Testosterone-dependent increase in blood pressure is mediated by elevated Cyp4A expression in fructose-fed rats
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.
KeywordsInsulin resistance Blood pressure Testosterone Cyp4A 20-HETE
This project was funded by grants-in aid from The Heart and Stroke Foundation of BC and Yukon (HSFBCY) and Canadian Institutes of Health Research (CIHR-Priority announcement grant from the Institute of Gender and Health) to Dr. McNeill. Harish Vasudevan was funded by a Doctoral Research Award from the Heart and Stroke Foundation of Canada and a Senior Graduate Studentship from the Michael Smith Foundation for Health Research British Columbia, Canada.
- 13.Vasudevan H, Lau SM, Jiang J, Galipeau D, McNeill JH (2010) Effects of insulin resistance and testosterone on the participation of cyclooxygenase isoforms in vascular reactivity. J Exp Pharmacol 2:169–179Google Scholar
- 14.Vasudevan H (2009) Testosterone-dependent vascular arachidonic acid metabolism in the regulation of insulin resistance and blood pressure. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, pp 1–151Google Scholar
- 16.Holla VR, Adas F, Imig JD, Zhao X, Price E Jr, Olsen N, Kovacs WJ, Magnuson MA, Keeney DS, Breyer MD, Falck JR, Waterman MR, Capdevila JH (2001) Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension. Proc Natl Acad Sci USA 98:5211–5216PubMedCrossRefGoogle Scholar
- 26.Benter IF, Yousif MH, Canatan H, Akhtar S (2005) Inhibition of Ca2+/calmodulin-dependent protein kinase II, RAS-GTPase and 20-hydroxyeicosatetraenoic acid attenuates the development of diabetes-induced vascular dysfunction in the rat carotid artery. Pharmacol Res 52:252–257PubMedCrossRefGoogle Scholar
- 40.Vasudevan H (2005) Potential role of sex hormones in altered vascular relaxation following insulin resistance. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, pp 1–99Google Scholar
- 46.Nagareddy PR (2009) Mechanisms of vascular dysfunction in diabetes and hypertension. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, p 267Google Scholar