MODERATE ALCOHOL USE--CARDIOVASCULAR RISKS AND BENEFITS

描述：(改编自《调查者摘要》)摄入 中高剂量的酒精(Etoh)会导致Etoh诱导 高血压(EIH)和现有高血压的恶化。这个 机制仍未明确。然而，Etoh在经济中产生了不平衡 强大的血管扩张剂一氧化氮(NO)和血管生成 可能导致血管收缩的超氧化物歧化酶(SO)和血管紧张素II(AII) 无水乙醇所产生的剂量依赖性血流动力学后遗症。慢性 摄入乙醇会减少抗氧化剂(例如，一氧化氮，超氧化物歧化酶[SOD]， 谷胱甘肽过氧化物酶)和上调SO和过氧化氢 (H202)。酪氨酸激酶(TYR-K)及其选择性同工酶的上调 蛋白激酶C(PKC)可能参与其中。TYR-K体外上调NADPH的作用 氧化酶和血管紧张素II(AII)转换酶(ACE)，而PKC 同工酶和乙醇在转录和转录水平下调NO 翻译并促进ACE的转录，从而生成 强效的血管收缩药。这促进了一个正反馈循环， 可在EIH中达到顶峰，因为NO减少，从而增加细胞内 钙(Ca+)和钠(Na+)离子与血压之间的关系。我们假定 EIH的原因是乙醇诱导的自由基平行增加和 TYR-K/PKC级联反应通过增加AII和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。所有的，通过形成SO，in 反过来，会增加血管中的钙和钠离子，从而产生高血压。这个 我们将测试的问题是：(A)Etoh是否增加了 血管？使用在线化学、电生理和分子 生物技术我们将测量SO，NO和 H202通过肠系膜血管和肾血管的灌流及其相互关系 不同年龄组大鼠血管钙、钠离子含量变化的关系 慢性酒精(AR)或等卡路里饮食(NAI)在糖尿病进展中的作用 EIH。(B)检验乙醇激活磷脂酶D增加的概念 Tyr-K上调氧自由基和PKC同工酶 调节血管紧张素转换酶和下调一氧化氮合酶及抗氧化酶引起 SO/NO比值和血管紧张素转换酶的长期变化。计划中的实验将 确定乙醇上调这些酶的磷酸化的位置， 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 自由基/NO比值升高，易致EIH。(C)测试EIH的概念 是由SO-PKC/TYR-K-AII级联途径介导的。NAI和AR大鼠将被 长期使用血管紧张素转换酶抑制剂，聚乙二醇超氧化物歧化酶，谷胱甘肽 单乙酯，一种选择性的TTYR-K和PKC同工酶抑制剂，以及 不可逆一氧化氮合酶抑制剂和L精氨酸。加重或预防 EIH的发生将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，并提供新的和 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.