The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent

Abstract

The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT(2)R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT(2)R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17β-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg(-1)·min(-1) sc) or saline. MAP significantly decreased in females treated with ANG II (-10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (-6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.

Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension

“…Denton and colleagues previously demonstrated that infusion with a subpressor dose of ANG II produces a decrease in BP in intact female rats and mice (2,23). This fall in BP was mediated by an enhanced renal AT 2 R mechanism that in part offset ANG II-induced sensitization of the tubuloglomerular feedback (2).…”

“…There are many differences in the way that males and females respond to stimulation and inhibition of the RAS (13,15,23,24) in relation to its role in the generation of hypertension. The present studies provide further evidence of a role for E 2 in protection against the induction of the increased vulnerability to and enhanced expression of hypertension in response to pressor challenges.…”

Central endogenous angiotensin-(1–7) protects against aldosterone/NaCl-induced hypertension in female rats

“…Aldo enhances ANG II-induced increases in expression of renin, AT1-R, and ACE1 mRNA in the LT (31). In contrast, estrogen is recognized to directly interact with the RAS, downregulating renin and ACE1 activity and AT1-R mRNA expression, as well as upregulating AT2-R mRNA expression (1,16,19). Moreover, estrogen regulation of the expression of RAS components has been shown to be different between normal and abnormal conditions (1,9,11).…”

Reduced sensitivity of the renal vasculature to angiotensin II in young rats: the role of the angiotensin type 2 receptor

“…A large body of evidence now exists that the RAS is differentially modulated between the sexes, and elicits sex-specific effects on renal function, including the AT 2 R (18,(25)(26)(27)(28)(29)(30). Moreover, we have previously identified significant sex differences in the postnatal ontogeny of many RAS components, at least in male and female rats (11).…”