High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet.

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.

Deciphering Latent Health Information in Social Media Using a Mixed-Methods Design.

Natural language processing techniques have increased the volume and variety of text data that can be analyzed. The aim of this study was to identify the positive and negative topical sentiments among diet, diabetes, exercise, and obesity tweets. Using a sequential explanatory mixed-method design for our analytical framework, we analyzed a data corpus of 1.7 million diet, diabetes, exercise, and obesity (DDEO)-related tweets collected over 12 months. Sentiment analysis and topic modeling were used to analyze the data. The results show that overall, 29% of the tweets were positive, and 17% were negative. Using sentiment analysis and latent Dirichlet allocation (LDA) topic modeling, we analyzed 800 positive and negative DDEO topics. From the 800 LDA topics-after the qualitative and computational removal of incoherent topics-473 topics were characterized as coherent. Obesity was the only query health topic with a higher percentage of negative tweets. The use of social media by public health practitioners should focus not only on the dissemination of health information based on the topics discovered but also consider what they can do for the health consumer as a result of the interaction in digital spaces such as social media. Future studies will benefit from using multiclass sentiment analysis methods associated with other novel topic modeling approaches.

Sex differences in vascular aging and impact of GPER deletion.

Aging is a nonmodifiable risk factor for cardiovascular disease associated with arterial stiffening and endothelial dysfunction. We hypothesized that sex differences exist in vascular aging processes and would be attenuated by global deletion of the G protein-coupled estrogen receptor. Blood pressure was measured by tail-cuff plethysmography, pulse wave velocity (PWV) and echocardiography were assessed with high-resolution ultrasound, and small vessel reactivity was measured using wire myography in adult (25 wk) and middle-aged (57 wk) male and female mice. Adult female mice displayed lower blood pressure and PWV, but this sex difference was absent in middle-aged mice. Aging significantly increased PWV but not blood pressure in both sexes. Adult female carotids were more distensible than males, but this sex difference was lost during aging. Acetylcholine-induced relaxation was greater in female than male mice at both ages, and only males showed aging-induced changes in cardiac hypertrophy and function. GPER deletion removed the sex difference in PWV and ex vivo stiffness in adult mice. The sex difference in blood pressure was absent in KO mice and was associated with endothelial dysfunction in females. These findings indicate that the impact of aging on arterial stiffening and endothelial function is not the same in male and female mice. Moreover, nongenomic estrogen signaling through GPER impacted vascular phenotype differently in male and female mice. Delineating sex differences in vascular changes during healthy aging is an important first step in improving early detection and sex-specific treatments in our aging population.NEW & NOTEWORTHY Indices of vascular aging were different in male and female mice. Sex differences in pulse wave velocity, blood pressure, and large artery stiffness were abrogated in middle-aged mice, but the female advantage in resistance artery vasodilator function was maintained. GPER deletion abrogated these sex differences and significantly reduced endothelial function in adult female mice. Additional studies are needed to characterize sex differences in vascular aging to personalize early detection and treatment for vascular diseases.

Sex and the G Protein-Coupled Estrogen Receptor Impact Vascular Stiffness.

[Figure: see text].

Alterations in the estrogen receptor profile of cardiovascular tissues during aging.

Estrogen exerts protective effects on the cardiovascular system via three known estrogen receptors: alpha (ERα), beta (ERß), and the G protein-coupled estrogen receptor (GPER). Our laboratory has previously showed the importance of GPER in the beneficial cardiovascular effects of estrogen. Since clinical studies indicate that the protective effects of exogenous estrogen on cardiovascular function are attenuated or reversed 10 years post-menopause, the hypothesis was that GPER expression may be reduced during aging. Vascular reactivity and GPER protein expression were assessed in female mice of varying ages. Physiological parameters, blood pressure, and estrogen receptor transcripts via droplet digital PCR (ddPCR) were assessed in the heart, kidney, and aorta of adult, middle-aged, and aged male and female C57BL/6 mice. Vasodilation to estrogen (E2) and the GPER agonist G-1 were reduced in aging female mice and were accompanied by downregulation of GPER protein. However, ERα and GPER were the predominant receptors in all tissues, whereas ERß was detectable only in the kidney. Female sex was associated with higher mRNA for both ERα and GPER in both the aorta and the heart. Aging impacted receptor transcript in a tissue-dependent manner. ERα transcript decreased in the heart with aging, while GPER expression increased in the heart. These data indicate that aging impacts estrogen receptor expression in the cardiovascular system in a tissue- and sex-specific manner. Understanding the impact of aging on estrogen receptor expression is critical for developing selective hormone therapies that protect from cardiovascular damage.

