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...

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The results indicate that chronic estrogen treatment modifies the insulin-induced hypertension by increasing insulin sensitivity in ovariectomized rats.

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Previous experiments have shown that chronic estrogen treatment via subcutaneous implants prevented insulin-induced blood pressure elevation and increased insulin sensitivity in ovariectomized female rats. In vitro vascular studies were performed using isolated mesenteric arteries to determine the effect of chronic estrogen and insulin treatments on vascular responses to vasoconstrictor agents. Female Wistar rats were assigned to the following groups: sham-operated, sham-operated plus insulin, sham-operated plus insulin plus estrogen, ovariectomized, ovariectomized plus insulin, and ovariectomized plus insulin plus estrogen. Chronic insulin and estrogen treatments were initiated with subcutaneous placement of insulin implants (2 U/d) and 17beta-estradiol implants (0.5 mg/pellet, 60 day release) at the back of the neck. After 8 weeks of treatment, mesenteric arteries were isolated for assessment of constrictor responses to norepinephrine and the thromboxane A2 analogue U46619 in the presence or absence of the endothelium. The results show that chronic estrogen treatment attenuated the vascular constrictor responses to norepinephrine and U46619 only in endothelium intact vessels. Incubation with insulin did not significantly affect norepinephrine-induced vascular smooth muscle contraction. The study provides evidence that the mechanism by which estrogen prevents insulin-induced blood pressure elevation in insulin-treated ovariectomized rats is by influencing endothelium-derived vasoactive factors such as thromboxane A2.

The venous system plays a crucial role in regulating cardiac output and blood pressure. Although the relationship between obesity and hypertension is well recognized, little is known about the effect of obesity on venous function. We examined if 16-week-old obese Zucker rats, relative to age-matched lean Zucker rats, had altered in vivo venoconstriction to noradrenaline. The obese rats, compared to the controls, had higher mean arterial pressure (MAP), body weight, and plasma insulin and triglycerides, but reduced pressor and mean circulatory filling pressure (MCFP, index of venous tone) responses to noradrenaline (2.5-30x10(-9) mol/kg/min, i.v.). N(G)-nitro-L-arginine methyl ester (L-NAME, 8 mg/kg, i.v., non-selective inhibitor of nitric oxide synthase) did not alter MCFP in either group, but increased MAP of both groups, though the increase was markedly less in the obese than lean rats. Therefore, obese Zucker rats had increased baseline MAP, but impaired in vivo pressor and MCFP responses to noradrenaline, and reduced pressor response to L-NAME. The increased baseline MAP in the obese rats was not due to increased arterial and venous constriction to noradrenaline but rather to reduced influence of the nitric oxide/L-arginine system.