Sex hormones regulate the renin-angiotensin system. For example, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner.

378T he development and progression of hypertension differs between men and women. Before menopause, arterial pressure is lower in women than in men of similar age. 1 However, after menopause, this cardioprotection in women is lost, and a higher proportion of women than men have hypertension after the age of 65 years.1 Similar differences in arterial pressure control have been observed in other mammalian species, including spontaneously hypertensive rats (SHRs). 2,3These sex-related differences in the development of hypertension have been strongly linked to sexual dimorphism in the renin-angiotensin system (RAS), which plays a pivotal role in the long-term regulation of arterial pressure. 3,4 Classically, angiotensin II (AngII) acts via the angiotensin type 1 receptor (AT 1 R) to cause vasoconstriction and sodium retention. Activation of the pressor RAS is a key mediator in the development of hypertension, and drugs that target this system are mainstays of current antihypertensive therapy. More recently, a depressor arm of the RAS has been recognized, which counterbalances the actions of AngII at AT 1 R. AngII together with other biologically active angiotensin peptides, including angiotensin (1-7) and angiotensin III, interact with angiotensin type 2 receptor (AT 2 R) to evoke vasodilatation and natriuresis. Overwhelming evidence suggests that the depressor RAS is upregulated in women by estrogen, and this contributes to sexual dimorphism in arterial pressure control.3,4 It is, therefore, plausible that enhancement of the depressor RAS, and in particular the AT 2 R, may represent a novel therapeutic target in the treatment of hypertension, particularly in women.Our recent data from normotensive rats support the notion that AT 2 R plays an integral, yet sexually dimorphic, functional Abstract-Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT 2 R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension, we examined the influence of the AT 2 R agonist, compound 21 (100-300 ng/kg per minute), on renal function in 18-to 19-weekold anesthetized male and female spontaneously hypertensive rats. AT 2 R stimulation significantly increased renal blood flow in female hypertensive rats (P Treatment <0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P<0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT 2 R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any sign...

A role for maladaptive regulation of TLR and HIF-1α induced by an imbalance in inflammatory cytokines is implicated in the pathogenesis of pre-eclampsia.

Unmasking the potential of the angiotensin AT 2 receptor as a therapeutic target in hypertension in men and women: What we know and what we still need to find out Lucinda M Hilliard, Katrina M Mirabito and Kate M DentonDepartment of Physiology, Monash University, Melbourne, Vic., Australia SUMMARY 1. Major sex differences exist in the development and progression of hypertension and cardiovascular disease. Prior to menopause, women have lower arterial pressure and, furthermore, are protected from hypertension and cardiovascular disease relative to age-matched men. However, after menopause this cardiovascular protection in women is lost. These sex differences have been linked to sexual dimorphism in the physiological mechanisms that regulate arterial pressure, including the renin-angiotensin system (RAS), which can also impact on the male and female response to different therapeutic approaches. This suggests that antihypertensive regimens need to be tailored according to sex.2. Newly discovered components of the RAS have emerged in recent years, allowing us to look beyond the classical RAS for novel therapeutic targets for hypertension. In this context, it is now well established that the angiotensin AT 2 receptor (AT 2 R) elicits depressor and natriuretic effects and that these effects are greater in females due to enhanced AT 2 R levels modulated by oestrogen.3. In light of knowledge that AT 2 R expression is regulated by oestrogen and that the prevalence of hypertension and cardiovascular risk is greater in women after menopause, AT 2 R agonist therapy may represent an innovative therapeutic approach to treat hypertension. Consequently, understanding how ageing and changes in the sex hormone balance influence the RAS is vital if we are to evaluate the potential of the AT 2 R as a therapeutic target in women and also in men.

Background: The pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT 2 R)-dependent pathway. We hypothesized that adult female mice are protected against AngII-induced hypertension via an enhanced AT 2 R-mediated pathway and that in reproductively senescent females this pathway is no longer operative.

Abstract-During normal pregnancy the renin-angiotensin system is activated, yet pregnant women are resistant to the pressor effects of angiotensin II. Our aim was to determine the role of the angiotensin type 2 receptor (AT 2 R) in the regulation of arterial pressure, natriuresis, and immune cell infiltration during pregnancy. Mean arterial pressure was measured via telemetry, and flow cytometry was used to enumerate immune cell infiltration in 14-week-old wild-type and AT 2 R knockout mice during gestation. In wild-type mice, mean arterial pressure decreased during gestation, reaching a nadir at gestational day 9 (-6±2 mm Hg) and returned to near preconception levels during late gestation. In AT 2 Rdeficient mice, the midgestational decrease in mean arterial pressure was absent. Furthermore, mean arterial pressure was significantly increased during late gestation compared with wild-type mice (≈10 mm Hg). As expected, circulating immune cell activation was suppressed during pregnancy. However, this response was absent in AT 2 R-deficient mice. While renal immune cell infiltration was similar between the genotypes, there was a significant T cell phenotypic switch toward a proinflammatory T-helper 1 phenotype in AT 2 R-deficient mice. These data indicate that the AT 2 R plays an important role in arterial pressure regulation and may modulate T cell activation and renal cytokine production during pregnancy. Therefore, deficits in AT 2 R expression may contribute to pregnancy-induced hypertension and thus represents a potential therapeutic target.

Background:The angiotensin type-2 receptor (AT 2 R) opposes the vasoconstrictor actions of angiotensin II (AngII) mediated through the angiotensin type-1 receptor (AT 1 R). Renal AT 2 R levels are high during fetal life, but decrease significantly during postnatal maturation. To provide insight into the functional role of the AT 2 R in the kidney during postnatal development, we investigated the effects of AT 2 R antagonism on cardiovascular responses to AngII in young and adult male rats. Methods: In anesthetized 3-and 6-wk-old male SpragueDawley rats, mean arterial pressure (MAP) and renal blood flow (RBF) were measured in response to AngII in the presence of vehicle treatment or AT 2 R blockade with PD123319. results: The pressor effect of AngII and associated reduction in RBF were significantly less in 3-wk-than 6-wk-old rats. AT 2 R blockade potentiated the reduction in RBF in response to AngII in 3-wk-old rats only. conclusion: In young rats, the AT 2 R modulates the response to AngII, blunting renal vasoconstriction. This effect is attenuated with age in association with a developmental reduction in renal AT 2 R expression. These findings may have implications for the development of novel therapies that target the reninangiotensin system for the improvement of renal function in term and, in particular, preterm infants.

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