Jane F. Reckelhoff

Gender differences in the regulation of blood pressure.

Abstract—Men are at greater risk for cardiovascular and renal disease than are age-matched, premenopausal women. Recent studies using the technique of 24-hour ambulatory blood pressure monitoring have shown that blood pressure is higher in men than in women at similar ages. After menopause, however, blood pressure increases in women to levels even higher than in men. Hormone replacement therapy in most cases does not significantly reduce blood pressure in postmenopausal women, suggesting that the loss of estrogens may not be the only component involved in the higher blood pressure in women after menopause. In contrast, androgens may decrease only slightly, if at all, in postmenopausal women. In this review the possible mechanisms by which androgens may increase blood pressure are discussed. Findings in animal studies show that there is a blunting of the pressure-natriuresis relationship in male spontaneously hypertensive rats and in ovariectomized female spontaneously hypertensive rats treated chronically with testosterone. The key factor in controlling the pressure-natriuresis relationship is the renin-angiotensin system (RAS). The possibility that androgens increase blood pressure via the RAS is explored, and the possibility that the RAS also promotes oxidative stress leading to production of vasoconstrictor substances and reduction in nitric oxide availability is proposed.

Role of Angiotensin and Oxidative Stress in Essential Hypertension

In this review, we examine the possibility that small increments in angiotensin II are responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. A low dose of angiotensin II (2 to 10 ng x kg(-1) x min(-1), which does not elicit an immediate pressor response), when given for 7 to 30 days by continuous intravenous infusion, can increase mean arterial pressure by 30 to 40 mm Hg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress, as measured by a significant increase in levels of 8-iso-prostaglandin F(2alpha) (F(2)-isoprostane). Superoxide radicals and nitric oxide can combine chemically to form peroxynitrite, which can then oxidize arachidonic acid to form F(2)-isoprostanes. F(2)-isoprostanes exert potent vasoconstrictor and antinatriuretic effects. Furthermore, angiotensin II can stimulate endothelin production, which also has been shown to stimulate oxidative stress. In this way, a reduction in the concentration of nitric oxide (which is quenched by superoxide) along with the formation of F(2)-isoprostanes and endothelin could potentiate the vasoconstrictor effects of angiotensin II. We hypothesize that these mechanisms, which underlie the development of the slow pressor response to angiotensin II, also participate in the production of hypertension when circulating angiotensin II levels appear normal, as occurs in many cases of essential and renovascular hypertension.

Testosterone Exacerbates Hypertension and Reduces Pressure-Natriuresis in Male Spontaneously Hypertensive Rats

Studies were performed in intact male and female, gonadectomized male and female, and gonadectomized female rats given testosterone for 5 weeks to investigate the role played by testosterone in altered blood pressure control and pressure-natriuresis in male SHR. Serum testosterone levels reached a peak at 12 weeks of age in intact male SHR. Systolic blood pressure, measured weekly from 5 to 20 weeks of age, was similar between groups until 12 weeks of age when blood pressure became higher in males (195+/-3 mm Hg) than in females (168+/-3 mm Hg) or males castrated at 4 weeks (173+/-4 mm Hg). At 17 to 19 weeks direct measurement of arterial pressure in anesthetized rats confirmed that mean arterial pressure was higher in male (182+/-1 mm Hg) than in female (159+/-2 mm Hg) and castrated male SHR (159+/-2 mm Hg). In addition, testosterone (5 mg in Silastic pellets, SC for 5 weeks) administered to ovariectomized (ovx+T) females caused arterial pressure to increase by mm 11% (175+/-2 mm Hg), which was significantly higher than in intact female, castrated male, or untreated ovariectomized (ovx) female SHR (158+/-2 mm Hg). Acute pressure-natriuresis was blunted in male SHR compared with females, castrated males, or ovx females, in which this relationship was similar. Pressure-natriuresis was also blunted in ovx+T females as found in intact male SHR. These data support the hypothesis that male sex hormones contribute to the exacerbation of hypertension in SHR by reducing pressure-natriuresis.

Gender Differences in Development of Hypertension in Spontaneously Hypertensive Rats: Role of the Renin-Angiotensin System

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 (n=10 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.

Reduced Uterine Perfusion Pressure During Pregnancy in the Rat Is Associated With Increases in Arterial Pressure and Changes in Renal Nitric Oxide

Abstract—A reduction in nitric oxide (NO) synthesis has been suggested to play a role in pregnancy-induced hypertension. We have recently reported that normal pregnancy in the rat is associated with significant increases in whole-body NO production and renal protein expression of neuronal and inducible NO synthase. The purpose of this study was to determine whether whole-body and renal NO production is reduced in a rat model of pregnancy-induced hypertension produced by chronically reducing uterine perfusion pressure starting at day 14 of gestation. Chronic reductions in uterine perfusion pressure resulted in increases in arterial pressure of 20 to 25 mmthinsp;Hg, decreases in renal plasma flow (<23%) and glomerular filtration rate (<40%), but no difference in urinary nitrite/nitrate excretion relative to control pregnant rats. In contrast, reductions in uterine perfusion pressure in virgin rats resulted in no significant effects on arterial pressure. Renal endothelial (<4%) and inducible (<11%) NO synthase protein expression did not decrease significantly in the chronically reduced uterine perfusion pressure rats relative to normal pregnant rats; however, significant reductions in neuronal NO synthase were observed (<30%). The results of this study indicate that the reduction in renal hemodynamics and the increase in arterial pressure observed in response to chronic decreases in uterine perfusion pressure in pregnant rats are associated with no change in whole-body NO production and a decrease in renal protein expression of neuronal NO synthase.

