Abstract-Blood pressure increases in many women after menopause. Hypertension is one of the major risk factors for cardiovascular disease. However, the mechanisms responsible for the postmenopausal increase in blood pressure are yet to be elucidated. Various humoral systems have been proposed to play a role in postmenopausal hypertension, such as changes in estrogen/androgen ratios, increases in endothelin and oxidative stress, and activation of the renin-angiotensin system (RAS). In addition, obesity, type II diabetes, and activation of the sympathetic nervous system are common in postmenopausal women and may also play important roles. However, progress in elucidating the mechanisms responsible for postmenopausal hypertension has been hampered by the lack of a suitable animal model. The aging female spontaneously hypertensive rat (SHR) exhibits many of the characteristics found in postmenopausal women. In this review, some of the possible mechanisms that could play a role in postmenopausal hypertension are discussed, as well as the characteristics of the aged female SHR as a model to study. Key Words: endothelin Ⅲ renin-angiotensin system Ⅲ oxidative stress Ⅲ obesity Ⅲ diabetes mellitus Ⅲ sympathetic nervous system B efore menopause, blood pressure is typically lower in women than in age-matched men. 1 In aging men and women, systolic and diastolic blood pressures increase, although in later years the diastolic plateaus or even declines. [1][2][3] However, in postmenopausal women, the prevalence of hypertension and cardiovascular disease risk increases regardless of ethnic origin. Results from the National Health and Nutrition Examination Survey (NHANES III) showed that in Hispanic women and non-Hispanic black women, the prevalence of hypertension was similar to, or higher than, that in men by age 60 years. 4 In non-Hispanic white populations, the prevalence of hypertension was higher in women than in men by age 70 years. 4 The increase in blood pressure in postmenopausal women does not occur as soon as the ovary becomes senescent, but rather over a number of years. 5 The mechanisms responsible for the increased blood pressure in women after menopause are not known. This review focuses on the use of the spontaneously hypertensive rat as a model of postmenopausal hypertension and evaluates the possible mechanistic roles of the sex hormones, oxidative stress, endothelin, renin-angiotensin system (RAS), weight gain, and sympathetic activation in postmenopausal hypertension. Animal Model for the Study of Postmenopausal HypertensionThe elucidation of mechanisms responsible for postmenopausal hypertension has been stunted by lack of an animal model. Sheep, rabbits, nonhuman primates, rats, and mice have been used as models of various menopausal changes; 6 however, to our knowledge, there is no animal model of naturally occurring postmenopausal hypertension. There have been attempts to mimic menopause by ovariectomizing animals; 7,8 however, these have rarely taken into account the effect of aging and cessation of ova...

Abstract-Blood pressure (BP) increases in postmenopausal women. The mechanisms responsible are unknown. The present study was performed to characterize a model of postmenopausal hypertension in the rat and to determine the role that oxidative stress may play in mediating the postmenopausal hypertension. Spontaneously hypertensive rats were ovariectomized (ovx) or left intact (PMR) at 8 months and were aged to 18 months. These animals were compared with young females (YF; 4 or 8 months of age) and old males (18 months) for some measurements. Estradiol levels were decreased in PMR rats to levels not different from YF rats in proestrous or from old males. BP increased progressively with age in PMR rats but not in ovx or male rats, such that the gender difference in hypertension disappeared by 18 months. Glomerular filtration rate was lower in ovx and PMR rats than in YF rats. Renal plasma flow and renal vascular resistance were similar between YF and ovx rats, but lower and higher, respectively, in PMR rats. Serum testosterone increased by 60% in ovx rats and 400% in PMR rats compared with YF rats. Plasma renin activity also increased in PMR rats but not in ovx rats. Chronic treatment (for 8 months beginning at 8 months of age) of PMR rats with vitamins E and C, but not tempol, resulted in a significant reduction in BP and excretion of F 2 -isoprostanes. In contrast, tempol, but not vitamins E and C, reduced BP in old males. These data suggest that the PMR rats, but not ovx rats, may be a suitable model for the study of postmenopausal hypertension, and that oxidative stress plays a role in the increased BP. Key Words: women Ⅲ menopause Ⅲ oxidative stress Ⅲ hormones Ⅲ renin-angiotensin system Ⅲ nitric oxide B lood pressure (BP) increases after menopause in women such that the prevalence of hypertension becomes higher in women than in men. 1 The postmenopausal increase in BP does not occur as soon as the ovary stops producing estradiol, but occurs over a period of 5 to 10 years. The mechanisms responsible for the postmenopausal increase in BP are not known.Many factors have been suggested to play a role in the increased BP in postmenopausal women (PMW). For example, activation of renin-angiotensin system has been implied by data showing that plasma renin activity (PRA) was increased in PMW compared with premenopausal women. 2 An increase in angiotensin (Ang) II would not only cause vasoconstriction but also influence sodium reabsorption to increase BP. Another factor that could impact BP is NO. Oxidative stress has also been shown to be increased in PMW. 3 Ang II is known to cause increases in superoxide production, 4 and NO is scavenged by superoxide. 5,6 This is a mechanism by which the renin-angiotensin system and NO could interact to increase BP. Furthermore, oxidants, such as peroxynitrite, which is formed from superoxide and NO, has been shown to cause increases in vasoconstrictors and reductions in vasodilators. 7 One problem with the study of postmenopausal hypertension has been the lack of a suitable animal ...

