Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl‐Induced Hypertension in Female Rats

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.

Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor

“…A blood pressure lowering effect mediated by central AT2R has recently been shown by several groups using normotensive rats [24–26] and in models of genetic hypertension (spontaneously hypertensive rats/SHR) [24], angiotensin II induced hypertension [26], (DOCA)/NaCl-induced hypertension [27] and 2-kidney 1-clip renovascular hypertension [28]. In conscious animals, this effect could be achieved either by prior over expression of AT2R in certain brain areas (NTS, RVLM) via microinjection of recombinant adeno- or adeno-associated viruses encoding AT2R [26,28], or by chronic intracerebroventricular (icv) infusion of an AT2R agonist over an extended period of time (7 days to 4 weeks) [24,27,29].…”

“…In conscious animals, this effect could be achieved either by prior over expression of AT2R in certain brain areas (NTS, RVLM) via microinjection of recombinant adeno- or adeno-associated viruses encoding AT2R [26,28], or by chronic intracerebroventricular (icv) infusion of an AT2R agonist over an extended period of time (7 days to 4 weeks) [24,27,29]. It is further noteworthy that the anti-hypertensive effect of chronic central AT2R stimulation is powerful and significantly attenuated the development of hypertension in SHR and in DOCA/NaCl-treated animals [24,27].…”

Effects of Intrauterine Growth Restriction and Female Sex on Future Blood Pressure and Cardiovascular Disease

“…In a study by Ji et al, ovariectomy decreased the activity of ACE2 (37); Baiardi et al reported a similar effect on AT 2 receptor expression in female rats (38) implicating that physiological changes in E2 can also alter the counter-regulatory arm of the RAS. In a study by Dai and colleagues, treatment with an AT 2 receptor agonist attenuated salt/DOCA–induced hypertension in female rats in conjunction with increased ACE2 and AT 2 receptor expression (39). Thus, this study by Dai et al demonstrated that direct activation of the AT 2 receptor is cardio-protective in the female rat (39).…”

“…In a study by Dai and colleagues, treatment with an AT 2 receptor agonist attenuated salt/DOCA–induced hypertension in female rats in conjunction with increased ACE2 and AT 2 receptor expression (39). Thus, this study by Dai et al demonstrated that direct activation of the AT 2 receptor is cardio-protective in the female rat (39). However, whether hypertension in females after reproductive senescence involves an imbalance in the ACE/Ang II pathway versus the ACE2/AT 2 receptor pathway of the RAS is not yet clear.…”

“…However, whether hypertension in females after reproductive senescence involves an imbalance in the ACE/Ang II pathway versus the ACE2/AT 2 receptor pathway of the RAS is not yet clear. Furthermore, whether modulation of the RAS via E2 as noted in experimental studies conducted in young female rats (36, 37, 38, 39) translates towards the etiology of postmenopausal hypertension is not known.…”