MODERATE ALCOHOL USE--CARDIOVASCULAR RISKS AND BENEFITS

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DESCRIPTION: (Adapted from the Investigator's Abstract) Ingestion of moderate and high amounts of alcohol (ETOH) results in ETOH-induced hypertension (EIH) and exacerbation of existing hypertension. The mechanisms remain undefined. However, ETOH produces imbalances in the vascular production of the potent vasodilator nitric oxide (NO) and the vasoconstrictors superoxide (SO) and angiotensin II (AII) that may be causal to the dose-dependent hemodynamic sequelae produced by ETOH. Chronic ingestion of ETOH decreases antioxidants (e.g. NO, SO dismutase [SOD], glutathione peroxidase [GP]) and up regulates SO and hydrogen peroxide (H202). Up regulation of tyrosine kinases (TYR-K) and selective isozymes of protein kinase C (PKC) may be involved. In vitro TYR-K up regulates NADPH oxidase and angiotensin II (AII) converting enzyme (ACE), whereas PKC isozymes and ETOH down regulate NO at the level of transcription and translation and facilitate the transcription of ACE which generates the potent vasoconstrictor AII. This promotes a positive feedback cycle which can culminate in EIH, since NO decreases and SO increases intracellular calcium (Ca2+) and sodium (Na+) ions and blood pressure. We postulate that EIH results from ETOH-induced parallel increases of free radials and the TYR-K/PKC cascade which increase SO via increased AII and increased NADPH oxidase activity and decreased DOS and GP activity and uncoupling of NOS. This increases the SO/NO balance in the VSM. AII, via formation of SO, in turn, increases Ca2+ and Na+ in smooth muscle producing hypertension. The questions we will test are: (a) Does ETOH increase the SO/NO balance in blood vessels? Using on-line chemical, electrophysiologic and molecular biologic techniques we will measure the changes in production of SO, NO, and H202 by the perfused mesenteric and renal vasculature and their relationship to changes in vascular Ca2+ and Na+ in cohorts of male and female fed a chronic alcoholic (AR) or isocaloric diet (NAI) during the progression of EIH. (b) Test the concept that ETOH activates phospholipase D to increase TYR-K which up regulates oxygen free radicals and PKC isozymes which up regulates ACE and down regulates NOS and the anti-oxidant enzymes to cause the long-term changes in SO/NO ratio and ACE. Planned experiments will define the site at which ETOH up regulates phosphorylation of these enzymes, the specific isozymes of TYR-K and PKC involved and the mechanism by which ETOH prevents their down regulation and their temporal relationship to the increased free radical/NO ratio and to EIH. (c) Test the concept that EIH is mediated by the SO-PKC/TYR-K - AII cascade. NAI and AR rats will be chronically treated with an ACE inhibitor, PEG-SOD, glutathione monoethylester, a selective TTYR-K and PKC isozyme inhibitor, an irreversible NOS inhibitor and l-arginine. The exacerbation or prevention of EIH will be related to drug effects on the cell-signaling pathway. This research can define the cell-signaling pathway in EIH and provide new and novel approaches to treating EIH.