Novel Mechanisms Responsible for Postmenopausal Hypertension

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.

Gender Differences in Hypertension in Spontaneously Hypertensive Rats: Role of Androgens and Androgen Receptor

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; n=8) or the 5alpha-reductase inhibitor finasteride (30 mg x kg(-1) x d(-1) SC; n=11) daily for 5 to 6 weeks. Control rats (n=10) 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 178+/-5 mm Hg; flutamide 159+/-3 mm Hg; P<0.01), but finasteride had no effect (180+/-5 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.

Menopause and Hypertension: An Age-Old Debate

Premenopausal women (pre-MW) have lower blood pressure (BP) than age-matched men, and women have higher rates of hypertension than men as they age.1 These findings suggest that gender or sex hormones have a prominent role in hypertension. Determining the role of sex hormones in the pathogenesis or progression of hypertension is complex given the effects of aging on the cardiovascular system and its relationship to other powerful risk factors such as body weight and cholesterol level.2 Longitudinal and cross-sectional studies report conflicting results concerning the role of menopause in the pathogenesis of hypertension. Large randomized trials of hormone replacement therapy (HRT) have called into question the long assumed protective effect of estrogen in heart disease risk.3,4 There are excellent reviews on the effects of gender and sex hormones on vascular tone and pathophysiologic abnormalities associated with hypertension in animals.5,6 This review focuses on studies in postmenopausal women (PMW), the relationship between menopause and hypertension, factors contributing to hypertension in PMW, and discussion of identification and treatment of hypertension in PMW. ### Studies Indicating Menopause Leads to Increasing Hypertension Cross-sectional studies suggest a relationship between menopause and both hypertension and serum cholesterol7 (Table⇓). Both systolic and diastolic BP are reported to be related to menopause independent of age, body mass index (BMI), pulse rate, and HRT, and PMW had greater odds of being hypertensive than pre-MW (OR 2.2, P =0.03).8 In addition, the association between BP and age is steeper in PMW. View this table: Table. Studies Describing Relationship Between Menopausal Status and Blood Pressure or Cardiovascular Events View this table: Table. Continued Longitudinal cohort studies also demonstrated a relationship between menopause and hypertension. In a study of 315 women and age- and BMI-matched men followed for 5 years, PMW had higher systolic BP at baseline and systolic BP increased by approximately 5 mm Hg over 5 years …

Sex Steroids, Cardiovascular Disease, and Hypertension: Unanswered Questions and Some Speculations

The roles that both male and female sex steroids play in mediating or protecting against cardiovascular disease (CVD) and hypertension are controversial. For example, whereas animal studies have strongly implicated androgens as being mediators of CVD and hypertension, human epidemiological studies have shown that with chronic disease, including hypertension, serum testosterone levels are actually reduced.1 Thus, whether androgens are truly causative of CVD is not clear. However, premenopausal women are typically protected from CVD and hypertension compared with men, and this has been hypothesized to be because of the protective effects of estrogens. The negative findings of Heart and Estrogen/progestin Replacement Study (HERS) I and II2,3 and Women’s Health Initiative (WHI)4,5 studies on hormone replacement therapy (HRT) in postmenopausal women have shaken our previous ideas that HRT was protective against CVD. In this short review, the latest findings regarding the roles of sex steroids in hypertension and CVD are discussed, questions yet to be answered are suggested, and some speculations are made. In both males and females, the hypothalamus secretes gonadotropin-releasing hormone, which stimulates the anterior pituitary to release both luteinizing hormone and follicular-stimulating hormone. Luteinizing hormone binds to receptors on thecal cells in ovaries of females and Leydig cells in testes of males to cause testosterone to be synthesized. Follicular-stimulating hormone, however, binds to receptors on granulosa cells in females or Sertoli cells in males and stimulates the synthesis of aromatase, which converts testosterone to estradiol. There are 2 main types of estrogen receptors, ERα and ERβ, but several variants of both have also been identified. ERβ is present in a greater number of tissues than is ERα, but both isoforms are present in kidneys and the vasculature. ERβ has been found to be the predominant isoform in human vascular smooth muscle cells. The androgen receptor …

Estrogen, hormonal replacement therapy and cardiovascular disease.

Purpose of reviewPremenopausal women have a lower risk and incidence of hypertension and cardiovascular disease (CVD) compared to age-matched men and this sex advantage for women gradually disappears after menopause, suggesting that sexual hormones play a cardioprotective role in women. However, randomized prospective primary or secondary prevention trials failed to confirm that hormone replacement therapy (HRT) affords cardioprotection. This review highlights the factors that may contribute to this divergent outcome and could reveal why young or premenopausal women are protected from CVD and yet postmenopausal women do not benefit from HRT. Recent findingsIn addition to the two classical estrogen receptors, ERα and ERβ, a third, G-protein-coupled estrogen receptor GPR30, has been identified. New intracellular signaling pathways and actions for the cardiovascular protective properties of estrogen have been proposed. In addition, recent Womens Health Initiative (WHI) studies restricted to younger postmenopausal women showed that initiation of HRT closer to menopause reduced the risk of CVD. Moreover, dosage, duration, the type of estrogen and route of administration all merit consideration when determining the outcome of HRT. SummaryHRT has become one of the most controversial topics related to womens health. Future studies are necessary if we are to understand the divergent published findings regarding HRT and develop new therapeutic strategies to improve the quality of life for women.