Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations

Tatchum-Talom, Rabelais; Eyster, Kathleen M.; Martin, Douglas

doi:10.1139/y05-012

Cited by 71 publications

(58 citation statements)

References 47 publications

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“…8,10 Xue et al 8 showed a reduced pressor response to Ang II in female mice as compared with males, which has been confirmed by others in rats. 9,13 Consistent with this previous work, the current study demonstrated sex differences in response to the chronic high-dose Ang II infusion with an attenuated increase in MAP in females as compared with their male counterparts. Remarkably, we were able to show a significant decrease in MAP in normotensive females in response to low-dose Ang II, and this effect was achieved without concomitant AT 1 R blockade.…”

Section: Discussionsupporting

confidence: 91%

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

et al. 2008

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Abstract-The renin-angiotensin system is a far more complex enzymatic cascade than realized previously. Mounting evidence suggests sex-specific differences in the regulation of the renin-angiotensin system and arterial pressure. We examined the hemodynamic responses, angiotensin II receptor subtypes, and angiotensin-converting enzyme 2 gene expression levels after graded doses of angiotensin II in males and females. Mean arterial pressure was measured via telemetry in male and female rats in response to a 2-week infusion of vehicle, low-dose (50 ng/kg per minute SC) or high-dose (400 ng/kg per minute SC) angiotensin II. The effect of concurrent infusion of the angiotensin II type 2 receptor (AT 2 R) blocker (PD123319) was also examined. The arterial pressure response to high-dose angiotensin II was attenuated in females compared with males (24Ϯ8 mm Hg versus 42Ϯ5 mm Hg; P for the interaction between sex and treatment Ͻ0.002). Remarkably, low-dose angiotensin II decreased arterial pressure (11Ϯ4 mm Hg; P for the interaction between sex and treatment Ͻ0.02) at a dose that did not have an effect in males. This decrease in arterial pressure in females was abolished by AT 2 R blockade. Renal AT 2 R, angiotensin-converting enzyme 2, and left ventricular AT 2 R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT 2 R ratio of Ϸ1 in females. Angiotensin II infusion did not affect renal AT 2 R mRNA expression but resulted in significantly less left ventricular mRNA expression. Renal angiotensin-converting enzyme 2 mRNA expression levels were greater in females than in males treated with high-dose angiotensin II (Ϸ2.5 fold; P for the interaction between sex and treatment Ͻ0.05). In females, enhancement of the vasodilatory arm of the renin-angiotensin system, in particular, AT 2 R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation. (Hypertension. 2008;52:666-671.)Key Words: basic science Ⅲ gender differences Ⅲ gene expression/regulation Ⅲ hypertension Ⅲ angiotensin receptors C ardiovascular disease is the leading cause of death in the Western world, and, contrary to popular belief, mortality rates for cardiovascular disease are greater in women than men. 1,2 Significant differences in survival after a heart attack have been revealed, with 42% of women who experience heart attacks dying within 1 year, compared with 24% of men. 2 The reasons for these differences in outcomes are unknown but require urgent explanation.Hypertension is a major risk factor for cardiovascular disease, with the renin-angiotensin system (RAS) playing a predominant role in the regulation of arterial pressure in both sexes. The potent end product, angiotensin II (Ang II), acts via 2 main subtypes of receptors responsible for vasoconstriction, sodium reabsorption and cell proliferation (in the rodents there are 2 further subtypes: type 1a [AT 1a R] and type 1b [AT 1b R]), as well as vasodil...

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Section: Discussionsupporting

confidence: 91%

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

et al. 2008

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“…26,27 In the Ang II-induced model of hypertension, we and others have also demonstrated that the pressor response to Ang II infusion is less in females than that in males. 7,9,28 Xue et al 10 demonstrated that testosterone and estrogen play important roles in the development of Ang II-induced hypertension, because the rise in arterial pressure was attenuated in males by castration and augmented in females by either ovariectomy or inhibition/deletion of the …”

Section: Discussionmentioning

confidence: 99%

Sex Differences in the Pressor and Tubuloglomerular Feedback Response to Angiotensin II