Treatment of aging men and women with testosterone supplements is increasing. The supplements are given to postmenopausal women mainly to improve their libido and to aging men to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, such as sildenafil, to treat erectile dysfunction. The increased use of testosterone supplements in aging individuals has occurred despite the fact that there have been no rigorous clinical trials examining the effects of chronic testosterone on the cardiovascular-renal disease risk. Studies in humans and animals have suggested that androgens can increase blood pressure and compromise renal function. Androgens have been shown to increase tubular sodium and water reabsorption and activate various vasoconstrictor systems in the kidney, such as the renin-angiotensin system and endothelin. There is also evidence that androgens may increase oxidative stress. Furthermore, the kidney contains the enzymes necessary to produce androgens de novo. This review presents an overview of the data from human and animal studies in which the role of androgens in promoting renal and cardiovascular diseases has been investigated.

Abstract-Recent reports have indicated that endothelin-induced vasoconstriction in isolated aortic vascular rings may be mediated by the production of superoxide anion. The purpose of this study was to determine the role of superoxide anion in mediating the chronic renal and hypertensive actions of endothelin. Endothelin-1 (5 pmol/kg per minute) was chronically infused into the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats and in rats treated with the superoxide anion scavenger tempol (30 mg/kg per day). Mean arterial pressure in the endothelin-1-treated rats was 141Ϯ3 mm Hg, compared with 125Ϯ2 mm Hg in control rats. Endothelin-1 increased renal vascular resistance (15.3Ϯ2.5 versus 10Ϯ1.3 mm Hg/mL per minute) and decreased renal plasma flow (6.5Ϯ0.9 versus 8.7Ϯ0.7 mL/min) in control rats. Endothelin-1 also significantly increased TBARS in the kidney and urinary 8-isoprostaglandin F 2␣ excretion. The increase in arterial pressure in response to endothelin-1 was completely abolished by tempol (127Ϯ4 versus 127Ϯ4 mm Hg). Tempol also markedly attenuated the renal plasma flow and renal vascular resistance response to endothelin-1. Tempol also significantly decreased the level of 8-isoprostaglandin F 2␣ in the endothelin-1-treated rats. Tempol had no effect on arterial pressure or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating hypertension induced by chronic elevations in endothelin.

SUMMARY1. In the present review, we addressed studies in humans and rats to determine the role that oxidative stress may play in mediating cardiovascular outcomes.2. Biochemical evaluation of oxidative stress in both humans and spontaneously hypertensive rats gives equivocal results as to the relative levels in males versus females. Clinical trials with anti-oxidants in humans have not shown consistent results in protecting against detrimental cardiovascular outcomes. In spontaneously hypertensive rats (SHR), blockade studies using tempol or apocynin reduce renal oxidative stress and blood pressure in male SHR, but not in female rats. In addition, increasing oxidative stress with molsidomine increases blood pressure in male, but not female, SHR. Treatment with vitamins E and C reduces blood pressure in young male, but not aged, animals. Furthermore tempol is unable to reduce blood pressure in young male SHR in the absence of a functional nitric oxide system. 3. Neither human nor animal studies are consistent in terms of whether oxidative stress levels are higher in males or females. Furthermore, anti-oxidant therapy in humans often does not ameliorate, or even attenuate, the negative cardiovascular consequences of increased oxidative stress. Our studies in SHR shed light on why these outcomes occur.

