Negative Impact of Alcohol on Antihypertensive Therapy Grant uri icon

abstract

  • 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). These studies will build on our recent intriguing findings that site dependent neurochemical (norepinephrine, NE) and lEG gene/protein expression (c-jun/c-Jun) elicited by ethanol in the ventrolateral medulla (RVLM) and nucleus tractus solitarius (NTS) determine the differential blood pressure and baroreflex responses in hypertensive and normotensive rats. Given the altered cardiovascular neurobiology and neuronal sensitivity to ethanol in SHRs, compared with normotensive Wistar Kyoto (WKY) rats, we hypothesize that heme oxygenase (DO) derived carbon monoxide (CO) constitutes a novel molecular mechanism for the central cardiovascular effects of ethanol. To test this hypothesis, we propose a series of integrative, signal transduction and molecular studies under three aims. Aim 1 establish brainstem neuronal HO-CO pathway as a molecular mechanism for the differential cardiovascular actions of ethanol in SHRs and WKY rats. Aim 2 will elucidate the effect of ethanol and its first metabolite, acetaldehyde, on the spatial distribution / association of HO with its regulatory proteins caveolin-l and calmodulin in brainstem neurons of SHRs and WKY rats. Aim 3 characterizes the signal transduction mechanisms implicated in ethanol neuronaly-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 evaluated in aims 2 and 3 studies. The proposal adopts a well designed experimental approach that incorporates an established model system, appropriate controls and pharmacological 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 and the potential contribution of acetaldehyde to these effects. The proposed research whose primary focus is to probe the molecular mechanisms implicated in the adverse effects of ethanol on cardiovascular neurobiology, addresses a significant biomedical problem and is expected to yield clinically relevant information.

date/time interval

  • June 2004 - March 2010