Abstract-Previous data strongly support a role for androgens in promoting the gender difference in hypertension in the spontaneously hypertensive rat(s) (SHR), but the mechanism is not clear. Because males develop higher blood pressures than do females, we hypothesize that androgens may affect the renin-angiotensin system to promote the development of hypertension in male SHR. The present study was performed to determine the effect of converting enzyme inhibition (CEI) on the development of hypertension in SHR. Male, female, castrated male, and ovariectomized (ovx) female SHR (nϭ10 per gender per treatment group) received enalapril (250 mg/L) in drinking water for 8 to 10 weeks. Some ovx females were also given testosterone chronically. At 17 to 19 weeks of age, 24-hour protein excretion and mean arterial pressure were measured. By 13 weeks of age, male rats had higher systolic blood pressures by tail plethysmography than did the other rats, and CEI reduced blood pressures to similar levels in all groups. At 17 to 19 weeks, the same trend was found by direct measurement of mean arterial pressure. The ovx females treated with testosterone had serum testosterone and blood pressure levels similar to those found in males. CEI reduced mean arterial pressure to similar levels in all gender groups. Untreated males and ovx females given testosterone had significantly higher levels of urinary protein excretion than did the other groups, and CEI had no effect on proteinuria in any of the rats. These data suggest that the development of hypertension in SHR regardless of sex steroids is mediated by the renin-angiotensin system. However, the data further suggest that androgens promote the exacerbation of hypertension in male SHR via a mechanism involving the renin-angiotensin system. Key Words: gender Ⅲ renin-angiotensin system Ⅲ angiotensin-converting enzyme Ⅲ testosterone R ecent studies using the technique of 24-hour ambulatory blood pressure monitoring have confirmed that blood pressure is higher in men than in premenopausal women at similar ages. 1-3 Gender differences in blood pressure are also present in hypertensive rat models: males have higher blood pressures than do females. 4 -7 For example, the male spontaneously hypertensive rat(s) (SHR) has higher blood pressures than does the female SHR at a similar age. 4 Although the mechanism(s) responsible for higher blood pressures in men and male SHR is not clear, androgens have been shown to promote hypertension in rats, in view of the fact that castration of male SHR decreases blood pressure, and chronic testosterone treatment of ovariectomized (ovx) female SHR increases blood pressure. 4 Ovariectomy alone does not affect hypertension in females, suggesting that it is not estrogen that protects female SHR from the development of hypertension but a lack of androgens. In humans, the link between androgens and blood pressure has been further strengthened by studies using ambulatory blood pressure monitoring in children; these studies have shown that boys have higher blo...
Abstract-Males are at greater risk of cardiovascular and renal disease than are females. For example, male spontaneously hypertensive rats (SHR) have higher blood pressures than females. Androgens have been strongly implicated in the hypertension of male SHR, because castration attenuates the hypertension. This study determined whether the androgen receptor plays a role in hypertension in male SHR and whether testosterone alone can cause the hypertension or whether conversion to dihydrotestosterone is necessary. Male SHR, aged 10 weeks, were given the androgen receptor antagonist flutamide (8 mg/kg SC; nϭ8) or the 5␣-reductase inhibitor finasteride (30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 SC; nϭ11) daily for 5 to 6 weeks. Control rats (nϭ10) received vehicle (20% benzyl benzoate or ethanol in castor oil). After 5 to 6 weeks, blood pressure (mean arterial pressure) and glomerular filtration rate were measured. Long-term flutamide treatment caused a reduction in mean arterial pressure (control 178Ϯ5 mm Hg; flutamide 159Ϯ3 mm Hg; PϽ0.01), but finasteride had no effect (180Ϯ5 mm Hg). There were no differences in glomerular filtration rate among the groups. These data indicate that hypertension in male SHR is mediated via the androgen receptor and does not require conversion of testosterone to dihydrotestosterone. Key Words: flutamide Ⅲ finasteride Ⅲ blood pressure Ⅲ gender M ales are at greater risk of cardiovascular and renal disease than are females. For example, studies using the technique of ambulatory blood pressure monitoring have shown that blood pressure is higher in men than in women of similar ages. 1,2 In hypertensive rat models, we and other investigators have found that males have higher blood pressures than do females. [3][4][5][6][7][8] For example, male spontaneously hypertensive rats (SHR) have higher blood pressures than do females of similar ages. 3,4,6 Although the incidence of higher blood pressure in men and in male animals has been documented, the mechanisms responsible for the increase in blood pressure in the males are unknown, but androgens have been shown to have a potential role in both humans and rats. For example, studies using ambulatory blood pressure monitoring techniques have also shown that after the onset of puberty, boys have higher blood pressures than do age-matched girls. 9,10 In animal studies, castration at a young age (3 to 5 weeks) attenuates the development of hypertension in rat models such as SHR and Dahl salt-sensitive rats. 3,4,6,11,12 In contrast, ovariectomy has no effect on the development of hypertension in females. 3 These data not only support a role for androgens in mediating the higher blood pressure in male SHR, they also demonstrate that it is not estrogen in SHR females that protects them from developing the higher pressures found in males.Although our previous studies have implicated androgens in the gender difference in control of blood pressure in SHR, there is little information concerning whether the androgen receptor is involved in hypertension in males. To further inve...
