Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.
Mol Cell Biochem. 2012 Jan;359(1-2):409-18. doi: 10.1007/s11010-011-1035-7. Epub 2011 Sep 6.
Endothelial dysfunction and increased blood pressure following insulin resistance play an important role in the development of secondary cardiovascular complications. The presence of testosterone is essential for the development of endothelial dysfunction and increased blood pressure. Testosterone regulates the synthesis of vasoconstrictor eicosanoids such as 20-hydroxyeicosatetranoic acid (20-HETE). In a series of studies, we examined: (1) the role of the androgen receptor in elevating blood pressure and (2) the effects of Cyp4A-catalyzed 20-HETE synthesis on vascular reactivity and blood pressure in fructose-fed rats. In the first study, intact and castrated male rats were made insulin resistant by feeding fructose for 9 weeks following which their superior mesenteric arteries (SMA) were isolated and examined for changes in endothelium-dependent relaxation in the presence and absence of 1-aminobenzotriazole (ABT) and N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), which are inhibitors of 20-HETE synthesis. In another study, male rats were treated with either ABT or the androgen receptor blocker, flutamide, following which changes in insulin sensitivity, blood pressure, and vascular Cyp4A expression were measured. In the final study, HET0016, which is a more selective inhibitor of 20-HETE synthesis, was used to confirm our earlier findings. Treatment with HET0016 or ABT prevented or ameliorated the increase in blood pressure. Gonadectomy or flutamide prevented the increase in both the Cyp4A and blood pressure. Furthermore, both ABT and DDMS improved relaxation only in the intact fructose-fed rats. Taken together our results suggest that in the presence of testosterone, the Cyp4A/20-HETE system plays a key role in elevating the blood pressure secondary to insulin resistance.
胰岛素抵抗引起的内皮功能障碍和血压升高在继发性心血管并发症的发展中起着重要作用。睾酮的存在对于内皮功能障碍和血压升高的发展至关重要。睾酮调节血管收缩性二十碳烷类物质（如 20-羟二十碳四烯酸[20-HETE]）的合成。在一系列研究中，我们研究了：（1）雄激素受体在升高血压中的作用；（2）Cyp4A 催化的 20-HETE 合成对果糖喂养大鼠血管反应性和血压的影响。在第一项研究中，完整和去势雄性大鼠通过喂养果糖 9 周使其产生胰岛素抵抗，然后分离其肠系膜上动脉（SMA），并在存在和不存在 1-氨基苯并三唑（ABT）和 N-甲基磺酰基-12,12-二溴十二碳-11-烯酰胺（DDMS）的情况下检查内皮依赖性松弛的变化，ABT 和 DDMS 是 20-HETE 合成的抑制剂。在另一项研究中，雄性大鼠在用 ABT 或雄激素受体阻滞剂氟他胺治疗后，测量胰岛素敏感性、血压和血管 Cyp4A 表达的变化。在最后一项研究中，使用更特异性的 20-HETE 合成抑制剂 HET0016 来证实我们之前的发现。用 HET0016 或 ABT 治疗可预防或改善血压升高。去势或氟他胺可预防 Cyp4A 和血压的升高。此外，ABT 和 DDMS 仅在完整的果糖喂养大鼠中改善了松弛度。总之，我们的研究结果表明，在睾酮存在的情况下，Cyp4A/20-HETE 系统在胰岛素抵抗引起的血压升高中起着关键作用。
