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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK037050-09A1
Application #
2139950
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1989-01-01
Project End
1996-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Jacobson, E D; Bunnett, N W (1997) G protein-coupled receptor signaling: implications for the digestive system. Dig Dis 15:207-42
Brooks, E C; Mahr, N N; Radisavljevic, Z et al. (1997) Nitric oxide attenuates and xanthine oxidase exaggerates lung damage-induced gut injury. Am J Physiol 272:G845-52
Terada, L S; Radisavljevic, Z; Mahr, N N et al. (1997) Xanthine oxidase decreases production of gut wall nitric oxide. Proc Soc Exp Biol Med 216:410-3
Terada, L S; Mahr, N N; Jacobson, E D (1996) Nitric oxide decreases lung injury after intestinal ischemia. J Appl Physiol 81:2456-60
Pawlik, W W; Gustaw, P; Jacobson, E D et al. (1995) Nitric oxide mediates intestinal hyperaemic responses to intraluminal bile-oleate. Pflugers Arch 429:301-5
Levine, J S; Jacobson, E D (1995) Intestinal ischemic disorders. Dig Dis 13:3-24
Remak, G; Hottenstein, O D; Jacobson, E D (1994) Multifactorial mediation of post norepinephrine induced intestinal hyperemia. J Physiol Pharmacol 45:241-57
Remak, G; Hottenstein, O D; Jacobson, E D (1994) Adrenergic, purinergic, and endothelial mediators and modulators of norepinephrine-induced mesenteric autoregulatory escape. Dig Dis Sci 39:1655-64
Jacobson, E D; Pawlik, W W (1994) Adenosine regulation of mesenteric vasodilation. Gastroenterology 107:1168-80
Berguer, R; Hottenstein, O D; Palen, T E et al. (1993) Bradykinin-induced mesenteric vasodilation is mediated by B2-subtype receptors and nitric oxide. Am J Physiol 264:G492-6

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