in isolated preparations of jejunum in which the enteric sympathetic nerves are stimulated. The effect of AII upon the distribution of blood flow within the jejunal wall will be determined either using microspheres or inert gas washout techniques. In-vivo microscopy will be used to determine the effect of AII upon the jejunal microcirculation. To determine the intestinal cell types having Alpha1 and AII receptors, electronmicroscope autoradiography for 125[I] AII and 3[H]-prazosin will be performed in combination with fluorescence microscopy for catecholamines and immunohistochemistry for dopamine beta hydroxylase. Finally, the local formation and expression of AII within the small intestine will be prevented by perfusing inhibitors of the renin-angiotensin system (RAS) specifically through the mesenteric circulation. In this manner, the role of the enteric RAS in the control of intestinal absorption can be assessed. The long term objective of this study is to increase understanding of the normal physiological control of intestinal absorption by hormones and the sympathetic nervous system.
