Gauthier Kathryn M, Falck J R, Reddy L Manmohan, Campbell William B
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Pharmacol Res. 2004 Jun;49(6):515-24. doi: 10.1016/j.phrs.2003.09.014.
Arachidonic acid metabolites contribute to the regulation of vascular tone and therefore tissue blood flow. The vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The placement of the epoxide group can occur on any of the double bonds of arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15-EET. In the vasculature, EETs are key components of cellular signaling cascades that culminate in the activation of smooth muscle potassium channels to induce membrane hyperpolarization and vascular relaxation. In some vasculatures such as bovine coronary arteries, EET regioisomers are equipotent in inducing relaxations, while in other arteries, a specific EET regioisomer induces relaxation while others do not. Therefore, the position of the double bonds and/or the epoxide group may alter vascular agonist activity. This observation suggests that small alterations in the chemical structure of EETs can significantly impact vascular activity. To explore this hypothesis, we synthesized a series of EET analogs and characterized their vasodilator agonist and antagonist activity in bovine coronary arteries. In this chapter, we first review the mechanisms of EET-dependent relaxations in bovine coronary arteries to familiarize the reader with the role of EETs in these arteries. The second component is a synopsis of the functional characterization of the 14,15-EET analogs and the resulting description of structural components required for vascular dilator activity. Lastly, we discussed the characterization of three 14,15-EET analogs with specific EET-antagonist activity and compared this to the activity of similar 11,12-EET analogs. These studies have revealed that specific structural components of the 14,15-EET molecule are critical for dilator activity and that alteration of these components influences agonist activity and may confer antagonist properties.
花生四烯酸代谢产物有助于调节血管张力，进而调节组织血流量。血管内皮细胞通过细胞色素P450环氧化酶将花生四烯酸代谢为环氧二十碳三烯酸（EETs）。环氧基团可位于花生四烯酸的任何一个双键上，从而产生四种EET区域异构体：5,6-、8,9-、11,12-和14,15-EET。在脉管系统中，EETs是细胞信号级联反应的关键组成部分，最终导致平滑肌钾通道激活，从而诱导膜超极化和血管舒张。在一些脉管系统中，如牛冠状动脉，EET区域异构体在诱导舒张方面具有同等效力，而在其他动脉中，特定的EET区域异构体可诱导舒张，而其他异构体则不能。因此，双键和/或环氧基团的位置可能会改变血管激动剂活性。这一观察结果表明，EETs化学结构的微小改变可能会显著影响血管活性。为了探究这一假设，我们合成了一系列EET类似物，并在牛冠状动脉中对其血管舒张激动剂和拮抗剂活性进行了表征。在本章中，我们首先回顾牛冠状动脉中EET依赖性舒张的机制，以使读者熟悉EETs在这些动脉中的作用。第二部分是对14,15-EET类似物功能表征的概述，以及由此得出的血管舒张剂活性所需结构成分的描述。最后，我们讨论了三种具有特定EET拮抗剂活性的14,15-EET类似物的表征，并将其与类似的11,12-EET类似物的活性进行了比较。这些研究表明，14,15-EET分子的特定结构成分对舒张活性至关重要，这些成分的改变会影响激动剂活性，并可能赋予拮抗剂特性。
