The long-term goals of the proposed research are to understand both the intrinsic factors which normally regulate the circulation of the gut and the intrinsic mechanisms whereby vasodilator agents increase mesenteric blood flow. There will be two specific aims: 1) to test the hypothesis that a physiological phenomenon, autoregulation of intestinal blood flow, is mediated by an intrinsic substance, histamine; and 2) to determine whether calcium entry blockers which vasodilate the intestinal circulation act only at sarcolemmal sites on mesenteric vascular smooth muscle or also act intracellularly. The clinical significance of this research relates to non-occlusive intestinal ischemia, an acute and usually lethal state of intestinal vasospasm whose cause is unknown and whose treatment is unsatisfactory. The hypothesis that histamine is the chemical transducer of autoregulation in the gut will be tested by evoking three intrinsic autoregulatory events, namely pressure autoregulation of blood flow, reactive hyperemia and autoregulatory escape, and then attempting to block these events with histamine H-1 and H-2 receptor antagonists, as well as agents which interfere with histamine metabolism. Several hemodynamic and metabolic parameters will be used in anesthetized and conscious canine preparations to assess the effects of histamine receptor antagonists and enzyme inhibitors, namely mesenteric blood flow, arterial and venous pressures, intestinal oxygen extraction and consumption, autoregulatory indices and mesenteric vascular resistance. The study of vasodilator mechanisms with calcium entry blockers will utilize similar techniques as well as in vitro preparations, namely excised mesenteric arterial strips mounted in a muscle bath and the binding of radiolabeled calcium entry blockers to sarcolemmal membrane preparations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK037050-04
Application #
3235744
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1988-01-01
Project End
1988-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
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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