et al. 2012

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Abstract-Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT 2 R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT 2 R mechanism that, in part, offsets Ang II-induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT 2 R knockout (AT 2 R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28Ϯ6 mm Hg), male AT 2 R-KO (26Ϯ2 mm Hg), and female AT 2 R-KO (26Ϯ4 mm Hg) mice, however, the response was attenuated in female WT mice (12Ϯ4 mm Hg; P between sex and genotypeϭ0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT 2 R-KO, and female AT 2 R-KO but not in the female WT mice (P between sex and genotype Ͻ0.05; both). In conclusion, these data indicate that an enhanced AT 2 R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II-dependent resetting of TGF activity in females. Thus, the enhancement of the AT 2 R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease. Key Words: sex differences Ⅲ renin-angiotensin system Ⅲ Ang II Ⅲ mean arterial pressure Ⅲ hypertension Ⅲ renal hemodynamics Ⅲ tubuloglomerular feedback M en have a greater prevalence for hypertension and cardiovascular disease than premenopausal women of the same age. 1 The mechanisms underlying these differences in the pathophysiology of cardiovascular disease between men and women remain unclear. One of the suggested mechanisms underlying this sexual dimorphism is differences in the function of the renin-angiotensin system (RAS). [2][3][4] Angiotensin II (Ang II), the main effector peptide of the RAS, exerts its effects through 2 main receptor subtypes. Stimulation of the angiotensin type 1 receptor (AT 1 R) causes vasoconstriction, sodium reabsorption, and cell proliferation. The angiotensin type 2 receptor (AT 2 R) opposes the AT 1 R, causing vasodilation, sodium excretion, and apoptosis. 5,6 Earlier studies have shown that females have a greater AT 2 R:AT 1 R ratio. 7,8 We, and others, have demonstrated previously that the rise in arterial pressure in response to Ang II is blunted in females compared with males. 7,9 -11 Furthermore, we have provided evidence to suggest that arteria...

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“…This effect may represent another mechanism by which androgens potentiate hypertension in the NZGH model. Interestingly, recent studies have reported that there were sex differences in the development of ANG II-induced hypertension in conscious mice and rats with males developing higher blood pressure than females in response to chronic administration of ANG II (43,46).…”

Section: Discussionmentioning

confidence: 99%

Androgens augment renal vascular responses to ANG II in New Zealand genetically hypertensive rats

Song¹,

Kost²,

Martin³

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Song, Jin, Curtis K. Kost Jr., and Douglas S. Martin. Androgens augment renal vascular responses to ANG II in New Zealand genetically hypertensive rats. Am J Physiol Regul Integr Comp Physiol 290: R1608 -R1615, 2006. First published February 9, 2006 doi:10.1152/ajpregu.00364.2005.-Males develop higher blood pressure than do females. This study tested the hypothesis that androgens enhance responsiveness to ANG II during the development of hypertension in New Zealand genetically hypertensive (NZGH) rats. Male NZGH rats were obtained at 5 wk of age and subjected to sham operation (Sham) or castration (Cas) then studied at three age groups: 6 -7, 11-12, and 16 -17 wk. Mean arterial blood pressure (MAP), heart rate (HR), and renal blood flow (RBF) measurements were recorded under Inactin anesthesia. These variables were measured after enalapril (1 mg/kg) treatment and during intravenous ANG II infusion (20, 40, and 80 ng/kg/min). Plasma testosterone was measured by ELISA. Angiotensin type 1 (AT1) receptor expression was assessed by Western blot analysis and RT-PCR. ANG II-induced MAP responses were significantly attenuated in Cas NZGH rats. At the highest ANG II dose, MAP increased by 40 Ϯ 4% in Sham vs. 22 Ϯ 1% in Cas NZGH rats of 16 -17 wk of age. Similarly, renal vascular resistance (RVR) responses to ANG II were reduced by castration (209 Ϯ 20% in Sham vs. 168 Ϯ 10% in Cas NZGH rats at 16 -17 wk of age). Castration also reduced MAP recorded in conscious NZGH rats of this age group. Testosterone replacement restored baseline MAP and the pressor and RVR responses to ANG II. Castration reduced testosterone concentrations markedly. Testosterone treatment restored these concentrations. Neither castration nor castrationϩtestosterone treatment affected AT1 receptor mRNA or protein expression. Collectively, these data suggest that androgens modulate renal and systemic vascular responsiveness to ANG II, which may contribute to androgen-induced facilitation of NZGH rat hypertension.angiotensin; sex steroids; kidney; hypertension MALES DEVELOP HIGHER BLOOD pressure than do age-matched, premenopausal females. Gender-associated differences in blood pressure regulation have been demonstrated in both human and animal studies (31). The relative contribution of estrogens and androgens to these gender differences remains unclear (11,20,31). Nevertheless, several observations suggest that androgens play an important role in gender differences of blood pressure regulation. For example, castration attenuated the development of hypertension in several animal models (2, 15), whereas androgen treatment restored hypertension in castrated males (21, 36). The mechanism(s) of this prohypertensive effect of androgens remain(s) to be fully established.The kidneys are critical in regulating sodium and water balance and play an important role in controlling the long-term level of arterial pressure (17). Evidence from the spontaneously hypertensive rat (SHR) model suggested that aging males showed exacerbated glomerular injury, increased prote...

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Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations

Cited by 71 publications

References 47 publications

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

Sex Differences in the Pressor and Tubuloglomerular Feedback Response to Angiotensin II

Androgens augment renal vascular responses to ANG II in New Zealand genetically hypertensive rats

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