A sustained increase in arterial blood pressure-i.e. hypertension-is a major cause of excess morbidity and mortality around the world. Chronic arterial pressure levels are thought to be established primarily by the kidney through regulation of total blood volume. The central hypothesis of this project is that veins contribute to long-term control of arterial pressure by actively redistributing blood from high compliance vascular compartments (peripheral, particularly splanchnic veins) to compartments of lower compliance (central veins, heart and arteries). Our goal is to show in intact conscious animals how neurohumoral mechanisms controlling the diameter of peripheral veins (peripheral vascular capacitance) affect arterial pressure and the development of hypertension. We will use two models of hypertension in rats: DOCA-salt;and a new model that we believe is based primarily on venoconstriction, i.e. S6c-induced hypertension. We will address our central hypothesis with the following Specific Aims. 1) Determine if venoconstriction causes body fluid volume redistribution during the development of hypertension by using three complementary methods to assess blood volume redistribution in conscious rats. 2) Establish that one mechanism of decreased vascular capacitance in hypertension is increased sympathetic nerve activity (and/or release of norepinephrine) in the splanchnic region using both direct nerve recording and regional norepinephrine spillover methods. 3) Show how sympathetic innervation to the splanchnic region affects regulation of vascular capacitance and arterial pressure by testing the effects on hypertension development of chronic splanchnic sympathetic denervation, and decreasing elevated superoxide levels in splanchic sympathetic ganglia using gene transfer methods. 4) Determine how venoconstriction ultimately leads to increased arterial pressure by testing the influence of small artery myogenic tone, large artery compliance, and cardiac sympathetic activity on the development of S6c-induced hypertension. Our ultimate objective is to identify novel strategies for treating human hypertension. Lay Summary: High blood pressure (hypertension) is a major human health problem. Many scientists feel the causes of hypertension can be found in abnormal function of the kidney or arteries. This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070687-10
Application #
8452151
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$205,153
Indirect Cost
$64,265
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Jackson, William F (2016) Boosting the signal: Endothelial inward rectifier K(+) channels. Microcirculation :
Matin, Nusrat; Fisher, Courtney; Jackson, William F et al. (2016) Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles. Am J Physiol Heart Circ Physiol 310:H1321-9
Hammond, Bradley; Kreulen, David L (2016) Gene Therapy of the Peripheral Nervous System: Celiac Ganglia. Methods Mol Biol 1382:275-83
Ismail, Alex; Ayala-Lopez, Nadia; Ahmad, Maleeha et al. (2016) 3T3-L1 cells and perivascular adipocytes are not equivalent in amine transporter expression. FEBS Lett :
Seitz, Bridget M; Krieger-Burke, Teresa; Fink, Gregory D et al. (2016) Serial Measurements of Splanchnic Vein Diameters in Rats Using High-Frequency Ultrasound. Front Pharmacol 7:116
Matin, Nusrat; Pires, Paulo W; Garver, Hannah et al. (2016) DOCA-salt hypertension impairs artery function in rat middle cerebral artery and parenchymal arterioles. Microcirculation 23:571-579
Jackson, William F (2016) Arteriolar oxygen reactivity: where is the sensor and what is the mechanism of action? J Physiol 594:5055-77
Diaz-Otero, Janice M; Garver, Hannah; Fink, Gregory D et al. (2016) Aging is associated with changes to the biomechanical properties of the posterior cerebral artery and parenchymal arterioles. Am J Physiol Heart Circ Physiol 310:H365-75
Xu, Hui; Garver, Hannah; Fernandes, Roxanne et al. (2015) BK channel β1-subunit deficiency exacerbates vascular fibrosis and remodelling but does not promote hypertension in high-fat fed obesity in mice. J Hypertens 33:1611-23
Pires, Paulo W; Jackson, William F; Dorrance, Anne M (2015) Regulation of myogenic tone and structure of parenchymal arterioles by hypertension and the mineralocorticoid receptor. Am J Physiol Heart Circ Physiol 309:H127-36

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