Department of Veterinary Pharmacology & Toxicology, College of Veterinary Science & Animal Husbandry, Pandit Deen Dayal Upadhyaya Veterinary University & Go-Anusandhan Sansthan (DUVASU), Mathura, UP, India.
Eur J Pharmacol. 2010 Jun 25;636(1-3):108-13. doi: 10.1016/j.ejphar.2010.02.041. Epub 2010 Mar 27.
It is known that long chain polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have beneficial effects on cardiovascular function including pulmonary hypertension. The purpose of the present study was to examine the mechanisms involved in EPA-induced relaxation of sheep isolated pulmonary artery by measuring isometric tension. Nitric oxide (NO) derived from constitutive nitric oxide synthase (cNOS) was measured by Greiss method in the presence of the inducible nitric oxide synthase (iNOS) selective inhibitor N-[[3-(aminomethyl) phenyl]methyl]-ethanimidamide, dihydrochloride (1400 W). EPA (10(-)(7)-10(-)(4)M) caused concentration-dependent relaxation of sheep pulmonary artery with a pD(2) of 5.56+/-0.09 and E(max) of 87.40+/-3.10% (n=9). N(G)-nitro-L-arginine methyl ester (L-NAME) 100 microM significantly attenuated (E(max) 41.95+/-6.70%; n=8) EPA-induced relaxation of endothelium intact arterial rings. Similarly, endothelium denudation markedly inhibited (E(max) 17.60+/-1.21%; n=4) EPA-induced relaxation. EPA (30 microM) significantly increased the cNOS-derived NO release (10.17+/-0.96; n=8 versus control 7.43+/-0.78 pmol/mg tissue wet wt./h; n=7) in endothelium intact vessels. However, EPA-stimulated NO release was markedly blunted by either 100 microM L-NAME (7.07+/-0.54 pmol/mg tissue wet wt./h; n=8) or endothelium removal (6.97+/-0.87 pmol/mg tissue wet wt./h; n=17). In endothelium-denuded K(+) (80 mM)-depolarized arterial rings, EPA (30 microM) significantly inhibited CaCl(2)-induced contractions (E(max) 42.77+/-5.90% versus control 94.78+/-9.82%; n=5). The fatty acid also inhibited nifedipine (1 microM)-insensitive 5-HT-induced contractions in this vessel (E(max) 70.57+/-4.88% versus control 161.50+/-17.46%; n=5). In conclusion, EPA relaxes sheep pulmonary artery primarily through endothelium-dependent NO release, and the residual endothelium-independent relaxation may result from inhibition of Ca(2+)-influx through L-type calcium channels, as well as 5-HT-stimulated intracellular Ca(2+) release.
据了解，长链多不饱和脂肪酸，如二十碳五烯酸（EPA），对心血管功能有有益影响，包括肺动脉高压。本研究的目的是通过测量等长张力来研究 EPA 诱导绵羊离体肺动脉松弛的机制。在诱导型一氧化氮合酶（iNOS）选择性抑制剂 N-[[3-（氨甲基）苯基]甲基]-乙亚胺二盐酸盐（1400 W）存在的情况下，通过 Greiss 法测量来源于组成型一氧化氮合酶（cNOS）的一氧化氮（NO）。EPA（10-（7）-10-（4）M）引起绵羊肺动脉的浓度依赖性松弛，pD2 为 5.56+/-0.09，E（max）为 87.40+/-3.10%（n=9）。N（G）-硝基-L-精氨酸甲酯（L-NAME）100 μM 显著减弱（E（max）41.95+/-6.70%；n=8）内皮完整动脉环中 EPA 诱导的松弛。同样，内皮去垢显著抑制（E（max）17.60+/-1.21%；n=4）EPA 诱导的松弛。EPA（30 μM）显著增加 cNOS 衍生的 NO 释放（10.17+/-0.96；n=8 与对照 7.43+/-0.78 pmol/mg 组织湿重/ h；n=7）在内皮完整的血管中。然而，100 μM L-NAME（7.07+/-0.54 pmol/mg 组织湿重/ h；n=8）或内皮去除（6.97+/-0.87 pmol/mg 组织湿重/ h；n=17）明显削弱了 EPA 刺激的 NO 释放。在去内皮的 K+（80 mM）去极化动脉环中，EPA（30 μM）显著抑制 CaCl2 诱导的收缩（E（max）42.77+/-5.90%与对照 94.78+/-9.82%；n=5）。该脂肪酸还抑制这种血管中硝苯地平（1 μM）不敏感 5-HT 诱导的收缩（E（max）70.57+/-4.88%与对照 161.50+/-17.46%；n=5）。总之，EPA 通过内皮依赖性 NO 释放松弛绵羊肺动脉，而残留的非内皮依赖性松弛可能是由于抑制 L 型钙通道的 Ca2+内流以及 5-HT 刺激的细胞内 Ca2+释放所致。
