Hypertension is a significant public health concern around the world because it is an important risk factor for cardiovascular and renal disease. Most efforts to understand and treat this condition have focused logically on either the kidney or arteries. The three central and complementary themes of this Program Project are: veins play an important role in the long-term control of arterial pressure;neurohumoral mechanisms regulating venous smooth muscle activity are fundamentally different from those of arteries;and abnormalities in neurohumoral regulation specific to veins are a significant part of the etiology of hypertension. The overall strategy for achieving the experimental goals listed above will be to capitalize on the diverse scientific expertise of individual project investigators - from whole animal studies to molecular approaches - to test in detail a single integrated hypothesis linking the sympathetic nervous system, ET-1 and reactive oxygen species to the control of venomotor tone and blood pressure. We will focus our efforts on understanding the etiology of hypertension primarily using the DOCA-salt model of hypertension in rats. Project 1 will assess venous function in conscious rats using a number of whole body measures including blood pressure, mean circulatory filling pressure, cardiac output, and fluid volume distribution using bioimpedance. Project 2 focuses on differences in adrenergic neurotransmission in veins versus arteries and the adaptive mechanisms of veins to hypertension. Project 3 aims at comparing properties of sympathetic neurons targeting arteries, veins and the heart in normotensive and hypertensive rats, and the generation and effects of superoxide and other reactive oxygen species in sympathetic ganglia. Project 4 will investigate arterial vs venous function by examining how ET receptors operate differently in arteries versus veins, why arteries and veins have different reactive oxygen species metabolizing systems and why veins and arteries have a different response (adaptive or otherwise) to the stresses of 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 #
8452150
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Maric-Bilkan, Christine
Project Start
2002-07-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$1,366,846
Indirect Cost
$457,142
Name
Michigan State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Tykocki, Nathan R; Wu, BinXi; Jackson, William F et al. (2015) Divergent signaling mechanisms for venous versus arterial contraction as revealed by endothelin-1. J Vasc Surg 62:721-33
Ayala-Lopez, N; Martini, M; Jackson, W F et al. (2014) Perivascular adipose tissue contains functional catecholamines. Pharmacol Res Perspect 2:e00041
Wehrwein, Erica A; Yoshimoto, Misa; Guzman, Pilar et al. (2014) Role of cardiac sympathetic nerves in blood pressure regulation. Auton Neurosci 183:30-5
Sangsiri, Sutheera; Dong, Hua; Swain, Gregory M et al. (2013) Impaired function of prejunctional adenosine A1 receptors expressed by perivascular sympathetic nerves in DOCA-salt hypertensive rats. J Pharmacol Exp Ther 345:32-40
Tykocki, N R; Thompson, J M; Jackson, W F et al. (2013) Ryanodine receptors are uncoupled from contraction in rat vena cava. Cell Calcium 53:112-9
Watts, Stephanie W; Dorrance, Anne M; Penfold, Mark E et al. (2013) Chemerin connects fat to arterial contraction. Arterioscler Thromb Vasc Biol 33:1320-8
Johnson, Kyle B; Petersen-Jones, Humphrey; Thompson, Janice M et al. (2012) Vena cava and aortic smooth muscle cells express transglutaminases 1 and 4 in addition to transglutaminase 2. Am J Physiol Heart Circ Physiol 302:H1355-66
Xu, Hui; Kandlikar, Sachin S; Westcott, Erika B et al. (2012) Requirement for functional BK channels in maintaining oscillation in venomotor tone revealed by species differences in expression of the ýý1 accessory subunits. J Cardiovasc Pharmacol 59:29-36
Kandlikar, Sachin S; Fink, Gregory D (2011) Splanchnic sympathetic nerves in the development of mild DOCA-salt hypertension. Am J Physiol Heart Circ Physiol 301:H1965-73
Jackson, William F (2011) Quick change artist: endothelium-derived relaxing factor in resistance arteries. Hypertension 57:686-8

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