Medroxyprogesterone opposes estradiol-induced renal damage in midlife ovariectomized Long Evans rats.

OBJECTIVE: Our laboratory previously published that long-term administration of estradiol (E2) was detrimental to the kidneys of midlife ovariectomized Long Evans rats, contrasting clinical studies in showing that menopausal hormone therapy is associated with decreased albuminuria. However, it is unknown whether this renal benefit was due to estrogen and/or the combination with progestogen. Therefore, the objective of the current study was to determine the impact of medroxyprogesterone (MPA) on E2-mediated renal damage using a rodent model. METHODS: Female Long Evans retired breeders underwent ovariectomy at 11 months of age and were treated for 40 days with subcutaneous E2, E2+MPA or vehicle at doses mimicking that of menopausal hormone therapy (N = 5-7 per group). Systolic blood pressure was measured along with indices of renal damage and function to investigate the impact of MPA on E2-mediated renal outcomes. Renal estrogen receptor alpha and G protein-coupled estrogen receptor transcript copy numbers were measured in all treatment groups through droplet digital PCR. RESULTS: Middle-aged female Long Evans rats displayed spontaneous hypertension with similar systolic blood pressures and heart weights between groups. Even though blood pressure was comparable, E2 reduced glomerular filtration rate and increased proteinuria indicating pressure-independent renal damage. Coadministration with MPA prevented E2-induced glomerular filtration rate impairment and proteinuria by promoting renal hypertrophy and preventing renal interstitial fibrosis. Both E2 and E2+MPA reduced renal estrogen receptor alpha (ERα) and increased renal G protein-coupled estrogen receptor mRNA, but neither ERα nor ERß protein was different between groups. CONCLUSION: MPA was protective against E2-induced renal damage and dysfunction in middle-aged female Long Evans rats. Assessing the impact of hormone therapy on renal outcomes may be an important clinical factor when considering treatment options for postmenopausal women.

Health information seeking behaviour: a concept analysis.

BACKGROUND: In 2007, Lambert and Loiselle conducted an extensive concept analysis of the term health information seeking behaviour (HISB) to examine the concept's level of maturity and critically analyse its characteristics. Since their groundbreaking work, HISB has evolved with the proliferation of ICTs. The Internet is now a common and often preferred medium for the pursuit of health information. OBJECTIVES: The previous analysis spanned 42 years of literature; this article describes an analysis of the last 10 years of literature on HISB and how online seeking has caused the concept to evolve in the literature. METHODS: This study used the concept analysis methodology employed by Lambert and Loiselle in the original analysis. It also included a systematic search conducted in five databases to identify studies from 2007 to 2017, using similar inclusion criteria from the original study. RESULTS: Of the more than 500 articles retrieved, 85 journal articles met the inclusion criteria. Consistent with the original work, articles that included outcomes were identified as either behavioural or cognitive. CONCLUSION: Most of the attention of the works studied focused on individuals and their information source preferences. This HISB analysis can be incorporated with studies to understand how various communities seek information in online versus non-online contexts.

G Protein-Coupled Estrogen Receptor Protects From Angiotensin II-Induced Increases in Pulse Pressure and Oxidative Stress.

