Sustained elevated blood pressure-hypertension is a prominent cause of morbidity and deaths throughout the world. Hypertension is associated with increased activity in the sympathetic nervous system resulting in constriction of blood vessels, increased heart contractility and retention of sodium and water. It is the central hypothesis of this project that veins and arteries are innervated by separate neurons in sympathetic ganglia and that alterations in properties of vein neurons contribute to venoconstriction in hypertension. In normotensive and DOCA-salt hypertensive rats we will compare the properties of identified arterial and venous neurons in the prevertebral sympathetic ganglia that innervate the splanchnic blood vessels and and determine their properties with respect to firing behavior, generation of reactive oxygen species and function of the norepinephrine uptake system. We also will compare the properties of prevertebral neurons to those in stellate ganglia that provide the sympathetic innervation to the heart and associated great vessels in the thorax. We will pursue the following specific aims. 1) Determine the localization and electrophysiologic characteristics of arterial and venous sympathetic neurons in the intact inferior mesenteric ganglion of the rat and characterize arterial and venous neurons in primary dissociated cell culture. 2) Determine the localization and regulation of ROS-generating enzymes within the arterial and venous neurons of celiac ganglia and within stellate ganglion neurons. 3) Determine the mechanisms of regulation of sympathetic neuron function by ETB receptors. 4) Compare the properties of celiac ganglion neurons (peripheral volume regulation) to those of stellate ganglion neurons (central volume regulation). Our long-term objective is to discover novel properties of the sympathetic nervous system that will be susceptible to treatment of human hypertension. LAY SUMMARY: High blood pressure is a major health problem. The sympathetic nervous system, the part of the nervous system that functions when the body is stressed, is hyperactive in hypertension. This overactivity is a cause of the disease and many of the bad effects that accompany it. This study tries to find out what malfunctions in the nerve cells that are outside the brain and spinal cord that innervate the arteries, veins and heart. We think that the nerves that innervate veins cause them to contract too much and this is one cause of high blood pressure. We hope to discover a treatment based on this idea.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070687-10
Application #
8452154
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
$289,410
Indirect Cost
$94,576
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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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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