The role of inflammation and oxidative stress on alpha 2-adrenergic receptor-mediated inhibition of calcium channels in DOCA-salt and obesity-related hypertension
DOCA-salt and obesity-related hypertension are associated with inflammation and sympathetic nervous system hyperactivity. Prejunctional 2-adrenergic receptors (2ARs) provide negative feedback to norepinephrine release from sympathetic nerves through inhibition of N-type Ca2+ channels. Increased neuronal norepinephrine release in DOCA-salt and obesity-related hypertension occurs through impaired 2AR signaling, however, the mechanisms involved are still unclear. Mesenteric arteries are resistance arteries that receive sympathetic innervation from the superior mesenteric and celiac ganglia (SMCG). We tested the hypothesis that macrophages and oxidative stress impair 2AR-mediated inhibition of Ca2+ channels in SMCG neurons in hypertension development and maintenance in DOCA-salt hypertensive rats and obesity-related hypertensive Sprague Dawley (SD) and Dahl salt-sensitive (DahlS) rats. DOCA-salt treated rats developed severe hypertension. On a high fat diet (HFD), SD rats developed obesity with mild hypertension while Dahl S rats developed obesity with severe hypertension. Only DOCA-salt hypertension was associated with increased vascular macrophage accumulation in mesenteric arteries and increased SMCG mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-. Impaired 2AR-mediated inhibition of Ca2+ currents occurred in SMCG neurons from DOCA-salt hypertensive rats and to a milder extent, in obese mildly hypertensive SD rats. This did not occur in SMCG neurons from obese hypertensive DahlS rats. In DOCA-salt hypertension, 2AR dysfunction was not associated with changes in receptor expression, GRK-mediated desensitization, or downstream signaling. In DOCA-salt treated rats, macrophage depletion using clodronate-liposomes preserved 2AR function in SMCG neurons and protected against hypertension development. Oxidative stress, specifically thiol-oxidation, impaired 2AR-mediated inhibition of Ca2+ currents in SMCG neurons and resulted in receptor internalization to the perinuclear cytoplasm in HEK-293T cells. These results suggest that macrophage-mediated 2AR dysfunction may be more relevant in states of mineralocorticoid-salt excess. Furthermore, oxidative stress may impair 2AR signaling by promoting mechanisms of receptor internalization.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Mui, Ryan Kwun-Yee
- Thesis Advisors
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Galligan, James J.
- Committee Members
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Busik, Julia V.
Fink, Gregory D.
Parameswaran, Narayanan
Wiseman, Robert W.
- Date
- 2017
- Subjects
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Sympathetic nervous system
Salt--Physiological effect
Mineralocorticoids
Inflammation
Corticosterone--Physiological effect
Cardiovascular system--Diseases--Animal models
Hypertension
Research
Physiology
Obesity
- Program of Study
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Physiology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xvi, 207 pages
- ISBN
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9780355390254
0355390256