[Show abstract][Hide abstract] ABSTRACT: Hypertension in postmenopausal women is less well controlled than in age-matched men. The aging female SHR is a model of postmenopausal hypertension that is mediated in part by activation of the renin-angiotensin system (RAS) and by the renal sympathetic nervous system. In this study, the hypothesis was tested that renal denervation would lower the blood pressure in old female SHR and would attenuate the antihypertensive effects of AT1 receptor antagonism. Retired breeder female SHR were subjected to right uninephrectomy (UNX) and left renal denervation (RD) or UNX and sham, and 2 weeks later, baseline mean arterial pressure (MAP; radiotelemetry) was measured for 4 days, and then rats were treated with angiotensin (AT1) receptor antagonist, losartan (40 mg/kg/day po) for 6 days. Renal denervation reduced MAP in old females compared to sham (172 ± 6 vs. 193 ± 6 mm Hg; P < 0.05). Losartan reduced MAP in both sham and RD rats similarly (numerically and by percentage) (142 ± 10 vs. 161 ± 6 mm Hg; P < 0.05 vs. RD, P < 0.05 vs. baseline). However, female SHR rats remained significantly hypertensive despite both pharmacological intervention and RD. The data suggest that both the renal sympathetic nervous system and the RAS have independent effects to control the blood pressure in old female SHR. Since the denervated rats treated with losartan remained hypertensive, the data also suggest that other mechanisms than the RAS and renal sympathetic nervous system contribute to the hypertension in old female SHR. The data also suggest that multiple mechanisms may mediate the elevated blood pressure in postmenopausal women.
[Show abstract][Hide abstract] ABSTRACT: The mechanisms responsible for the gender difference in blood pressure (BP) in humans are not clear. Over the past several years we have studied the spontaneously hypertensive rat (SHR) as a model of sex differences in BP control. In the present study, we tested the hypothesis that renal vascular and microsomal epoxyeicosatrienoic acid (EET) levels are higher in females than males, and increasing vascular EETs by blocking epoxide hydrolase with AUDA will reduce BP more in males than females. Renal vascular and microsomal EETs were higher in female SHR than males. Mean arterial pressure (MAP by telemetry) was higher in males than females during the baseline period of 6 days, and although the epoxide hydrolase inhibitor, AUDA, given for 10 days increased renal microvascular EETs in both groups, AUDA did not affect MAP in either group. These data suggest that EETs do not contribute to the sex differences in hypertension in young SHR.
[Show abstract][Hide abstract] ABSTRACT: 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. Alpha-1, beta-1,2-adrenergic blockade reduced blood pressure in both young (3-4 mos) and old (18-19 mos) 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 vs 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.
Preview · Article · Dec 2013 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract] ABSTRACT: In recent years, the interest in studying the impact of sex steroids and gender on the regulation of blood pressure and cardiovascular disease has been growing. Women are protected from most cardiovascular events compared with men until after menopause, and postmenopausal women are at increased risk of cardiovascular complications compared with premenopausal women. The pathophysiological mechanisms have not been elucidated, but are not likely to be as simple as the presence or absence of oestrogens, since hormone replacement therapy in elderly women in the Women's Health Initiative or HERS (Heart and Estrogen/progestin Replacement Study) did not provide primary or secondary prevention against cardiovascular events. Men are also thought to be at risk of cardiovascular disease at earlier ages than women, and these mechanisms too are not likely to be as simple as the presence of testosterone, since androgen levels fall in men with cardiovascular and other chronic diseases. In fact, many investigators now believe that it is the reduction in androgen levels that frequently accompanies chronic disease and may exacerbate cardiovascular disease in men. In the present review, the roles of sex steroids and gender in mediating or protecting against hypertension and cardiovascular disease will be discussed.
[Show abstract][Hide abstract] ABSTRACT: Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease in general. In the present study we tested the hypothesis that I/R of the kidney reduces serum testosterone and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 hrs post reperfusion that remained at 24 hr. Infusion of testosterone 3 hrs after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 hrs, prevented the reduction in outer medullary blood flow, attenuated the increase in intrarenal TNF-α, and the decrease in intrarenal vascular endothelial growth factor at 48 hrs. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 hrs than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol.
[Show abstract][Hide abstract] ABSTRACT: Men with end-stage renal disease are frequently given androgen supplements to improve sexual function. Endogenous androgens contribute to hypertension and renal injury in various animal models. We hypothesized that testosterone supplements exacerbate hypertension and renal injury in rats with reduced renal mass (RRM). Rats subjected to surgical ablation of 80% of renal mass were given 8% NaCl diet for 6 weeks. Testosterone was administered in Silastic® pellets throughout the study to groups of rats with intact or ablated kidneys. Arterial pressure was continuously monitored by telemetry. Renal injury was assessed by measurements of urinary protein and neutrophil gelatinase-associated lipocalin (NGAL) excretion. RRM developed hypertension on the high salt diet as compared with intact rats (154±12 vs 111±3mmHg). Testosterone supplementation did not alter the course of hypertension in RRM, nor increased blood pressure in Sham rats (156±12 vs 113±8mmHg, RRM vs Sham). Testosterone-supplemented RRM consistently excreted 20 to 30% more protein than untreated RRM. Urinary levels of NGAL, an index of tubulointerstitial injury, were also higher in RRM as compared to intact rats and were further augmented by testosterone supplements. Our data indicate that testosterone supplements worsen renal injury in a model of chronic hypertensive renal disease without affecting blood pressure.
[Show abstract][Hide abstract] ABSTRACT: Prevalence of hypertension (HT) increases in women after menopause, and there is evidence that HT is not as well controlled in postmenopausal women as men. The reasons for this are not clear, but may be related to the lack of adequate blockade of the systems contributing to HT in women. This study aimed to determine the roles of three of the systems known to contribute to HT in animal studies, angiotensin II (ANG II; enalapril inhibitor), eicosanoids (1-ABT inhibitor), and endothelin (ET(A) receptor antagonist), on blood pressure (BP) in 3 groups of female spontaneously hypertensive rats (SHR), aged 18 mos. Following baseline telemetry BP, three drug periods were performed for 5 days each: single blockade (ABT or enalapril); double blockade (ABT+enalapril or enalapril+ABT); and triple blockade (all 3 drugs). Controls received no treatment until the third period when they received ET(A) receptor antagonist alone. Single drug blockade reduced BP in PMR to similar levels. Double blockade reduced MAP more in ABT+enalapril rats than in the other group (enalapril+ABT). Triple drug blockade reduced BP to similar levels in both groups, but the BP remained above 110 mm Hg. The data suggest that these three systems, Ang II, eicosanoids, and endothelin, contribute together and independently to BP control in old female SHR. However, other systems also contribute to the HT since the BP was not normalized, supporting the notion that HT in postmenopausal women may require complex multi-drug therapy to be better controlled, and that may require the development of additional drugs.
Preview · Article · Dec 2012 · AJP Regulatory Integrative and Comparative Physiology