Our previous work showed that the G protein-coupled estrogen receptor (GPER) is protective in the vasculature and kidneys during angiotensin (Ang) II-dependent hypertension by inhibiting oxidative stress. The goal of the current study was to assess the impact of GPER deletion on sex differences in Ang II-induced hypertension and oxidative stress. Male and female wildtype and GPER knockout mice were implanted with radiotelemetry probes for measurement of baseline blood pressure before infusion of Ang II (700 ng/kg/min) for 2 weeks. Mean arterial pressure was increased to the same extent in all groups, but female wildtype mice were protected from Ang II-induced increases in pulse pressure, aortic wall thickness, and Nox4 mRNA. In vitro studies using vascular smooth muscle cells found that pre-treatment with the GPER agonist G-1 inhibited Ang II-induced ROS and NADP/NADPH. Ang II increased while G-1 decreased Nox4 mRNA and protein. The effects of Ang II were blocked by losartan and Nox4 siRNA, while the effects of G-1 were inhibited by adenylyl cyclase inhibition and mimicked by phosphodiesterase inhibition. We conclude that during conditions of elevated Ang II, GPER via the cAMP pathway suppresses Nox4 transcription to limit ROS production and prevent arterial stiffening. Taken together with our previous work, this study provides insight into how acute estrogen signaling via GPER provides cardiovascular protection during Ang II hypertension and potentially other diseases characterized by increased oxidative stress.

Estrogen receptor profiles across tissues from male and female Rattus norvegicus.

BACKGROUND: Estrogen is formed by the enzyme aromatase (CYP19A1) and signals via three identified receptors ERα (ESR1), ERß (ESR2), and the G protein-coupled estrogen receptor (GPER). Understanding the relative contribution of each receptor to estrogenic signaling may elucidate the disparate effects of this sex hormone across tissues, and recent developments in PCR technology allow absolute quantification and direct comparison of multiple targets. We hypothesized that this approach would reveal tissue- and sex-specific differences in estrogen receptor mRNA. METHODS: ESR1, ESR2, GPER, and CYP19A1 were measured in four cardiovascular tissues (heart, aorta, kidney, and adrenal gland), three brain areas (somatosensory cortex, hippocampus, and prefrontal cortex), and reproductive tissues (ovaries, mammary gland, uterus, testes) from six male and six female adult Sprague-Dawley rats. RESULTS: GPER mRNA expression was relatively stable across all tissues in both sexes, ranging from 5.49 to 113 copies/ng RNA, a 21-fold difference. In contrast, ESR1/ESR2 were variable across tissues although similar within an organ system. ESR1 ranged from 4.46 to 614 copies/ng RNA (138-fold difference) while ESR2 ranged from 0.154 to 83.1 copies/ng RNA (540-fold). Significant sex differences were broadly absent except for renal ESR1 (female 206 vs. male 614 copies/ng RNA, P < 0.0001) and GPER (62.0 vs. 30.2 copies/ng RNA, P < 0.05) as well as gonadal GPER (5.49 vs. 47.5 copies/ng RNA, P < 0.01), ESR2 (83.1 vs. 0.299 copies/ng RNA, P < 0.01), and CYP19A1 (322 vs. 7.18 copies/ng RNA, P < 0.01). Cardiovascular tissues showed a predominance of ESR1, followed by GPER. In contrast, GPER was the predominant transcript in the brain with similarly low levels of ESR1 and ESR2. CYP19A1 was detected at very low levels except for reproductive tissues and the hippocampus. CONCLUSION: While the data indicates a lack of sex differences in most tissues, significant differences were found in the range of receptor gene expression across tissues as well as in the receptor profile between organ systems. The data provide a guide for future studies by establishing estrogen receptor expression across multiple tissues using absolute PCR quantification. This knowledge on tissue-specific estrogen receptor profiles will aid the development of hormonal therapies that elicit beneficial effects in specific tissues.

Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol.