Abstract-Men have an increased risk of cardiovascular and renal diseases and develop greater renal injury despite similar levels of blood pressure when compared with women. The mechanisms responsible for this predisposition are unknown. Using the spontaneously hypertensive rat (SHR), we have found that androgens play an important role in the development of hypertension in young male SHR. However, the role that androgens play in age-related renal injury and dysfunction in SHR is unknown. Our hypothesis was that despite reductions in serum testosterone with age, androgens mediate renal injury and dysfunction in male SHR. Male SHR were castrated at 8 months of age, studied at 18 months of age, and compared with age-matched, intact males and young intact males (4 months). Serum testosterone was reduced by 30% in aging males compared with young SHR. With castration, blood pressure (mean arterial pressure [MAP]) was decreased by Ͼ20 mm Hg compared with old males, glomerular filtration rate (GFR) was increased by Ͼ35%, and renal vascular resistance (RVR) was reduced by Ͼ40%. MAP, GFR, and RVR in castrated, old males were similar to values in young males. With castration, glomerular sclerosis was reversed and proteinuria was also decreased by Ͼ80% when compared with old intact males. In addition, in castrated old males, plasma renin activity was decreased by 30% compared with old males and by 60% compared with young rats. The data support the hypothesis that despite a reduction in testosterone with age, androgens play an important role in age-related renal injury and dysfunction in SHR. Key Words: age Ⅲ aging Ⅲ androgens Ⅲ hypertension, renal Ⅲ renal disease C omparisons performed in age-matched groups show that men have higher blood pressures than women until old age, when blood pressures become similar. 1,2 Men also have a greater incidence of renal disease and proceed to end-stage renal failure faster than do women, even when exhibiting similar levels of blood pressure. 3 The kidneys of men also undergo greater decline in renal function with age than do the kidneys of women. 4,5 This suggests that male sex hormones might play a role in mediating cardiovascular disease in men. However, the role that androgens play in the control of blood pressure and renal injury in men, especially with age, is not clear.We have previously found that androgens play a role in the development of hypertension in young, spontaneously hypertensive rats (SHR), because castration at 5 to 7 weeks of age reduces blood pressure when measured at 4 months of age, and testosterone treatment of ovariectomized females increases blood pressure. 6,7 This difference in blood pressure between intact and castrated males is still present at 8 months of age, the oldest age we have studied thus far. 8 We also found that the renin-angiotensin system (RAS) plays an important role in the development of hypertension in young SHR, because blockade of the RAS with converting-enzyme inhibitors removed the sex difference in blood pressure, and testosterone treatmen...

The roles of nitric oxide (NO) and plasma renin activity (PRA) in the depressor response to chronic administration of Tempol in spontaneously hypertensive rats (SHR) are not clear. The present study was done to determine the effect of 2 wk of Tempol treatment on blood pressure [mean arterial pressure (MAP)], oxidative stress, and PRA in the presence or absence of chronic NO synthase inhibition. SHR were divided into four groups: control, Tempol (1 mmol/l) alone, nitro-L-arginine methyl ester (L-NAME, 4.5 mg x g(-1).day(-1)) alone, and Tempol + L-NAME or 2 wk. With Tempol, MAP decreased by 22%: 191 +/- 3 and 162 +/- 21 mmHg for control and Tempol, respectively (P < 0.05). L-NAME increased MAP by 16% (222 +/- 2 mmHg, P < 0.01), and L-NAME + Tempol abolished the depressor response to Tempol (215 +/- 3 mmHg, P < 0.01). PRA was not affected by Tempol but was increased slightly with L-NAME alone and 4.4-fold with L-NAME + Tempol. Urinary nitrate/nitrite increased with Tempol and decreased with L-NAME and L-NAME + Tempol. Tempol significantly reduced oxidative stress in the presence and absence of L-NAME. In conclusion, in SHR, Tempol administration for 2 wk reduces oxidative stress in the presence or absence of NO, but in the absence of NO, Tempol is unable to reduce MAP. Therefore, NO, but not changes in PRA, plays a major role in the blood pressure-lowering effects of Tempol. These data suggest that, in hypertensive individuals with endothelial damage and chronic NO deficiency, antioxidants may be able to reduce oxidative stress but not blood pressure.

Development of hypertension in SHR is mediated in part by oxidative stress independent of sex. Also, tempol is effective in reducing blood pressure in females only when given prior to the onset of hypertension.