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首页> 外文期刊>Nutrition Research >Maintenance of cytosolic calcium is crucial to extend L-arginine therapeutic benefits during continuous dosing
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Maintenance of cytosolic calcium is crucial to extend L-arginine therapeutic benefits during continuous dosing

机译：在连续给药期间，维持胞质钙对于延长L-精氨酸的治疗作用至关重要

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The therapeutic benefits associated with short-term L-arginine supplementation are lost during continuous dosing. AMP-activated protein kinase (AMPK) functional modulation has been correlated with L-arginine therapeutic effectiveness, and with tolerance development during continuous supplementation. However, the metabolic link that is responsible for AMPK functional modulation during continuous L-arginine exposure is currently not known. To explore this, we incubated HUVECs for 7 days with 100 mu mol/L L-arginine, in the presence or absence of other agents; and monitored their effects for eNOS function, and on tolerance sparing effects (viz, cellular glucose accumulation, and oxidative stress). HUVEC co-incubation with 100 mu mol/L L-arginine and <= 1200 mg/mL calcium (Ca2+) for 7 days avoided tolerance development, with an at least 1-fold increase in the eNOS and AMPK functional activity; and an 1-fold increase in overall cellular glucose uptake. The overall cellular cytosolic Ca(2+)was below 200 nmol/L, with no change in cellular glucose and superoxide/peroxynitrite (O-2(.-)/ONOO-) level from control. However, tolerance sparing effects of at least 70% decrease in eNOS and AMPK functional response, with an 1-fold reduction in glucose uptake, and at least 2-fold increase in O-2(.-)/ONOO- were observed in cells exposed for 7 days to 100 mu mol/L L-arginine at Ca2+ co-incubation concentration of >1200 mg/mL. The >1200 mg/mL Ca2+ co-incubation condition, also improved the overall cellular Ca(2+)to >200 nmol/L. Similar tolerance response was observed in cells co-treated with 100 mu mol/L L-arginine and <= 1200 mg/mL Ca2+ in the presence of Ca2+ influx inhibitor (20 mu mol/L 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid), or eNOS activity inhibitor (30 mu mol/L l-N-G-nitroarginine methyl ester). No tolerance response was seen in cells incubated for 7 days with 100 mu mol/L L-arginine and <= 1200 mg/mL Ca2+; even in the presence of the inhibitor for cellular glucose induction (30 mol/L 5-chloro-2-(n-(2,5-dichlorobenzenesulfonamide))-benzoxazole). The present study thus provides the first definitive evidence that shows the need to maintain cytosolic Ca2+ within a threshold limit of less than 200 nmol/L to extend L-arginine therapeutic efficacy during continuous dosing, without any potential tolerance development. (C) 2016 Elsevier Inc. All rights reserved
机译：在连续给药过程中，与短期补充L-精氨酸有关的治疗益处消失了。 AMP激活的蛋白激酶（AMPK）的功能调节与L-精氨酸的治疗效果以及连续补充过程中的耐受性发展有关。但是，目前尚不知道在连续L-精氨酸暴露过程中负责AMPK功能调节的代谢环节。为了探索这一点，我们在有或没有其他药物的情况下，将HUVEC与100μmol/ L L-精氨酸一起孵育7天。并监测其对eNOS功能的影响以及对耐受性保留的影响（即，细胞葡萄糖积累和氧化应激）。 HUVEC与100μmol / L L-精氨酸和<= 1200 mg / mL钙（Ca2 +）共同孵育7天避免了耐受性的发展，eNOS和AMPK功能活性提高了至少1倍;总细胞葡萄糖摄取量增加了1倍。总体细胞质Ca（2+）低于200 nmol / L，细胞葡萄糖和超氧化物/过氧亚硝酸盐（O-2（.-）/ ONOO-）水平与对照组相比没有变化。但是，在细胞中观察到耐受性降低eNOS和AMPK功能反应至少70％，葡萄糖摄取减少1倍，O-2（.-）/ ONOO-至少增加2倍。将Ca2 +共孵育浓度> 1200 mg / mL暴露于100μmol / L L-精氨酸中7天。 > 1200 mg / mL Ca2 +共孵育条件，也将整体细胞Ca（2+）改善至> 200 nmol / L。在Ca2 +流入抑制剂（20μmol/ L 1,2-双（邻氨基苯氧基））存在下，用100μmol/ L L-精氨酸和<= 1200 mg / mL Ca2 +共处理的细胞观察到相似的耐受性反应乙烷-N，N，N'，N'-四乙酸）或eNOS活性抑制剂（30μmol / L 1NG-硝基精氨酸甲酯）。在与100μmol / L L-精氨酸和<= 1200 mg / mL Ca2 +孵育7天的细胞中未观察到耐受反应。即使在存在细胞葡萄糖诱导抑制剂的情况下（30 mol / L 5-氯-2-（n-（2,5-二氯苯磺酰胺））-苯并恶唑）。因此，本研究提供了第一个明确的证据，表明需要在连续给药期间将胞质Ca2 +维持在小于200 nmol / L的阈限内，以扩展L-精氨酸的治疗功效，而没有任何潜在的耐受性发展。 （C）2016 Elsevier Inc.保留所有权利

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