The main theme of this theme is that there is differential control of mesenteric arteries (MA) and veins (MV) by sympathetic nerves. We will identify these differences in detail and we will also identify the molecular mechanisms mediating deoxycorticosterone acetate (DOCA)-salt hypertension associated changes in sympathetic transmission to MA and MV in rats.
Specific aim 1 will test the hypothesis that sympathetic transmission to MA and MV is different and these mechanisms are differentially altered in hypertension. These studies will use intracellular electrophysiological techniques to record purinergic excitatory junction potentials (EJPs) caused by ATP released from sympathetic nerves supplying MA in vitro. We show that oxidative stress is responsible for impairment of purinergic signaling to MA in hypertension. We will also use continuous amperometry and fast scan cyclic voltametry (FSCV) to make electrochemical measurements of neurotransmitter release profiles from sympathetic nerves associated with MA and MV in vitro. Finally, these studies will use FSCV to study neurotransmitter release profiles from adrenal chromaffin cells in primary culture. The studies in this aim will show that sympathetic nerves supplying MA and MV use different neurotransmitters, release and clearance mechanisms and that sympathetic transmission to MA but not MV is altered in DOCA-salt hypertension. Adrenal chromaffin cells will used as a model of periarterial sympathetic nerves.
Specific aim 2 will test the hypothesis that B2-adrenergic receptor (AR)-mediated vasodilation is reduced in DOCA-salt rats. We propose that increased vascular tone in DOCA-salt hypertension is partly due to impairment of the link between the B2-AR-cAMP-protein kinase A signaling pathway and large conductance Ca[2+] activated K[+] (BK) channels in MA and MV. These studies will measure: B2-AR agonist-induced relaxations of MA and MV in vitro, BK channel currents using patch clamp methods and heterologous receptor and ion channel expression to study molecular mechanisms linking B2- ARs to BK channels.
Specific aim 3 will test the hypothesis that MV "reverse remodel" in DOCA-salt rats. Reverse remodeling is caused by activation of endothelin-B and a1-adrenergic receptor activation on venous smooth muscle cells which couple to activation of matrix metalloproteinase-2 and tenascin-C. Reverse remodeling is an adaptive response of veins to the decreased venous volume caused by volume shifts from the capacitance to the resistance side of the circulation in hypertension. These studies will provide new information about differential neurohumoral control of arteries and veins. We will also identify specific changes in neural control of arteries and veins in hypertension and this information will facilitate the development of new treatments for high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070687-10
Application #
8452152
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
$309,104
Indirect Cost
$105,744
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
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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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