Blood pressure is typically lower in premenopausal women than in men. However, after menopause, the prevalence of hypertension in women is higher than it is in men. Hypertension is a major risk factor for cardiovascular disease in women and men. Cardiovascular disease is the leading cause of death in women. Furthermore, there is evidence that blood pressure may not be as well-controlled in women as in men, despite the fact that most women adhere better to their therapeutic regimens and medications than do men, and have their blood pressures measured more frequently than do men. This review describes possible mechanisms by which blood pressure may be increased in postmenopausal women.
Background Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease at the time of PCOS and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS has not been elucidated. Objectives To characterize the cardiovascular-renal consequences of hyperandrogenemia in a female rat model. Methods Female Sprague Dawley rats, aged 4–6 weeks, were implanted with DHT or placebo pellets lasting 90 days. Following 10–12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, oral glucose tolerance test), inflammation (plasma TNF-α), oxidative stress (mRNA expression of NADPH oxidase subunits, p22phox, p47phox, gp91phox, and NOX4, nitrate/nitrite excretion), and mRNA expression of components of the renin-angiotensin system (RAS) (angiotensinogen, angiotensin-I-converting enzyme (ACE), AT1 receptor) were determined. Results Plasma DHT was increased 3-fold in hyperandrogenemic female 1 rats, whereas plasma estradiol levels were not different compared to control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression. Conclusions The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model in order to study the mechanisms responsible for hypertension.
In postmenopausal women the mechanisms responsible for hypertension have not been completely elucidated, and there are no gender-specific guidelines for women despite studies showing that blood pressure is not as well controlled to goal in women as in men. In the present study we tested the hypotheses that the sympathetic nervous system and the renal sympathetic nerves contribute to hypertension in aging female rats, that sympathetic activation may be mediated by the melanocortin 3/4 receptor (MC3/4R), and that MC3/4R activation may be due to increases in leptin. α-1, β-1,2-Adrenergic blockade reduced blood pressure in both young (3-4 mo) and old (18-19 mo) female spontaneously hypertensive rats (SHR). Renal denervation attenuated the hypertension more in old females than young females. MC3/4R antagonism with SHU-9119 given intracerebroventricularly had no effect on blood pressure in either young or old females but significantly reduced blood pressure in old males. Plasma leptin levels were similar in old male and female SHR and in old versus young females. These data suggest that the hypertension in old female SHR is in part due to activation of the sympathetic nervous system, that the renal nerves contribute to the hypertension, and that the mechanism responsible for sympathetic activation in old females is independent of the MC3/4R.
Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS.
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