Angiotensin AT2 receptors and the baroreflex control of renal sympathetic nerve activity

In this issue, there is an important article by Abdulla and Johns (Abdulla & Johns, 2014), which details a previously unknown role of brain nitric oxide (NO) in the modulation of central angiotensin II (type 2) receptor (AT2 receptor) stimulated high-pressure baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA). The authors provide the first experimental evidence that there is a facilitatory role for brain AT2 receptors in the high-pressure baroreflex regulation of RSNA and HR that is dependent of the presence of an operational central nitric oxide/nitric oxide synthase (NOS) system. These findings deepen our understanding of the interplay between brain NO and the angiotensin AT2 receptor system that acts to influence the cardiac and renal sympathetic baroreflex. Collectively, the presented studies highlight the complex interactions between brain angiotensin II (type 1) (AT1 receptor) (inhibitory) and angiotensin II (type 2) (stimulatory) receptors on the baroreflex response that is dependent on the actions of NO within the central nervous system (CNS). Owing to the significant adverse health impact of an impaired baroreflex response (Gerristen et al. 2001) studies such as these, which enhance our understanding of the baroreflex, have potential high significance for human health.

Multiple studies have demonstrated an action of brain NO, likely as a neurotransmitter or neuromodulator, on central sympathetic outflow and systemic cardiovascular function. Importantly NOS activity within the nucleus tractus solitarius (NTS), which evokes depressed baroreflex regulation of blood pressure and increased central sympathetic outflow, is established as a contributing factor in the neural mechanisms underlying the development of hypertension (Chan & Chan, 2013). Further, a role of endogenous NO in the stimulation of RSNA via NTS angiotensin AT1-receptors located within the NTS has been reported (Eshima et al. 2000). Recent immunolabeling studies have provided evidence that in neurons of the NTS angiotensin AT2 receptors are required to facilitate enhanced NO production following AT1 receptor antagonism – suggesting a potential interaction between AT1 and AT2 receptors upon NO (Wang et al. 2012). Functional in-vitro studies have also demonstrated that NO blockade is able to inhibit the angiotensin AT2 stimulated facilitation of neuronal membrane potassium currents (Gao & Zucker, 2010), data which supports a potential interaction between NO and the AT2 receptor. A recent paper from the lab of Dr Johns provided in-vivo evidence, generated in rats, that in response to the physiological challenge of an acute isotonic saline volume expansion there are significant, but independent, roles of both angiotensin AT2 receptors and NO in the sympathoinhibitory renal nerve response evoked by this stimuli (Abdulla & Johns, 2013a). The current studies (Abdulla & Johns, 2014) presented in this issue of Acta Physiologica extend their previous work to examine the role(s) of CNS generated NO and brain angiotensin AT2 receptors on the high-pressure arterial baroreceptor regulation of renal sympathetic nerve activity and heart rate.

The robust approach utilized by Abdulla and Johns has yielded several novel findings. A key finding of the current work is that under basal conditions both endogenous brain NO and angiotensin AT2 receptors contribute significantly to the high-pressure arterial baroreceptor control of RSNA and HR. Inhibition of CNS NO production by central administration of L-NAME enhanced cardiac and renal baroreflex sensitivity. These data provide evidence that under normal conditions endogenous CNS NO, potentially via acting as a neurotransmitter or modulator, provides an inhibitory action on the baroreflex regulation of RSNA and HR. Conversely the pharmacological blockade of central AT2 receptors attenuated baroreflex control of RSNA and heart rate – indicating that endogenous AT2 receptor activity contributes to the normal baroreflex regulation of RSNA and HR. A role of AT2 receptors in baroreflex regulation of RSNA and HR, as demonstrated by the data presented by Abdulla and Johns, is supported by localization of AT2 receptors in known neural control centers e.g., RVLM, NTS, SFO (Gao et al. 2008) and evidence that AT2 receptor activation produces sympatho-inhibition (Gao et al. 2008, Gao & Zucker, 2010).

The second major finding of the reported studies is that exogenous stimulation of angiotensin AT2 receptors, by i.c.v. administration of the AT2 agonist CGP42112, significantly increased the sensitivity of the renal and cardiac baroreflex versus a vehicle treatment. Critically, the authors also demonstrate that this enhanced baroreflex sensitivity following AT2 receptor activation is dependent on the presence of a functional central NO system. It should be noted that these data are in contrast to a previous report that i.c.v. CGP42112 decreases cardiac baroreflex sensitivity in rats (Oliveira et al. 1996). However, the present findings are supported by several lines of evidence including 1) microinjection of CGP42112 into the rostralventerolateral medulla of rats evokes global sympatho-inhibiton and a decrease in RSNA (Gao et al. 2008) and, 2) angiotensin AT2 receptor knock-out mice exhibit a greater AT1 receptor-mediated pressor response than wild-type mice, indicating the role of AT2 receptors in buffering the pressor response to AT1 activation (Gross et al. 2002). Further support for the key role of brain NO in AT2 receptor signaling is provided by evidence that antagonism of central AT1 receptors resulted in a significant increase in the sensitivity of the cardiac and renal baroreflex that was dependent on the actions of NO within the brain (Abdulla and Johns, 2014). These data support the hypothesis that exogenous activation of brain AT2 receptors impacts the baroreflex through a downstream pathway that requires a functional NO system.

The question of whether an imbalance in the endogenous activity of central angiotensin AT1 and AT2 receptors adversely affects the arterial baroreceptor response via a mechanism involving NO in disease states which feature autonomic dysregulation (e.g., heart failure, hypertension) is still to be definitively answered. The data generated in this study provide direct evidence of a role central of NO in mediating brain angiotensin AT2 receptor regulation of the cardiac and renal sympathetic baroreflex. This is evidenced by 1) the increased sensitivity of high-pressure baroreceptors following AT2 receptor activation or AT1 receptor antagonism and, 2) attenuation of the increased baroreflex sensitivity of high-pressure baroreceptors following L-NAME administration. The locus of the reported interaction of NO and AT2 receptors within the CNS remains to be established, and it is highly likely the actions of both NO and AT2 receptors upon the cardiac and renal sympathetic baroreflex will depend on the neural circuitry within the brain sites in which these systems are activated - as noted by the authors. Exploring the interactions of central AT2 receptors and NO on the renal baroreflex in animal models in which there is an impaired baroreflex response (e.g., the Spontaneously Hypertensive Rat, heart failure models), and determination of the endogenous levels/activity of angiotensin AT1 & AT2 receptors and NO throughout the CNS in these phenotypes, will provide important insight into the implications of the findings reported in this issue of Acta Physiologica (Abdulla & Johns, 2014). Collectively the findings presented by Abdulla and Johns increase our understanding of the actions of brain angiotensin AT2 receptors to influence the regulation of sympathetic outflow to the kidneys. Owing to the critical importance of the renal sympathetic nerves on long-term blood pressure regulation (Abdulla & Johns, 2013b) and fluid and electrolyte homeostasis in multiple disease states (e.g., hypertension, heart failure, renal failure) these findings may shed important insight into baroreflex impairment that is present as part of the pathophysiology of multiple cardiovascular diseases.