Pfister S L, Campbell W B
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
J Cardiovasc Pharmacol. 1996 Dec;28(6):784-91. doi: 10.1097/00005344-199612000-00008.
Because alterations in the aortic metabolism of arachidonic acid and in vascular responsiveness occur in hypercholesterolemic rabbits, we hypothesized that an arachidonic acid metabolite may contribute to the regulation of vascular tone. Aortic contractions to norepinephrine were investigated in rabbits fed either standard chow or chow containing 2% cholesterol. In normal rabbits, norepinephrine (10(-6) M) elicited a 126 +/- 2% contraction compared with a 95 +/- 2% contraction in cholesterol-fed rabbits. The factor mediating the depressed response was endothelium-dependent because removal of the endothelium blocked the decrease in norepinephrine-induced contractions observed in the cholesterol-fed rabbits. The endothelium-derived factor was not nitric oxide, because blockade of nitric oxide synthase with nitro-L-arginine did not abolish the decreased response in the cholesterol-fed rabbits. Pretreatment of aortas with a cyclooxygenase inhibitor, indomethacin (10(-5) M) caused a slight decrease in the norepinephrine-induced contractions, suggesting that the factor could be a vasoconstrictor cyclooxygenase metabolite or a vasodilatory lipoxygenase or cytochrome P450 epoxygenase metabolite. Pretreatment with the thromboxane A2/prostaglandin H2-receptor antagonist, SQ 29458, had no effect on norepinephrine-induced contractions. Whereas the lipoxygenase inhibitor, nordihydroguaiaretic acid (5 x 10(-5) M), caused a slight increase in the contractions to norepinephrine in cholesterol-fed rabbits compared with normal rabbits, the cytochrome P450 epoxygenase inhibitor, metyrapone (10(-4) M), produced a greater enhancement of norepinephrine-induced contractions in cholesterol-fed rabbits but had no effect on responses in the normal rabbits. Characterization of [3H]arachidonic acid metabolism in cholesterol-fed aortic tissue indicated that norepinephrine stimulated the synthesis of both lipoxygenase and epoxygenase metabolites in an endothelium-dependent manner. This study demonstrated that (a) an endothelium-derived metabolite of arachidonic acid regulates vascular tone, (b) this metabolite appears to be a lipoxygenase or cytochrome P450 product or both, and (c) the activity or synthesis of the factor is enhanced by hypercholesterolemia.
由于高胆固醇血症兔的主动脉花生四烯酸代谢和血管反应性发生改变，我们推测花生四烯酸代谢产物可能参与血管张力的调节。研究了喂食标准饲料或含2%胆固醇饲料的兔主动脉对去甲肾上腺素的收缩反应。在正常兔中，去甲肾上腺素（10⁻⁶ M）引起126±2%的收缩，而在喂食胆固醇的兔中为95±2%的收缩。介导反应减弱的因素是内皮依赖性的，因为去除内皮可阻断在喂食胆固醇的兔中观察到的去甲肾上腺素诱导收缩的降低。内皮衍生因子不是一氧化氮，因为用硝基-L-精氨酸阻断一氧化氮合酶并不能消除喂食胆固醇的兔中反应的降低。用环氧化酶抑制剂吲哚美辛（10⁻⁵ M）预处理主动脉会使去甲肾上腺素诱导的收缩略有降低，这表明该因子可能是一种血管收缩性环氧化酶代谢产物或血管舒张性脂氧合酶或细胞色素P450环氧合酶代谢产物。用血栓素A2/前列腺素H2受体拮抗剂SQ 29458预处理对去甲肾上腺素诱导的收缩无影响。与正常兔相比，脂氧合酶抑制剂去甲二氢愈创木酸（5×10⁻⁵ M）使喂食胆固醇的兔对去甲肾上腺素的收缩略有增加，而细胞色素P450环氧合酶抑制剂甲吡酮（10⁻⁴ M）在喂食胆固醇的兔中对去甲肾上腺素诱导的收缩有更大增强作用，但对正常兔的反应无影响。对喂食胆固醇的主动脉组织中[³H]花生四烯酸代谢的表征表明，去甲肾上腺素以内皮依赖性方式刺激脂氧合酶和环氧合酶代谢产物的合成。本研究表明：（a）花生四烯酸的内皮衍生代谢产物调节血管张力；（b）该代谢产物似乎是脂氧合酶或细胞色素P450产物或两者皆是；（c）高胆固醇血症会增强该因子的活性或合成。
