Increased Expression of Angiotensin II Type 2 Receptors in the Solitary–Vagal Complex Blunts Renovascular Hypertension

Abstract

Angiotensin II increases and decreases arterial pressure by acting at angiotensin type 1 and type 2 receptors respectively. Renovascular hypertensive rats exhibit a high level of activity of the peripheral and central renin-angiotensin system. Therefore, in the present study we evaluated the effect of increasing the expression of angiotensin type 2 receptors in the solitary-vagal complex [nucleus of the solitary tract/dorsal motor nucleus of the vagus], a key brainstem region for cardiovascular regulation, on the development of renovascular hypertension. Holtzman normotensive rats were implanted with a silver clip around the left renal artery to induce 2 kidney-1 clip renovascular hypertension. Three weeks later, rats were microinjected in the solitary-vagal complex with either an adeno-associated virus to increase the expression of angiotensin type 2 receptors, or with a control vector. We observed that increasing angiotensin type 2 receptor expression in the solitary-vagal complex attenuated the development of renovascular hypertension and also reversed the impairment of the baroreflex and the increase in the low frequency component of systolic blood pressure observed in renovascular hypertensive rats. Further, an observed decrease in mRNA levels of angiotensin converting enzyme 2 in the solitary-vagal complex of renovascular hypertensive rats was restored to control levels following viral-mediated increases in angiotensin type 2 receptors at this site. Collectively, these data demonstrate specific and beneficial effects of angiotensin type 2 receptors via the brain of hypertensive rats, and suggest that central angiotensin type 2 receptors may be a potential target for therapeutics in renovascular hypertension.

Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats

“…Our observation that C21 mediated stimulation of central AT 2 R prevented the spontaneous blood pressure increase in SHR is in line with the recent demonstration by Blanch et al that increased expression of AT 2 R in the solitary-vagal complex, a brainstem region important in the control of blood pressure, attenuates the increase in arterial pressure observed in a rat model with 2-kidney 1-clip renovascular hypertension [32]. …”

“…It is tempting to speculate that the prevention of the progression of hypertension in SHR induced by central AT 2 R stimulation observed in the present study is, in part, related to this restoration of baroreceptor function. These results also confirm the recent observation that increased expression of AT 2 R in the solitary-vagal complex restores baroreflex function and sympathetic modulation of arterial pressure to normal values in rats with 2-kidney 1-clip renovascular hypertension, another rat model characterized by baroreceptor impairment and increased sympathetic tone [32]. …”

Angiotensin II acting on brain AT1 receptors induces adrenaline secretion and pressor responses in the rat

“…Brain AT 1 receptors have been implicated in the regulation of blood pressure35, while brain AT 2 receptors seem to modulate the inhibition of the sympathetic nervous system36. Actually, increasing central AT 2 receptor expression attenuated the development of renovascular hypertension in the rat37. In the present study, we characterized which subtype (AT 1 or AT 2 ) in the brain is involved in the i.c.v.…”

Angiotensin type 2 receptors: blood pressure regulation and end organ damage

“…Electrophysiological studies examining the CNS cardiovascular control centres of AT1Ra knockout mice suggest that AT2R in the RVLM play an antagonistic role against AT1R-mediated actions of Ang II within this nucleus [34]. Furthermore, virally-mediated over expression of AT2R within the RVLM [35] or NTS [36] elicits respective decreases in mean arterial blood pressure of normotensive rats and in 2 kidney-1 clip hypertensive rats. In the latter study, it was also demonstrated that AT2R over expression in the NTS restores baroreflex sensitivity [36].…”

“…Furthermore, virally-mediated over expression of AT2R within the RVLM [35] or NTS [36] elicits respective decreases in mean arterial blood pressure of normotensive rats and in 2 kidney-1 clip hypertensive rats. In the latter study, it was also demonstrated that AT2R over expression in the NTS restores baroreflex sensitivity [36]. The recent availability of C21, has enabled Gao et al to demonstrate that infusion of this agent into the cerebroventricles lowers blood pressure in normotensive rats [37,38], and more recently to show that similar infusions into rats with heart failure suppresses sympathetic outflow by improving baroreflex sensitivity [39].…”