Abstract
The present study investigated whether central activation of angiotensin II type 2 receptor (AT2-R) attenuates deoxycorticosterone acetate (DOCA)/NaCl-induced hypertension in intact and ovariectomized (OVX) female rats and whether female sex hormone status has influence on the effects of AT2-R activation. DOCA/NaCl elicited a greater increase in blood pressure in OVX females than that in intact females. Central infusion of compound 21, a specific AT2-R agonist, abolished DOCA/NaCl pressor effect in intact females, whereas same treatment in OVX females produced an inhibitory effect. Real-time RT-PCR analysis revealed that DOCA/NaCl enhanced the mRNA expression of hypertensive components including AT1-R, ACE-1, and TNF-α in the paraventricular nucleus of hypothalamus in both intact and OVX females. However, the mRNA expressions of antihypertensive components such as AT2-R, ACE-2, and IL-10 were increased only in intact females. Central AT2-R agonist reversed the changes in the hypertensive components in all females, while this agonist further upregulated the expression of ACE2 and IL-10 in intact females, but only IL-10 in OVX females. These results indicate that brain AT2-R activation plays an inhibitory role in the development of DOCA/NaCl-induced hypertension in females. This beneficial effect of AT2-R activation involves regulation of renin-angiotensin system and proinflammatory cytokines.
Highlights
It has been well documented that activation of angiotensin II type 2 receptor (AT2-R) plays a critical role in antagonizing AT1-R overactivity, during pathological conditions [1,2,3]
Central activation of AT2-R by intracerebroventricular infusion of Compound 21 (C21), the first selective nonpeptide AT2-R agonist, or AT2-R overexpression in the rostral ventrolateral medulla (RVLM) of heart failure animals leads to sympathoinhibition [8, 9], which is accompanied with upregulation of neuronal nitric oxide synthase and downregulation of AT1-R in the several nuclei involved in regulation of blood pressure (BP) and sympathetic activity including the paraventricular nucleus of hypothalamus (PVN) [9]
Icv infusion of C21 plus 1% NaCl had no effects on basal mean arterial pressure (MAP) (100.9 ± 1.5 mmHg) and heart rate (HR) (385.6 ± 7.9 beats/min) in intact female rats
Summary
It has been well documented that activation of angiotensin II type 2 receptor (AT2-R) plays a critical role in antagonizing AT1-R overactivity, during pathological conditions [1,2,3]. Recent studies implicated that AT2-R in the central nervous system (CNS) may exert more critical actions on blood pressure (BP) regulation [4]. AT2-R has been shown to reside or be in close proximity to CNS nuclei involved in cardiovascular regulation, including the solitary tract nucleus (NTS), rostral ventrolateral medulla (RVLM), subfornical organ (SFO), and paraventricular nucleus of hypothalamus (PVN) [5, 6]. Central activation of AT2-R by intracerebroventricular (icv) infusion of Compound 21 (C21), the first selective nonpeptide AT2-R agonist, or AT2-R overexpression in the RVLM of heart failure animals leads to sympathoinhibition [8, 9], which is accompanied with upregulation of neuronal nitric oxide synthase and downregulation of AT1-R in the several nuclei involved in regulation of BP and sympathetic activity including the PVN [9]. Central administration of C21 lowered BP and plasma norepinephrine levels in both
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