Androgens Are Necessary for the Development of Fructose-Induced Hypertension

Abstract

Abstract-Hyperinsulinemia and insulin resistance are closely associated with hypertension in humans and in animal models. Gender differences have been found in the development of hypertension in fructose-fed rats. The objectives of the present study were, first, to clarify whether androgens are required in the development of hyperinsulinemia, insulin resistance, and hypertension in fructose-fed rats, and second, to determine if cyclooxygenase-1 and cyclooxygenase-2 are also increased in the arteries of these rats. Male rats were gonadectomized or sham-operated and fed a 60% fructose diet beginning at age 7 weeks. Blood pressure was measured by a tail-cuff method, and an oral glucose tolerance test was performed to assess insulin sensitivity after 8 weeks of fructose feeding. Cyclooxygenase-1 and cyclooxygenase-2 mRNA expression was also assessed in the thoracic aortae and mesenteric arteries. Gonadectomy prevented hypertension from developing in the fructose-fed rats, but hyperinsulinemia and insulin resistance developed. There was an increase in cyclooxygenase-2 expression in the thoracic aortae and mesenteric arteries of the fructose-fed sham-operated rats while the expression of cyclooxygenase-1 remained unchanged. Gonadectomy prevented the mRNA overexpression of vascular cyclooxygenase-2 in the fructose-fed rats. These results suggest that the presence of androgens is necessary for the development of fructose-induced hypertension. Androgens apparently act as a link between hyperinsulinemia/insulin resistance and hypertension in fructose-hypertensive rats. Furthermore, an increase in the expression of cyclooxygenase-2 is implicated in the development of hypertension. The mechanisms involved require further study. Key Words: fructose Ⅲ insulin resistance Ⅲ hyperinsulinemia Ⅲ hypertension H yperinsulinemia and insulin resistance are closely linked to the development of hypertension in humans and in animal models. [1][2][3] Several mechanisms have been proposed, including the sympathetic nervous system, 4 renal abnormalities in handling sodium, 5,6 and changes in endothelial function and vasoactive mediators such as endothelin-1, nitric oxide, and thromboxane A 2 (TXA 2 ) 3,7,8 However, the exact mechanisms remain to be clarified. Recently, we reported that chronic insulin treatment impaired insulin sensitivity in male and female rats; however, the impairment occurred to a greater degree in male rats. 9 Interestingly, increased blood pressure (BP) was seen only in male rats. These results suggest that the association between hyperinsulinemia/insulin resistance and hypertension is gender-dependent and exists only in male rats. Based on these findings, we speculated that androgens might play an essential role in the relationship between hyperinsulinemia/insulin resistance and hypertension.Gender-associated differences in BP have been widely observed and confirmed in humans. Women during their reproductive years are less prone to hypertension and hypertensionrelated diseases than men or postmenopausal women. 10 Stu...

Parasympathetic dysfunction is associated with insulin resistance in fructose-fed female rats

“…Contrary to other studies in males (3,5,11,12), our data showed that fructose-fed female rats presented increased body weight gain, which can be explained by the form in which fructose was provided (water vs chow) and by gender differences (5,11,13).…”

“…Vagal dysfunction in fructose-fed female rats www.bjournal.com.br which was observed in the fructose-fed group of the present study, and hyperinsulinemia are the main causes for increased AP in the fructose model, and they are possibly responsible for sympathetic nervous system activation (6), impairment of endothelium-dependent relaxation (12,14) and dysfunction in angiotensin-renin system (5). This is the first study to evaluate cardiac autonomic control in female rats after high fructose consumption, using an invasive method.…”

“…Animals were anesthetized with thiopental (40 mg/kg body weight, ip), and a drop of blood from the tail was collected to measure blood glucose by using a glucosimeter (ACCU-CHEK). This procedure was performed at 0 time, 4,8,12, and 16 min after insulin administration (0.75 U/kg). The rate constant for blood glucose disappearance (KITT) was calculated using the formula 0.693/t1/2, and the blood glucose half-time (t1/2) was calculated from the slope of the least squares regression of the blood glucose concentration during the linear phase of decline (9).…”

Effects of androgens on cardiovascular remodeling

“…In experimental animal models, castration reduced blood pressure in male rats with spontaneous (Martin et al 2005, Ojeda et al 2007 or fructose feeding-induced (Song et al 2004) hypertension. Testosterone has also been shown to inhibit L-type calcium channels via an AR-independent pathway, indicating nongenomic action of androgen on vasodilatation (Scragg et al 2004, Hall et al 2006.…”

Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II

“…Investigations regarding the actions of testosterone have produced contradictory results (Kravariti et al 2005, Rosano et al 2005. For example, both vasodilatory (Webb et al 1999) and anti-vasodilatory effects have been observed (Hutchison et al 1997, Ceballos et al 1999 and testosterone may be involved in the development of some forms of experimental hypertension (Song et al 2004, Reckelhoff 2005. Endothelial cells have receptors for both oestradiol (Losordo et al 1994) and testosterone (Sierra-Ramirez et al 2004), by which these steroids can directly influence blood vessels and hence the development of vascular disease and hypertension.…”