Alcohol elicits unique cardiovascular responses, which are not only dependent on the neuronal substrates within the brainstem but also on the genetic state of these neurons. The objective of this proposal is to elucidate the molecular mechanisms implicated in the differential effect of ethanol on specialized neurons in the brainstem that control blood pressure and cardiac reflexes in a model of essential hypertension, the spontaneously hypertensive rat (SHR). Our recent intriguing findings showed that site dependent neurochemical (norepinephrine, NE) and IEG gene/protein expression (c-jun/c-Jun) responses elicited by ethanol in the ventrolateral medulla (RVLM) and nucleus tractus solitarius (NTS) determine its divergent effects on blood pressure and baroreflex responses in hypertensive and normotensive rats. Given the altered cardiovascular neurobiology and neuronal sensitivity to ethanol in SHRs, we hypothesize that heme oxygenase (HO) derived carbon monoxide (CO) constitutes a novel molecular mechanism for the centra! cardiovascular effects of ethanol. To test this hypothesis, we propose a series of integrative, and molecular studies under three aims.
Aim 1 establishes brainstem HO-CO pathway as a molecular mechanism for the divergent cardiovascular actions of ethanol in SHRs and WKY rats.
Aim 2 will elucidate the effect of ethanol on the association of HO with its regulatory proteins caveolin-1 and calmodulin in brainstem neurons of SHRs and WKY rats.
Aim 3 characterizes the role of HO-CO-MAPK pathway in ethanol-mediated cardiovascular responses. Since catalase activity (the major enzyme that metabolizes ethanol in the brain) is altered in SHRs, the potential contribution of acetaldehyde to ethanol actions will be investigated. The proposal adopts a well designed experimental approach that incorporates an established model system, appropriate controls and pharmacological and siRNA interventions to: (i) establish a causal relationship between inhibition of HO-derived CO and the sympathoexcitatory (pressor) and baroreflex depressant effects of ethanol, and (ii) identify the molecular mechanisms implicated in the site- and strain-dependent neurochemical and cardiovascular effects of ethanol. The proposed research whose primary focus is to probe the molecular mechanisms implicated in the adverse ethanol effects on cardiovascular neurobiology, addresses a significant biomedical problem and is expected to yield clinically relevant information.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007839-18
Application #
7799676
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Orosz, Andras
Project Start
1988-09-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
18
Fiscal Year
2010
Total Cost
$418,428
Indirect Cost
Name
East Carolina University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Abdel-Rahman, Abdel A (2017) Influence of sex on cardiovascular drug responses: role of estrogen. Curr Opin Pharmacol 33:1-5
McGee, Marie A; Abdel-Rahman, Abdel A (2016) N-Methyl-D-Aspartate Receptor Signaling and Function in Cardiovascular Tissues. J Cardiovasc Pharmacol 68:97-105
McGee, Marie A; Abdel-Rahman, Abdel A (2015) Ethanol attenuates peripheral NMDAR-mediated vascular oxidative stress and pressor response. Alcohol 49:499-506
Ibrahim, Badr Mostafa; Abdel-Rahman, Abdel A (2015) A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats. Brain Res 1622:51-63
Penumarti, Anusha; Abdel-Rahman, Abdel A (2014) The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. J Pharmacol Exp Ther 349:29-38
McGee, Marie A; Abdel-Rahman, Abdel A (2014) Enhanced vascular PI3K/Akt-NOX signaling underlies the peripheral NMDAR-mediated pressor response in conscious rats. J Cardiovasc Pharmacol 63:395-405
El-Mas, Mahmoud M; Abdel-Rahman, Abdel A (2014) Ser/thr phosphatases tonically attenuate the ERK-dependent pressor effect of ethanol in the rostral ventrolateral medulla in normotensive rats. Brain Res 1577:21-8
Penumarti, Anusha; Abdel-Rahman, Abdel A (2014) Neuronal nitric oxide synthase-dependent elevation in adiponectin in the rostral ventrolateral medulla underlies g protein-coupled receptor 18-mediated hypotension in conscious rats. J Pharmacol Exp Ther 351:44-53
Ibrahim, Badr M; Abdel-Rahman, Abdel A (2014) Cannabinoid receptor 1 signaling in cardiovascular regulating nuclei in the brainstem: A review. J Adv Res 5:137-45
El-Mas, Mahmoud M; Fan, Ming; Abdel-Rahman, Abdel A (2013) Role of rostral ventrolateral medullary ERK/JNK/p38 MAPK signaling in the pressor effects of ethanol and its oxidative product acetaldehyde. Alcohol Clin Exp Res 37:1827-37

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