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

Abstract

This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.

Keywords: angiotensin II; angiotensin-(1–7), central nervous system; blood pressure; sex difference.

Fig. 1.

A: central infusion of 17β-estradiol (E₂) or angiotensin (ANG)-(1–7) during the induction (I) period blocked subpressor ANG II-induced sensitization of pressor effects initiated by subsequent ANG II during the expression (E) period in male rats. B and C: changes in mean arterial pressure (MAP) and heart rate (HR) after infusion of ANG II during E in all groups. I-S, peripheral treatment with saline during I; I-ANG II/icv V, peripheral treatment with subpressor ANG II plus central intracerebroventricular (icv) vehicle during I; E-ANG II, peripheral treatment with pressor ANG II during E; I-ANG II/icv E₂, peripheral ANG II plus central E₂ during I; I-ANG II/icv ANG-(1–7), peripheral ANG II plus central ANG-(1–7) during I. *P < 0.05 vs. baseline; #P < 0.05 vs. I-S + E-ANG II, I-ANG II/icv E₂ + E-ANG II or I-ANG II/icv ANG-(1–7) + E-ANG II.

Fig. 2.

A: central blockade of ANG-(1–7) during the I period augmented the pressor effects induced by a subsequent administration of ANG II during the E period in intact female rats. B: in contrast, central infusion of E₂ or ANG-(1–7) blocked subpressor ANG II-induced sensitization in ovariectomized (OVX) female rats. C and D: changes in mean arterial pressure (MAP) and heart rate (HR) after infusion of pressor ANG II during E in all groups. I-ANG II/icv A-779, peripheral ANG II plus central A-779 during I; I-ANG II/icv E₂, peripheral ANG II plus central E₂ during I; I-ANG II/icv ANG-(1–7), peripheral ANG II plus central ANG-(1–7) during I. *P < 0.05 vs. baseline; †P < 0.05 vs. intact I-S or I-ANG II + E-ANG II; #P < 0.05 vs. OVX I-S + E-ANG II, I-ANG II/icv E₂ + E-ANG II or I-ANG II/icv ANG-(1–7) + E-ANG II.

Fig. 3.

Changes of mRNA expression at the end of the delay period of renin-angiotensin system components in the lamina terminalis (LT) of male rats after subpressor ANG II alone or concurrent central infusion of E₂ or ANG-(1–7). *P < 0.05 vs. I-S; #P < 0.05 vs. I-ANG II/icv vehicle.

Fig. 4.

Changes in mRNA expression at the end of the delay period in renin-angiotensin system components in the LT of intact and OVX female rats after subpressor ANG II alone or concurrent central infusion of A-779, E₂, or ANG-(1–7). *P < 0.05 vs. intact I-S; †P < 0.05 vs. intact I-ANG II/icv vehicle; #P < 0.05 vs. OVX I-ANG II/icv vehicle.