OBJECTIVE: A new strategy for menopausal hormone therapy replaces medroxyprogesterone with the selective estrogen receptor modulator bazedoxifene. While the agonist or antagonist activity of bazedoxifene has been examined in other tissues, the current study explored the impact of bazedoxifene on resistance artery reactivity. We hypothesized that bazedoxifene may induce greater vasoprotective effects than estradiol due to enhanced activation of the G-protein-coupled estrogen receptor. METHODS: We measured the vasodilation of mesenteric resistance arteries from adult male and female wild-type and G-protein-coupled estrogen receptor knockout mice (n = 58) in response to increasing concentrations of bazedoxifene, medroxyprogesterone, and estradiol, and also the impact of these compounds on the responses to phenylephrine and sodium nitroprusside. RESULTS: Bazedoxifene-induced vasorelaxation was greater than estradiol and blunted phenylephrine-induced contraction-an effect not observed with estradiol. Neither estradiol nor bazedoxifene altered relaxation to sodium nitroprusside. The combination of bazedoxifene + estradiol promoted greater vasodilation than medroxyprogesterone + estradiol, and opposed phenylephrine-induced contraction, whereas medroxyprogesterone + estradiol failed to attenuate this response. Both bazedoxifene + estradiol and medroxyprogesterone + estradiol enhanced sodium nitroprusside-induced relaxation in females. Vascular responses were similar in both sexes in wild-type and G-protein-coupled estrogen receptor knockout mice. CONCLUSION: Bazedoxifene and bazedoxifene + estradiol relaxed mesenteric arteries and opposed vasoconstriction to a greater degree than estradiol or medroxyprogesterone + estradiol. These effects were independent of sex and G-protein-coupled estrogen receptor expression. We conclude that bazedoxifene may provide vascular benefits over estrogen alone or estrogen plus progestogen combinations in postmenopausal women.

New insights into arterial stiffening: does sex matter?

This review discusses sexual dimorphism in arterial stiffening, disease pathology interactions, and the influence of sex on mechanisms and pathways. Arterial stiffness predicts cardiovascular mortality independent of blood pressure. Patients with increased arterial stiffness have a 48% higher risk for developing cardiovascular disease. Like other cardiovascular pathologies, arterial stiffness is sexually dimorphic. Young women have lower stiffness than aged-matched men, but this sex difference reverses during normal aging. Estrogen therapy does not attenuate progressive stiffening in postmenopausal women, indicating that currently prescribed drugs do not confer protection. Although remodeling of large arteries is a protective adaptation to higher wall stress, arterial stiffening increases afterload to the left ventricle and transmits higher pulsatile pressure to smaller arteries and target organs. Moreover, an increase in aortic stiffness may precede or exacerbate hypertension, particularly during aging. Additional studies are needed to elucidate the mechanisms by which females are protected from arterial stiffness to provide insight into its mechanisms and, ultimately, therapeutic targets for treating this pathology.

Assessing the Reproductive Health-Related Information-Seeking Behavior of Low-Income Women: Describing a Two-Step Information-Seeking Process.

This paper explores the reproductive health-related information seeking of low-income women that has been found to be affected by digital divide disparities. A survey conducted with 70 low-income women explores what information sources women use for reproductive health-related information seeking, what process they go through to find information, and if they are using sources that they trust. The findings of this study detail a two-step information-seeking process that typically includes a preference for personal, informal sources. Women of this income group often rely upon sources that they do not consider credible. While there have been many studies on the end effects of a lack of accurate and accessible reproductive health information, little research has been conducted to examine the reproductive healthcare information-seeking patterns of women who live in poverty.

Long- but not short-term estradiol treatment induces renal damage in midlife ovariectomized Long-Evans rats.

Clinical recommendations limit menopausal hormone therapy to a few years, yet the impact of a shorter treatment duration on cardiovascular health is unknown. We hypothesized that both short- and long-term estradiol (E2) treatment exerts positive and lasting effects on blood pressure, vascular reactivity, and renal health. This study was designed to mimic midlife menopause, followed by E2 treatment, that either followed or exceeded the current clinical recommendations. Female Long-Evans retired breeders were ovariectomized (OVX) at 11 mo of age and randomized into three groups: 80-day (80d) vehicle (Veh>Veh), 40-day (40d) E2 + 40d vehicle (E2>Veh), and 80d E2 (E2>E2). In comparison to Veh>Veh, both the E2>Veh and E2>E2 groups had lower systolic blood pressure and enhanced mesenteric relaxation in response to estrogen receptor-α stimulation. Despite the reduced blood pressure, E2>E2 induced renal and cardiac hypertrophy, reduced glomerular filtration, and increased proteinuria. Interestingly, kidneys from E2>Veh rats had significantly fewer tubular casts than both of the other groups. In conclusion, long-term E2 lowered blood pressure but exerted detrimental effects on kidney health in midlife OVX Long-Evans rats, whereas short-term E2 lowered blood pressure and reduced renal damage. These findings highlight that the duration of hormone therapy may be an important factor for renal health in aging postmenopausal women.

