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Potential role of sex hormones in altered vascular relaxation following insulin resistance Vasudevan, Harish


Hypertension is one of the secondary complications associated with insulin resistance (IR). Previous studies from our laboratory have shown that female rats are protected from developing insulin resistance and hypertension, which was dependent on estrogen. Further, testosterone was suggested to regulate the development of hypertension secondary to IR. The present series of studies intended to extend these earlier findings on the influence of gender on the relationship between insulin resistance, hyperinsulinemia and hypertension. Experiments were aimed at examining two objectives. The first was to investigate and confirm the changes in the development of insulin resistance-induced hypertension in the absence and reimplantation of testosterone. To study the effect of sex hormones on insulin resistance and hypertension, we used the well-established fructose hypertensive rat (FHR) model. Male rats fed with fructose developed insulin resistance and hypertension. The loss of testosterone following gonadectomy prevented hypertension following fructose feeding. However gonadectomy did not prevent induction of insulin resistance. Replacing the testosterone reversed the fall in blood pressure due to gonadectomy without affecting IR. To test whether changes in blood pressure are reflected in vascular reactivity, we examined the relaxation responses to acetylcholine (ACh) in the mesenteric arteries of intact and gonadectomized fructose-fed rats. We found that relaxation was impaired in intact fructose-fed rats (F) and that the impairment did not occur in the gonadectomized fructose-fed rats (GF). To dissect out the specific contributions of endothelial vasodilators, we selectively inhibited nitric oxide (NO) synthesis using L-NAME. As EDHF (endothelium derived hyperpolarizing factor) relaxes blood vessels by opening the K[sub ca] (calcium sensitive potassium channel) function, we blocked EDHF action using a combination of charybdotoxin and apamin, which individually block the large and the small K[sub ca] respectively. The tissues were then evaluated for changes in relaxation to ACh. In the mesenteric arteries of normal chow-fed rats, inhibition of either NO or EDHF attenuated the relaxation to ACh by nearly 50%. Inhibition of EDHF decreased the relaxation in F, but not GF, whereas inhibition of NO production decreased the relaxation in both the fructose-fed groups (F and GF). Relaxation following inhibition of EDHF was appreciable in GF as compared to F due to an increased NOdependent response. Inhibition of NO abolished the vasorelaxant response due to an IR-induced loss in EDHF function. We conclude that gonadectomy prevents IR-induced hypertension in part by promoting NO-dependent vasodilation. Based on the above results, we hypothesized that testosterone-dependent vasoactive agents are involved in inducing endothelial dysfunction and hypertension, secondary to IR. We focused on the androgen-dependent synthesis of 20-hydroxyeicosatetranoic acid (20-HETE) in the vasculature. Arachidonic acid hydroxylases belonging to the Cyp4A family of enzymes catalyze the production of 20-HETE. In the presence of 1-aminobenzotriazole (ABT), which inhibits Cyp4A, relaxation to ACh was improved in the mesenteric arteries of sham-operated male FHR. Treatment with ABT did not affect the relaxation to ACh in intact normal chow-fed (C) or gonadectomized groups (G and GFE), suggesting an elevated action of 20-HETE in the presence of testosterone in male FHR. It is unclear as to whether it is the loss of estrogen or increase in testosterone that is responsible for the development of hypertension. Our second aim was to identify whether the development of insulin resistance and hypertension was gender dependent or whether a specific sex hormone regulated its development. In a separate series of experiments, intact and gonadectomized male fructose-fed rats were treated with estrogen implants, following which their insulin sensitivity improved. However, estrogen reduced the blood pressure only in the intact male fructose-fed rats (FE). Estrogen did not affect the blood pressure in gonadectomized fructose-fed rats (GFE). Furthermore, blood pressure in FE was higher than the estrogen implanted (GFE) or nonimplanted gonadectomized rats (G). Estrogen decreased plasma testosterone in the intact rats. However, detectable amounts of testosterone were still present. In summary we suggest the presence of potential prohypertensive pathways, which are dependent on the presence of testosterone and are activated only following insulin resistance. We also suggest that the development of insulin resistance and hypertension are governed not by gender per se, but by the actions of specific sex hormones such as estrogen and testosterone.

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