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

Abstract

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...

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…Our finding is in agreement with previous works showing that hypertension induced by AngII is lower in female than in male mice 40, 41. The protective effect of 17β‐estradiol is, at least in part, mediated by the AngII type 2 receptor 42.…”

Gender Differences in Pressure-Natriuresis and Renal Autoregulation

“…[5][6][7][8] Recently, with the discovery of angiotensin-converting enzyme 2, a depressor axis to the RAS has been identified 9 that incorporates the angiotensin type 2 receptor (AT 2 R), which is upregulated by estrogen. 7,10 Previously, we have demonstrated that the vasodepressor RAS pathways are enhanced in females and that the AT 2 R has a depressor influence on the response to chronic angiotensin II (Ang II) infusion in female but not in male rats.…”

“…7,10 Previously, we have demonstrated that the vasodepressor RAS pathways are enhanced in females and that the AT 2 R has a depressor influence on the response to chronic angiotensin II (Ang II) infusion in female but not in male rats. 5 Estrogen also has been shown to protect against Ang IIinduced hypertension in female mice, suggesting the importance of the interaction between estrogen and the RAS in this response in females. 6,11 Thus, the AT 2 R appears to play a role in countering the pressor actions of Ang II at the angiotensin type 1 receptor (AT 1 R) in females via an estrogen-dependent mechanism and may contribute to gender differences in arterial pressure control.…”

“…However, the AT 2 R has been implicated as a modulator of natriuresis. 15,16 Thus, it is plausible that the AT 2 R, which is upregulated in females, 5,7 may modulate the pressure-natriuresis relationship, contributing to gender-associated differences in blood pressure regulation.…”

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“…Also consistent with the effects of RapLo binding of EGF pathways are the observations that infusions of low dose angiotensin II stimulate AT2r to decrease arterial pressure in normal animals. The effect is expressed and enhanced in the presence of estrogens and is opposed by androgens [48].…”