Abstract-The present study was performed to determine whether physiologically relevant doses of angiotensin II (Ang II), which do not affect renal hemodynamics but do cause slow response hypertension, result in oxidative stress as measured by production of vasoconstrictor F 2 -isoprostane, a prostaglandin-like non-cyclooxygenase-produced arachidonic acid metabolite that is the end product of lipid peroxidation. Rats were instrumented with abdominal aortic and left femoral venous catheters, and before and throughout Ang II (or saline) infusion, all rats received enalapril (250 mg/L). Four days after the initiation of enalapril, rats were infused with Ang II (10 ng ⅐ kg Ϫ1 ⅐ min Ϫ1, nϭ6) or saline (nϭ6) for 14 days. Mean arterial pressure was measured 24 hours per day, and on day 12, glomerular filtration rate and renal plasma flow were measured. Mean arterial pressure in control rats averaged 85Ϯ1 mm Hg, and with Ang II infusion, mean arterial pressure increased slowly and reached a plateau on day 3, averaging 117Ϯ2 mm Hg (PϽ0.0001 compared with enalapril alone). Glomerular filtration rate and renal plasma flow were not affected by Ang II. Free F 2 -isoprostanes in plasma increased by 54% with Ang II (PϽ0.01), and the production of F 2 -isoprostanes esterified in plasma lipids tended to be higher with Ang II also but did not reach significance (Pϭ0.1). These studies suggest that low doses of Ang II are capable of producing oxidative stress in animals. Whether oxidative stress plays a causative role in Ang II-mediated slow-response hypertension or is secondary to the hypertension is not clear from these data and will require further study. Key Words: stress, oxidative Ⅲ blood pressure Ⅲ glomerular filtration rate Ⅲ renal blood flow Ⅲ angiotensin-converting enzyme S mall nonpressor doses of angiotensin II (Ang II) are capable of producing hypertension when given chronically for days. 1-3 However, the mechanism(s) responsible for the hypertension is not clear. In recent studies, Rajagopalan et al 4 infused rats with pharmacological doses of Ang II (0.7 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 SC by minipump) for 5 days and found that blood pressure increased by 50% on day 5. These investigators found that superoxide levels were increased by 2-fold in aortic segments from Ang II-treated rats. In contrast, norepinephrine infusion, which increased blood pressure to levels similar to those found with Ang II, had no effect on superoxide levels in vascular tissue, thus proving that the increase in superoxide associated with Ang II was not merely a secondary response to the higher blood pressure. In addition, these investigators found that the increased superoxide levels could be normalized with losartan, the Ang II receptor antagonist, or with liposomes containing superoxide dismutase. 4 These data clearly indicated that large pharmacological doses of Ang II, but not norepinephrine, were capable of causing oxidative stress, despite similar increases in blood pressure with Ang II and norepinephrine. Superoxide is also capable of inactivating nit...
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