MODERATE ALCOHOL USE--CARDIOVASCULAR RISKS AND BENEFITS

描述：（改编自研究者摘要）摄入 中度和高度酒精（ETOH）导致ETOH诱导的 高血压（EIH）和现有高血压恶化。 的 机制尚未确定。 然而，ETOH产生的不平衡， 血管产生的有效的血管扩张剂一氧化氮（NO）和 血管收缩剂超氧化物（SO）和血管紧张素II（AII），可能是因果关系 ETOH产生的剂量依赖性血流动力学后遗症。 慢性 ETOH的摄入降低了抗氧化剂（例如NO，SO歧化酶[SOD]， 谷胱甘肽过氧化物酶[GP]）和上调SO和过氧化氢 （H202）。 酪氨酸激酶（TYR-K）和选择性同工酶的上调 蛋白激酶C（PKC）可能参与其中。 体外TYR-K上调NADPH 氧化酶和血管紧张素II（AII）转换酶（ACE），而PKC 同工酶和ETOH在转录水平下调NO， 翻译并促进ACE的转录， 强效血管收缩剂AII。 这促进了一个积极的反馈循环， 由于NO减少，SO增加， 钙（Ca 2+）和钠（Na+）离子与血压的关系。 我们推测 EIH是由ETOH诱导的自由基平行增加引起的， TYR-K/PKC级联通过增加AII和增加NADPH增加SO 氧化酶活性降低，DOS和GP活性降低，NOS解偶联。 这增加了VSM中的SO/NO平衡。 所有，通过形成SO， 反过来，增加平滑肌中的Ca 2+和Na+，产生高血压。 的 我们将测试的问题是：（a）ETOH是否增加了SO/NO平衡， 血管？ 利用在线化学，电生理和分子 生物技术，我们将测量SO，NO， H202在肠系膜和肾血管中的表达及其相互关系 在雄性和雌性队列中， 慢性酒精性（AR）或等热量饮食（NAI）， EIH。 (b)测试ETOH激活磷脂酶D以增加 TYR-K上调氧自由基和PKC同工酶， 调节ACE，下调NOS和抗氧化酶， SO/NO比值和ACE的长期变化。 计划中的实验将 定义ETOH上调这些酶磷酸化的位点， TYR-K和PKC的特异性同工酶及其作用机制 ETOH阻止了它们的下调以及它们与细胞凋亡的时间关系。 增加自由基/NO比值和EIH。 (c)测试EIH的概念 由SO-PKC/TYR-K - AII级联介导。 NAI和AR大鼠将 长期接受ACE抑制剂、PEG-SOD、谷胱甘肽 单乙酯，选择性TTYR-K和PKC同工酶抑制剂， 不可逆NOS抑制剂和L-精氨酸。 恶化或预防 EIH的发生与药物对细胞信号通路的影响有关。 这 研究可以确定EIH中的细胞信号通路，并提供新的， 治疗EIH的新方法。

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.