Engler M B, Ma Y H, Engler M M
Department of Physiological Nursing, University of California, San Francisco 94143-0610, USA.
Am J Hypertens. 1999 Dec;12(12 Pt 1-2):1225-35. doi: 10.1016/s0895-7061(99)90060-2.
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 micromol/L (P<.01) in norepinephrine (NE) (10(-6) mol/L)-contracted aortic rings and at 30 micromol/L (P<.001) in high K+ (80 mmol/L)-contracted aortic rings. In the absence of extracellular Ca2+, EPA (10 to 30 micromol/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 micromol/ 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+li 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 micromol/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 micromol/L), indomethacin (10 micromol/L), tetraethylammonium (1 mmol/L), and glibenclamide (10 micromol/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.
我们之前已证明，ω-3脂肪酸二十碳五烯酸（EPA）对正常血压大鼠和自发性高血压大鼠（SHR）的主动脉具有血管舒张特性，尽管其作用机制尚未完全明确。由于在高血压大鼠主动脉中可观察到内皮功能障碍和细胞内游离钙浓度（[Ca2+]i）升高，我们研究了Ca2+信号传导、内皮及相关因子以及钾（K+）通道开放在EPA诱导的舒张中的潜在作用。在细胞外Ca2+存在的情况下，EPA在>10 μmol/L时可使去甲肾上腺素（NE）（10(-6) mol/L）预收缩的主动脉环产生显著舒张（P<.01），在30 μmol/L时可使高钾（80 mmol/L）预收缩的主动脉环产生显著舒张（P<.001）。在无细胞外Ca2+时，EPA（10至30 μmol/L）可抑制NE诱导收缩的张力成分（P<.0001）。EPA在SHR主动脉中的舒张特性似乎特定于与NE诱导的张力收缩相关的内部储存部位释放Ca2+。进一步使用fura-2测量SHR主动脉培养的血管平滑肌（VSM）细胞中[Ca2+]i的研究表明，EPA（30 μmol/L）预处理可使血管紧张素II（50 nmol/L）诱导的Ca2+瞬变减弱95%，这表明对Ca2+信号传导的抑制作用可能是EPA诱导血管舒张的基础。此外，EPA本身可使VSM细胞中的[Ca2+]i升高，持续约20分钟，且去除细胞外Ca2+后该效应未改变。对EPA（30 μmol/L）无肌醇-1,4,5-三磷酸水平升高的反应。EPA的作用独立于内皮衍生因子、环氧化酶代谢产物和K+通道的激活，因为去除内皮、N（ω）-硝基-L-精氨酸甲酯盐酸盐（L-NAME，100 μmol/L）、吲哚美辛（10 μmol/L）、四乙铵（1 mmol/L）和格列本脲（10 μmol/L）均不影响EPA诱导的NE预收缩主动脉环的血管舒张。这些结果表明，EPA直接调节VSM细胞内的Ca2+信号传导，这可能有助于其血管舒张作用，并且至少部分有助于鱼油的降压作用。
