MECHANISM OF DISEASE PREVENTION BY N 3 FATTY ACIDS

我们广泛的、长期的目标是了解(S) 常见的膳食多不饱和脂肪酸(PUFA)可以防止致命 由缺血、毒性、激素或其他因素引起的心律失常 神经体液应激，正如我们现在所展示的那样。膳食中的多不饱和脂肪酸中有两种 欧米茄-3(n-3)多不饱和脂肪酸、二十碳五烯酸(C2O：5n-3，EPA)和 二十二碳六烯酸(c22：6n-3)是最有效的抗心律失常药物 而花生四烯酸(C2O：4n-3，AA)是致心律失常的，如果 心脏细胞正在从AA中产生生态类板蓝素。 我们的具体目标是： (1)确定防止游离多不饱和脂肪酸的主要来源 心律失常是指多不饱和脂肪酸在细胞膜上占据sn-2位置。 磷脂或未酯化的脂肪酸池中的磷脂。 (2)确定强势之间是否存在关系 溶血磷脂酰胆碱的心律失常作用及预防 多不饱和脂肪酸致心律失常 (3)确定AA的哪个二十烷类化合物(氧化代谢物)是 节律异常，即环氧合酶、脂氧合酶或 环氧合酶，以及其抗心律失常作用的机制。 (4)多不饱和脂肪酸抑制时细胞内游离钙水平的测定 节律失常。 (5)用膜片钳确定要调制的离子通道(S) EPA和DHA在体内产生的兴奋性/自动性的变化 分离的心脏细胞。我们现在认为，这些变化构成了 这些多不饱和脂肪酸的抗心律失常作用。 这些研究与健康的相关性在于，它们将增加我们的 了解这些脂肪酸是如何在人体内慢性摄入的 饮食或在缺血应激前静脉注射可以 预防致命的心律失常。约60%的人死亡(每年约30万人) 由心源性猝死引起的急性心肌梗塞， 即室性快速心律失常，在美国，潜在的公众 这一知识对健康的益处可能是相当大的。

Our broad, long term objective is to understand the mechanism(s) by which common dietary polyunsaturated fatty acids (PUFA) can prevent lethal cardiac tachyarrhythmias resulting from ischemic, toxic, hormonal, or neurohumoral stress, as we now have demonstrated. Of the dietary PUFAs two omega-3 (n-3) PUFA, eicosapentaenoic acid (C2O:5n-3, EPA) and docosahexaenoic (c22:6n-3) are the most potent in their antiarrhythmic effects, whereas arachidonic acid (C2O:4n-3, AA) is proarrhythmic if the heart cells are making ecoisanoids from AA. Our specific aims are: (1) To determine if the primary source of the free PUFA which prevents cardiac arrhythmias is that PUFA occupying the sn-2 position in membrane phospholipids or that in the nonesterified fatty acid pool. (2) To determine if there exists a relationship between the potent dysrhythmic effects of lysophosphatidylcholine and the prevention of that arrhythmia by PUFA (3) To determine which eicosanoid (oxidized metabolite) of AA is prodysrhythmic, i.e., an AA product of cyclooxygenase, lipoxygenase, or epoxygenase, and what is the mechanism of its arrhythmic effect. (4) To determine cytosolic free Ca2+ levels when PUFA inhibit dysrhythmias. (5) To determine by patch clamp which ion channel(s) is modulated to make the changes in excitability/automaticity which EPA and DHA produce in isolated heart cells. These changes, we now think, constitute the primary antiarrhythmic action of these PUFAs. The health relatedness of these studies is that they will increase our understanding of how these fatty acids, when ingested chronically in the diet or injected intraveneously just prior to an ischemic stress can prevent fatal arrhythmias. With some 60% of deaths (some 300,000 annually) from acute myocardial infarctions resulting from sudden cardiac death, i.e., ventricular tachyarrhythmias, in the U.S.A., the potential public health benefits of this knowledge may be considerable.