左旋精氨酸在心臟血管醫學領域中之臨床應用及藥理學：今昔觀

Reappraisal of L-Arginine in the Field of Cardiovascular Medicine for Clinical Applications and Pharmacology: An Update

林廷燦(Mike Lin)

《內科學誌》 18卷5期 (2007/10) Pp. 225-235

https://doi.org/10.6314/JIMT.2007.18(5).01

摘要

精氨酸是一氧化氮的前身，是身體內因性之傳遞分子，在人體心血管系統扮演著不同及多樣化內皮主導的生理效應。一氧化氮是相當活躍的氣體分子，也是人體重要的傳遞信息分子。它的功能如血管擴張，神經傳導，發炎，以及規範基因之表現。在動物實驗中，動脈硬化及高膽固醇血症，急性及慢性投予精氨酸治療，皆可改善血管內皮功能，而人類亦然。對於精氨酸之反應度取決於心血管疾病之特殊情況，血管的片段，以及動脈血管的型態。尤有進者，血管發炎與內皮功能失全以及胰島素抗性習習相關，最好的證據是來自新陳代謝症候群。我們認為良好的均衡飲食以及微營養補充策略，將可降低血管發炎的反應。這可能是其中一項重要的機轉，解釋它為何能降低心臟病之原因。目前它已被證實可改善心血管疾病之臨床症狀。包括，心衰竭、冠心病、末梢循環疾病、X症候群、高脂血症、高血糖、雷諾氏症候群以及心臟移植之病人。因此，精氨酸能反轉內皮功能失全意謂著此種氨基酸的確有抗人類動脈硬化的功能。而此種作用牽涉到一氧化氮合成酶受質的供給面。最近研究，特別是血管疾病時，內因性一氧化氮合成醃抑制劑（不對稱性雙甲基精氨酸）會顯著上升，如在腎末期疾病等。尤有進者，在高血壓族群，不管是全身性或肺高壓，使用精氨酸並不能帶來內皮功能失全改善之明顯效應。平心而論，人類對於精氨酸耐受性很好，副作用少，頂多為輕微的胃腸不適症狀。而且劑量大時，副作用才會顯現。提高劑量時，內分泌效應及非特異性反應皆可導致精氨酸誘發之血管擴張。若干長期的研究證實，長期精氨酸療法可改善心血管疾病之臨床症狀。因此，精氨酸做為輔助療法，對於心血管疾病之預防及治療，包括糖尿病、細血管疾病，因此我們將內皮系統視為治療的器官，終將有良好的臨床效應。

關鍵字

內皮 ； 精氨酸 ； 一氧化氮 ； 一氧化氮合成酶 ； 不對稱性雙甲基精氨酸

並列摘要

L-arginine is the precursor for the endogenous synthesis of NO. NO generated from L-arginine is a highly reactive gas and an important messenger molecule that is involved in functions as diverse as neurotransmission, vasodilation, inflammation, and regulation of gene expression. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesteronemia and atherosclerosis. Larginine also improves endothelium-dependent vasodilatation in humans with hypercholesteronemia and atherosclerosis. The responsiveness to L-arginine depends on the specific cardiovascular disease studied, the vessel segment, and morphology of the artery. Moreover, it has become increasingly clear that vascular inflammation strictly correlates with endothelial dysfunction and insuline resistance, with the best evidence coming from patients with the metabolic syndrome. We put forward the new hypothesis that balanced dietary and micronutritional strategies associated with a lower generation of a proinflammatory milieu, which may be one important mechanism linking healthy diets and micronutritional supply to reduce coronary heart disease (CHD). Several long-term studies have been performed that show that chronic oral administration of L-arginine or intermittent infusion therapy can improve clinical symptoms of cardiovascular disease in man such as: congestive heart failure, coronary artery disease, peripheral arterial disease, Syndrome X, hyperlipidemia, hyperglycemia, Raynaud syndrome, as well as cardiac transplant patients. Therefore, reversal of endothelial dysfunction by L-arginine suggest that this amino acid exerts anti-atherosclerotic effects in humans. The latter action also involves NOS substrate supply. Recent clinical trails suggest that ADMA is a prognostic marker of cardiovascular and all-cause mortality in patients with end-stage renal disease. Elevated concentrations of ADMA have been found in patients with peripheral occlusive disease, hyperlipidemia, chronic heart failure, hypertension, and hyperhomocysteinemia. Moreover, the majority of studies with L-arginine in systemic hypertension or primary pulmonary hypertension revealed a lack of effect of this amino acid on endothelial function partly due to reduction of NO physiological utility in vascular endothelial cells. General speaking, L-arginine is well tolerated. Side effects are rare and mostly mild and dose dependent. Endocrine effects and unspecific reactions may contribute to L-arginine-induced vasodilation after higher doses. Several long-term clinical trials and observations have been demonstrated to improve clinical end points of cardiovascular disease in human beings. Thus, L-arginine as adjunctive therapy will do good on human vascular endothelium as target organ for the preventive and therapeutic strategy in certain types of cardiovascular disease.

並列關鍵字

Endothelium ； L-arginine ； NO ； NO(subscript s) ； ADMA