Information Poverty and Reproductive Healthcare: Assessing the Reasons for Inequity between Income Groups.

It is commonly known that in the United States women who are low income do not access reproductive healthcare services and information with the same reliability and regularity of women who are higher income. A qualitative research approach was undertaken to assess the root cause of this disparity. In-depth semistructured interviews were conducted with 15 women divided among socioeconomic lines. The primary barriers to care for women who are low income are clinical staff attitudes, knowledge of care available and needed, and cost or lack of insurance. This study adds to the current understanding of the barriers to reproductive healthcare for women of different socioeconomic statuses.

GPER-novel membrane oestrogen receptor.

The recent discovery of the G protein-coupled oestrogen receptor (GPER) presents new challenges and opportunities for understanding the physiology, pathophysiology and pharmacology of many diseases. This review will focus on the expression and function of GPER in hypertension, kidney disease, atherosclerosis, vascular remodelling, heart failure, reproduction, metabolic disorders, cancer, environmental health and menopause. Furthermore, this review will highlight the potential of GPER as a therapeutic target.

GPER activation ameliorates aortic remodeling induced by salt-sensitive hypertension.

The mRen2 female rat is an estrogen- and salt-sensitive model of hypertension that reflects the higher pressure and salt sensitivity associated with menopause. We previously showed that the G protein-coupled estrogen receptor (GPER) mediates estrogenic effects in this model. The current study hypothesized that GPER protects against vascular injury during salt loading. Intact mRen2 female rats were fed a normal (NS; 0.5% Na(+)) or high-salt diet (HS; 4% Na(+)) for 10 wk, which significantly increased systolic blood pressure (149 ± 5 vs. 224 ± 8 mmHg;P< 0.001). Treatment with the selective GPER agonist G-1 for 2 wk did not alter salt-sensitive hypertension (216 ± 4 mmHg;P> 0.05) or ex vivo vascular responses to angiotensin II or phenylephrine (P> 0.05). However, G-1 significantly attenuated salt-induced aortic remodeling assessed by media-to-lumen ratio (NS: 0.43; HS+veh: 0.89; HS+G-1: 0.61;P< 0.05). Aortic thickening was not accompanied by changes in collagen, elastin, or medial proliferation. However, HS induced increases in medial layer glycosaminoglycans (0.07 vs. 0.42 mm(2);P< 0.001) and lipid peroxidation (0.11 vs. 0.51 mm(2);P< 0.01), both of which were reduced by G-1 (0.20 mm(2)and 0.23 mm(2); both P< 0.05). We conclude that GPER's beneficial actions in the aorta of salt-loaded mRen2 females occur independently of changes in blood pressure and vasoreactivity. GPER-induced attenuation of aortic remodeling was associated with a reduction in oxidative stress and decreased accumulation of glycosaminoglycans. Endogenous activation of GPER may protect females from salt- and pressure-induced vascular damage.

Differences in angiotensin (1-7) between men and women.

UNLABELLED: In experimental animal models of hypertension, angiotensin (1-7) [ANG-(1-7)] is higher in females compared with males; however, it is less clear whether the same applies to humans. Therefore, this study sought to compare circulating concentrations of ANG-(1-7) in apparently healthy men and women under normal physiological conditions. With the use of a cross-sectional experimental design, blood was collected in EDTA anticoagulant from 42 volunteers (21 men and 21 women; and age range, 19-48 yr) for analysis of plasma concentrations of ANG-(1-7) and ANG II. Blood pressure was measured and vascular endothelial function was determined (n = 25) using the brachial artery flow-mediated dilation (FMD) test. As a result, women exhibited a higher circulating concentration of ANG-(1-7) (P = 0.04) compared with men, whereas values of ANG II were similar between groups. Baseline arterial diameter, peak diameter, and shear rate were significantly greater (P < 0.02) in men compared with women. No significant differences in FMD, FMD normalized for shear, or time to peak dilation were observed between men and women. In addition, a positive correlation between ANG-(1-7) and FMD (P = 0.04) and negative association between ANG-(1-7) with ANG II (P = 0.01) were only identified in men, whereas a positive relationship between ANG-(1-7) and diastolic blood pressure (P = 0.03) was observed in women. IN CONCLUSION: , women exhibit significantly higher plasma concentrations of ANG-(1-7) compared with men. In addition, this study describes a relationship between ANG-(1-7), vascular function, and diastolic blood pressure that appears to be sex dependent.

