Testosterone-dependent vascular arachidonic acid metabolism in the regulation of insulin resistance and blood pressure

• Main Author: Vasudevan, Harish
• Format: Others
• Language: English
• Published: University of British Columbia 2009
• Online Access: http://hdl.handle.net/2429/8704

Insulin resistance (IR) and elevated blood pressure (BP) are two key features of the metabolic syndrome, which play an important role in the development of secondary cardiovascular complications. Feeding rats a diet rich in sugars such as fructose induces IR followed by vascular abnormalities and elevation in BP. Insulin resistance impairs the fine balance between endothelial vasoconstrictors and vasorelaxants, which results in endothelial dysfunction (ED). Differences in sex hormones play an important role in the development of insulin resistance and blood pressure as testosterone is essential for the development of ED and the increase in BP. Testosterone regulates the cyclooxygenase and Cyp4A-catalyzed metabolites of arachidonic acid, which have been implicated in vascular homeostasis. However, their regulation by insulin is unclear. We hypothesized that In the presence of testosterone insulin resistance favors increased synthesis of vasoconstrictor metabolites of arachidonic acid, which contributes to the development of endothelial dysfunction and subsequent elevation of blood pressure. Intact and/or gonadectomized male Wistar rats were fed for 9-12 weeks with fructose following which changes in blood pressures and vascular reactivity were determined. Treatment with testosterone restored the elevated blood pressure in gonadectomized rats. In addition, fructose-feeding induced insulin resistance in intact rats, which was ameliorated by inhibiting the androgen receptor or 20-HETE synthesis. Insulin resistance increased Cyp4A1, 2/3 expression in the superior mesenteric artery (SMA), which was decreased by blocking testosterone function. Finally, the increase in BP and Cyp4A1, 2/3 were prevented by treating rats for 2 weeks with the Cyp4A inhibitor HET0016. The role of IR in arachidonate metabolism was evaluated by treatment with metformin (500 mg/kg) for 10 weeks. Prevention of insulin resistance prevented both endothelial dysfunction and the increase in BP. Further, inhibition of Cyp4A by DDMS improved endothelial relaxation in the SMA of only intact and untreated FFR but not the gonadectomized and metformin-treated groups. Similar effects were observed upon blocking COX with indomethacin. IR increased the participation of COX-2, which was testosterone-dependent in both aorta and SMA. In conclusion, in the presence of testosterone, IR induces vascular complications by altering arachidonic acid metabolism to increase vasoconstrictor levels. === Pharmaceutical Sciences, Faculty of === Graduate