The proposed research aim is to investigate the mechanisms involved in regulating increased intestinal blood flow. The specific, naturally occurring physiological regulators to be studied include peptidergic and nitroxidergic mediators, such as the neurotransmitter, calcitonin gene-related peptide (CGRP), the mostly non-neural peptide, bradykinin (BK), and the endothelium-derived relaxing factor, nitric oxide (NO). HYPOTHESIS: The working hypothesis is that CGRP and BK act in two ways to increase intestinal blood flow: 1) direct vasodilation involving peptide receptors on vascular smooth muscle, and 2) indirect vasodilation involving endothelial cell release of NO. This hypothesis implies that antagonism of NO release or actions alone will not abolish the vasodilator response to CGRP or BK, whereas specific peptide receptor blockade will fully prevent peptide induced increase in intestinal blood flow. METHODS: The experimental models to be employed include the anesthetized rat for in vivo experiments and excised rat mesenteric artery rings or segments for in vitro studies. In vivo studies of mesenteric artery blood flow, arterial pressure, vascular conductance, and intestinal mucosal blood flow will be performed using such methods as pulsed Doppler velocimetry, strain gauge manometry, and radiolabelled microsphere distribution. In vitro studies of arterial wall contractile force, vascular muscle potential difference, and intracellular calcium concentration will be conducted using force transducers, micropipettes, and biofluorescent probes. EXPERIMENTAL DESIGN: Intestinal vasodilation caused in vivo by CGRP or BK will be inhibited by receptor antagonists and this inhibition will be compared with inhibition caused by blocking NO biosynthesis or depleting peptide neurotransmitters. We will also examine dilator effects of receptor agonists for BK and other dilator neurotransmitters beside CGRP. HEALTH RELATEDNESS: Intestinal survival depends upon its capacity to increase blood flow when confronted by challenges which either reduce blood flow or increase metabolism of the gut. The mechanisms for this autoregulatory capacity are undefined. Furthermore, there are life- threatening human diseases in which blood flow to the gut is markedly reduced and for which there is no effective treatment currently.
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