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
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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