This proposal extends our previous findings on the altered hemodynamic actions of systemic ethanol in an animal model of human hypertension and its adverse interaction with centrally acting hypotensive drugs. The proposal addresses this important biomedical problem by investigating the central mechanisms implicated in alcohol actions on blood pressure, and its impact on antihypertensive therapy with clonidine and an emerging class of drugs, the imidazoline (I1) receptor agonists (e.g. rilmenidine). The proposal will focus on the actions of ethanol on the neuronal activity of two brainstem areas, the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS), known to play pivotal roles in cardiovascular regulation and in the hypotensive action of centrally-acting drugs. An innovative approach of this application is the blending of integrative cardiovascular biology studies, in vivo electrochemistry, in situ hybridization, and radiotelemetry to address three specific aims.
Aim 1 investigates the acute electrochemical (norepinephrine, NE) and cardiovascular actions of ethanol microinjection into the NTS vs. the RVLM of hypertensive and """"""""normotensive"""""""" rats. Additionally, it tests the hypothesis that ethanol selectively alters the neuronal signaling triggered by the I1-receptor in the RVLM. The powerful technique that permits real time monitoring of NE electrochemical signal (index of neuronal activity) and microinjections into, the NTS or RVLM of conscious rats will be used.
Aim 2 identifies the neuronal substrates in the brainstem implicated in ethanol attenuation of the baroreflex function and in its reversal of I1 mediated hypotension, using c-fos expression as a marker of neuronal activity.
Aim 3 utilizes a newly developed model system to investigate the chronic effects of moderate amounts of ethanol on blood pressure, cardiac autonomic function (spectral analysis of heart rate variability) in radiotelemetered hypertensive and normotensive rats. The hypothesis is tested that ethanol reductions in the """"""""2A-adrenergic receptor expression or I1-receptor binding in the brainstem or the inhibition of their function contribute to the chronic actions of ethanol on blood pressure and on clonidine hypotension. The proposed studies will contribute to the understanding of the mechanism(s) of central ethanol actions on cardiovascular neurobiology. The important aspects of the proposal are the utilization of newly developed model systems and two indices of neuronal activity to elucidate the role of the brainstem neurons in ethanol actions. This proposal, which addresses an important scientific problem, is expected to yield significant new information on the central cardiovascular actions of ethanol and on the treatment of hypertension in alcohol using individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007839-13
Application #
6629561
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Brown, Ricardo A
Project Start
1988-09-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
13
Fiscal Year
2003
Total Cost
$325,440
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
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
McGee, Marie A; Abdel-Rahman, Abdel A (2015) Ethanol attenuates peripheral NMDAR-mediated vascular oxidative stress and pressor response. Alcohol 49:499-506
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
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
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
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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