Chronic ANG II infusion induces sex-specific increases in renal T cells in Sprague-Dawley rats.

Recent studies suggest that sex of the animal and T cell impact ANG II hypertension in Rag(-/-) mice, with females being protected relative to males. This study tested the hypothesis that ANG II results in greater increases in proinflammatory T cells and cytokines in males than in females. Male and female Sprague-Dawley (SD) rats, aged 12 wk, were treated with vehicle or ANG II (200 ng·kg(-1)·min(-1)) for 2 wk. Renal CD4(+) T cells and Tregs were comparable between vehicle-treated males and females, although males expressed more Th17 and IL-17(+) T cells and fewer IL-10(+) T cells than females. ANG II resulted in greater increases in CD4(+) T cells, Th17 cells, and IL-17(+) cells in males; Tregs increased only in females. We previously showed that ANG (1-7) antagonizes ANG II-induced increases in blood pressure in females and ANG (1-7) has been suggested to be anti-inflammatory. Renal ANG (1-7) levels were greater in female SD at baseline and following ANG II infusion. Additional rats were treated with ANG II plus the ANG (1-7)-mas receptor antagonist A-779 (48 µg·kg(-1)·h(-1)) to test the hypothesis that greater ANG (1-7) in females results in more Tregs relative to males. Inhibition of ANG (1-7) did not alter renal T cells in either sex. In conclusion, ANG II induces a sex-specific effect on the renal T cell profile. Males have greater increases in proinflammatory T cells, and females have greater increases in anti-inflammatory Tregs; however, sex differences in the renal T cell profile are not mediated by ANG (1-7).

Female spontaneously hypertensive rats are more dependent on ANG (1-7) to mediate effects of low-dose AT1 receptor blockade than males.

ANG (1-7) contributes to the blood pressure (BP)-lowering effect of angiotensin receptor blockers (ARBs) in male experimental animals. Females have greater ANG (1-7) concentrations than males; however, the contribution of ANG (1-7) to ARB-mediated decreases in BP in females is unknown. The current study tested the hypothesis that female spontaneously hypertensive rats (SHR) have a larger ANG (1-7) contribution to the BP-lowering effects of the ARB candesartan than male SHR. Twelve-week-old male and female SHR were randomized to receive candesartan (0.5 mg·kg(-1)·day(-1); 7 days), candesartan plus ANG II (200 ng·kg(-1)·min(-1); 7 days), the ANG (1-7) antagonist A-779 (48 µg·kg(-1)·h(-1)) plus candesartan and ANG II. Candesartan decreased basal BP in males and females (baseline vs. candesartan: 142 ± 2 vs. 122 ± 3 and 129 ± 1 vs. 115 ± 1 mmHg, respectively; P < 0.05); however, the decrease was greater in males. ANG II increased BP in males in the presence of candesartan (149 ± 2 mmHg; P < 0.05); candesartan blocked ANG II-induced increases in BP in females (116 ± 1 mmHg). Pretreatment with A-779 abolished candesartan-mediated decreases in BP in females, but not males. A-779 also exacerbated ANG II-induced proteinuria (26 ± 6 vs. 77 ± 11 µg·kg(-1)·day(-1), respectively; P < 0.05) and nephrinuria (20 ± 5 vs. 202 ± 58 µg·kg(-1)·day(-1), respectively; P < 0.05) in candesartan-treated female SHR, with no effect in males. In conclusion, females are more sensitive to the BP-lowering effect of ARBs during ANG II infusion, whereas males are more sensitive under basal conditions. In addition, ANG (1-7) has a greater contribution to ARB-mediated decreases in BP, protein, and nephrin excretion in females relative to males.