This proposal is aimed at exploring the mechanisms underlying the hyperdynamic circulation in rats with cirrhosis and portal hypertension. Portal hypertension results from increased vascular resistance in the portal bed, a condition that leads to portasystemic shunting. The PI proposes that vasodilator substances, particularly glucagon, are shunted around the liver and contribute to arteriolar vasodilation and increased systemic blood flow, hallmarks of the cirrhotic hyperdynamic circulation. A second major mechanism in this pathophysiologic response is that small arterioles appear to be less sensitive to vasoconstrictor substances such as norepinephrine. These two mechanisms, increased circulating vasodilators and diminished response to vasoconstrictors, would be additive in causing or contributing to the vascular abnormalities of portal hypertension. The experimental model to be used in these studies will be an in vitro preparation of small mesenteric arteries (150-200 um diameter) taken from control rats or rats made cirrhotic with carbon tetrachloride. The vessel rings will be mounted in a myograph to measure contraction. The same vessel preparation will be loaded with a calcium sensitive flo (Flo 3 AM) to permit measurement of intracellular calcium. Using this experimental model, the PI proposes to test five major hypotheses: 1) portal hypertension depresses receptor and non receptor-mediated increases in intracellular calcium (Cai) and tension in small resistance arteries; 2) portal hypertension alters the rate of release and sequestration of calcium in vascular smooth muscle. Calcium movement across the plasma membrane and across the sarcoplasmic reticulum using agonists and antagonists will be studied; 3) will investigate whether glucagon interferes with the vasoconstrictor effect of non-epinephrine on vascular smooth muscle, and whether this effect is mediated by cAMP-dependent mechanisms; 4) will examine whether inhibition of adenylyl cyclase or protein kinase A restores the vascular responses to norepinephrine or vasopressin; 5) will examine whether release of NO from vascular endothelium augments cAMP-dependent vasodilator events in resistance arteries from portal hypertensive rats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051430-10
Application #
2905875
Study Section
Special Emphasis Panel (ZRG2-NTN (03))
Program Officer
Doo, Edward
Project Start
1991-02-01
Project End
2000-08-31
Budget Start
1999-07-01
Budget End
2000-08-31
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of South Alabama
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688
Chen, Xuesong; Pavlish, Kristin; Benoit, Joseph N (2008) Myosin phosphorylation triggers actin polymerization in vascular smooth muscle. Am J Physiol Heart Circ Physiol 295:H2172-7
Chen, Xuesong; Pavlish, Kristin; Zhang, Hai-Ying et al. (2006) Effects of chronic portal hypertension on agonist-induced actin polymerization in small mesenteric arteries. Am J Physiol Heart Circ Physiol 290:H1915-21
Anderson, Cindy M; Lopez, Faye; Zimmer, Ashley et al. (2006) Placental insufficiency leads to developmental hypertension and mesenteric artery dysfunction in two generations of Sprague-Dawley rat offspring. Biol Reprod 74:538-44
Anderson, Cindy M; Lopez, Faye; Zhang, Hai-Ying et al. (2006) Mesenteric vascular responsiveness in a rat model of pregnancy-induced hypertension. Exp Biol Med (Maywood) 231:1398-402
Chen, Xuesong; Zhang, Hai-Ying; Pavlish, Kristin et al. (2005) Effects of chronic portal hypertension on small heat-shock proteins in mesenteric arteries. Am J Physiol Gastrointest Liver Physiol 288:G616-20
Anderson, Cindy M; Lopez, Faye; Zhang, Hai-Ying et al. (2005) Reduced uteroplacental perfusion alters uterine arcuate artery function in the pregnant Sprague-Dawley rat. Biol Reprod 72:762-6
Anderson, Cindy M; Lopez, Faye; Zhang, Hai-Ying et al. (2005) Characterization of changes in leptin and leptin receptors in a rat model of preeclampsia. Am J Obstet Gynecol 193:267-72
Zhang, Hai-Ying; Shirasawa, Yuichi; Chen, Xuesong et al. (2005) Impaired agonist-dependent myosin phosphorylation and decreased RhoA in rat portal hypertensive mesenteric vasculature. Am J Physiol Gastrointest Liver Physiol 288:G603-8
Payne, Michael C; Zhang, Hai-Ying; Shirasawa, Yuichi et al. (2004) Dynamic changes in expression of myosin phosphatase in a model of portal hypertension. Am J Physiol Heart Circ Physiol 286:H1801-10
Young, J L; Benoit, J N; Dean, D A (2003) Effect of a DNA nuclear targeting sequence on gene transfer and expression of plasmids in the intact vasculature. Gene Ther 10:1465-70

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