Calcium-mediated mechanisms of eicosapentaenoic acid-induced relaxation in hypertensive rat aorta
Calcium-mediated mechanisms of eicosapentaenoic acid-induced relaxation in hypertensive rat aorta
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DOI：
10.1016/s0895-7061(99)90060-2
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发表时间：
1999-12-01
影响因子：
3.2
通讯作者：
Engler, MM
中科院分区：
文献类型：
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作者：
Engler, MB;Ma, YH;Engler, MM
我们以前已经证明了ω-3脂肪酸，二十碳五烯酸（EPA），在正常血压和自发性高血压大鼠（SHR）的主动脉血管舒张特性，虽然（S）的作用机制尚未完全理解。由于在高血压大鼠主动脉中观察到内皮功能障碍和细胞内游离钙浓度（[Ca 2 +]（i））增加，我们研究了Ca 2+信号、内皮和衍生因子以及钾（K+）通道开放在EPA诱导的舒张中的潜在作用。在细胞外Ca ~（2+）存在下，EPA在> 10 μ mol/L（P < .01）时可使去甲肾上腺素（NE）（10（-6）mol/L）收缩的主动脉环舒张，在30 μ mol/L（P < .001）时可使高K ~+（80 mmol/L）收缩的主动脉环舒张。在细胞外Ca ~（2+）缺乏的情况下，EPA（10 ~ 30 μ mol/L）抑制NE引起的收缩的紧张成分（P <0.0001）。EPA在SHR主动脉中的舒张特性似乎特异于与NE诱导的紧张性收缩相关的内部储存部位的Ca 2+释放。进一步研究使用fura-2测定培养的SHR主动脉血管平滑肌（VSM）细胞中的[Ca 2 +]（i），结果表明EPA（30 μ mol/L）预处理可使血管紧张素II（50 nmol/L）诱导的Ca 2+瞬变减弱95%，这表明对Ca 2+信号传导的抑制作用可能是EPA诱导的血管制剂舒张的基础。此外，EPA本身在VSM细胞中诱导[Ca 2 +]（i）增加，持续时间约为20 min，并且该效应不因去除细胞外Ca 2+而改变。EPA（30 μ mol/L）没有增加肌醇-1，4，5-三磷酸水平。EPA的作用不依赖于内皮衍生因子、环氧合酶代谢物和K+通道的激活，因为内皮去除、N-ω-硝基-L-精氨酸甲酯盐酸盐（L-NAME，100 μ mol/L）、吲哚美辛（10 μ mol/L）、四乙基铵（1 mmol/L）和格列本脲（10 μ mol/L）不影响NE预收缩主动脉环中EPA诱导的血管舒张。这些结果表明，EPA直接调节细胞内钙离子信号在VSM细胞，这可能有助于血管舒张作用，至少在一定程度上，鱼油的降血压作用。美国高血压杂志1999;12：1225-1235（C）1999美国高血压杂志有限公司。
We have previously demonstrated the vasorelaxant properties of the omega-3 fatty acid, eicosapentaenoic acid (EPA), in normotensive and spontaneously hypertensive rat (SHR) aorta, although the mechanism(s) of action are not fully understood. Because endothelial dysfunction and increased intracellular free calcium concentration ([Ca2+](i)) are seen in hypertensive rat aorta, we investigated the potential role of Ca2+ signaling, endothelium and derived factors, and the opening of potassium (K+) channels in EPA-induced relaxation. In the presence of extracellular Ca2+ EPA induced significant relaxations at > 10 mu mol/L (P < .01) in norepinephrine (NE) (10(-6) mol/L)-contracted aortic rings and at 30 mu mol/L (P < .001) in high K+ (80 mmol/L)-contracted aortic rings. In the absence of extracellular Ca2+, EPA (10 to 30 mu mol/L) inhibits the tonic component of NE-induced contraction (P < .0001). The relaxant properties of EPA in SHR aorta appear specific to Ca2+ release from an internal storage site associated with NE-induced tonic contraction. Further studies with the use of fura-2 to measure [Ca2+](i) in cultured vascular smooth muscle (VSM) cells from SHR aorta indicated that EPA (30 mu mol/L)-pretreatment attenuated angiotensin II (50 nmol/L)-induced Ca2+ transient by 95%, suggesting that an inhibitory effect on the Ca2+ signaling may underlie EPA-induced relaxation of the vessel preparation. In addition, EPA per se induced an increase in [Ca2+](i) with a duration of approximately 20 min in VSM cells, and the effect was not altered by removal of extracellular Ca2+. There was no increase in the level of inositol-1,4,5-trisphosphate in response to EPA (30 mu mol/L). The actions of EPA are independent of endothelium-derived factors, cyclooxygenase metabolites, and activation of K+ channels since endothelium removal, N-omega-nitro-L-arginine methyl ester hydrochloride, (L-NAME, 100 mu mol/L), indomethacin (10 mu mol/L), tetraethylammonium (1 mmol/L), and glibenclamide (10 mu mol/L) did not affect EPA-induced vasodilation in NE-precontracted aortic rings. These results suggest that EPA directly modulates intracellular Ca2+ signaling in VSM cells, and that this may contribute to the vasorelaxant effect and, at least in part, the blood pressure-lowering effect of fish oil. Am J Hypertens 1999;12:1225-1235 (C) 1999 American Journal of Hypertension, Ltd.