Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong SAR, China.
J Pharmacol Exp Ther. 2013 Jan;344(1):15-22. doi: 10.1124/jpet.112.198721. Epub 2012 Sep 24.
In the aorta of male spontaneously hypertensive rats (SHR), but not in that of normotensive Wistar-Kyoto rats (WKY), contractions to phenylephrine obtained in the presence of L-NAME [inhibitor of nitric oxide synthase (NOS)] and indomethacin (inhibitor of cyclooxygenase) are inhibited by an unknown endothelium-derived factor. The present study aimed to identify the mechanism underlying this endothelium-dependent inhibition in the SHR aorta. Aortic rings of male SHR and WKY, with and without endothelium, were suspended in organ chambers in the presence of indomethacin and L-NAME for the measurement of isometric tension. Contractions to phenylephrine were smaller in SHR aortae with endothelium than in those without, but were similar in the two types of preparations of WKY aortae. The endothelium-dependent, NOS-independent inhibition of phenylephrine-induced contraction was abolished by oxyhemoglobin [extracellular NO scavenger], carboxy-PTIO (NO scavenger) and ODQ (inhibitor of soluble guanylyl cyclase). It was unmasked not only by indomethacin but also by apocynin (antioxidant), but inhibited by diphenyleneiodonium (inhibitor of flavoproteins including cytochrome P450 reductase). The cytochrome P450 reductase protein expression was similar in SHR and WKY aortae. However, the level of nitrate and nitrite, substrates of cytochrome P450 reductase, were higher in SHR than WKY plasma and aortae. Therefore, in SHR but not WKY aortae, eNOS-independent NO is formed by cytochrome P450 reductase.
在雄性自发性高血压大鼠（SHR）的主动脉中，但在正常血压的 Wistar-Kyoto 大鼠（WKY）的主动脉中，在 L-NAME（一氧化氮合酶抑制剂）和吲哚美辛（环氧化酶抑制剂）存在下获得的苯肾上腺素收缩被一种未知的内皮衍生因子抑制。本研究旨在确定 SHR 主动脉中这种内皮依赖性抑制的机制。在存在吲哚美辛和 L-NAME 的情况下，雄性 SHR 和 WKY 的带和不带内皮的主动脉环被悬挂在器官室中，以测量等长张力。与没有内皮的 WKY 主动脉相比，带有内皮的 SHR 主动脉中苯肾上腺素引起的收缩较小，但在两种 WKY 主动脉的制剂中相似。苯肾上腺素诱导收缩的内皮依赖性、NOS 非依赖性抑制作用被氧合血红蛋白[细胞外 NO 清除剂]、羧基-PTIO（NO 清除剂）和 ODQ（可溶性鸟苷酸环化酶抑制剂）消除。它不仅被吲哚美辛暴露，而且被阿朴肉桂酸（抗氧化剂）暴露，但被二苯并碘（包括细胞色素 P450 还原酶在内的黄素蛋白抑制剂）抑制。细胞色素 P450 还原酶蛋白表达在 SHR 和 WKY 主动脉中相似。然而，SHR 血浆和主动脉中硝酸盐和亚硝酸盐的水平（细胞色素 P450 还原酶的底物）高于 WKY。因此，在 SHR 而不是 WKY 主动脉中，由细胞色素 P450 还原酶形成 eNOS 非依赖性 NO。
