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.
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