Another chapter in the understanding of angiotensin–catecholamine interactions relevant to blood pressure control

A series of studies using innovative molecular and cellular tools is providing new insights into the interactions between angiotensin (Ang II) and the catecholaminergic system. Historically, abundant evidence reveals that these two systems are intertwined both anatomically and functionally, as well as that interactions at sites in the brain and the periphery contribute to blood pressure and fluid volume regulation. It is precisely because of the extensive coexistence of the two systems that it has been difficult to dissect the contributions of individual brain nuclei or peripheral structures (ganglia, adrenal, cardiac and vascular elements) to pathologies associated with upregulation of either system. Jancovski and co-workers deleted the Ang II AT1A receptor (AT1AR) from all tyrosine hydroxylase-containing cells using Cre-lox techniques (Lindeberg et al. 2004; Jancovski et al. 2013). The resulting genetically modified mice exhibit a delay in the onset and a reduction in the increase in blood pressure in response to a 2 week subcutaneous administration of Ang II in comparison to normal animals expressing AT1ARs on catecholamine-containing cells. The Jancovsky et al. (2013) study clearly links participation of catecholamine-containing cells to a component of the pressor actions of Ang II, although other mechanisms account for the residual elevation in pressure. The pattern of responses to the Ang II infusion in these animals results from influences at many different locations. To focus on medullary sites of action as an example, the A2 cell group of the nucleus of the solitary tract normally facilitates baroreflex control of pressure, and Ang II impairs baroreceptor reflex functioning via actions on these neurons. Loss of the AT1AR on the A2 neurons would prevent the Ang II-mediated suppression of the baroreflex, with the resulting improvement in the baroreflex perhaps contributing to the delay in the onset of hypertension. Coupled with loss of AT1ARs in the C1 group, there would be less sympathetic nervous system activation by Ang II at this site, leading to a reduced magnitude of hypertension over the duration of the infusion. Importantly, in the study reported by Jancovski and co-workers in this issue of Experimental Physiology (Jancovski et al. 2014), the authors have taken a further step. They tested the hypothesis that activation of AT1ARs in C1 neurons of the rostral ventrolateral medulla is required for Ang II-dependent hypertension. The authors provide evidence to support the involvement of C1 neurons in the maintenance phase of Ang II-induced hypertension. Contrary to the loss of AT1ARs globally on all catecholamine-containing cells, the C1-restricted AT1AR deficiency did not alter the initial phase of the development of hypertension. To return to the example of medullary events for potential explanations of the differences, we can speculate that with the C1-targeted AT1AR deletion, Ang II actions at the A2 cell group to suppress the reflex would be expected, thus allowing the increase in pressure at early time points, in contrast to the mice with AT1AR deletion at both sites. The lack of activation of the AT1AR in the C1 cell group would limit the magnitude of the overall increase in pressure during the sustained phase of the hypertension. The A2 and C1 groups have been implicated in this manner in Ang II-dependent hypertension previously (Teschemacher et al. 2008). Spontaneously hypertensive rats have greater C1 release of noradrenaline associated with increased activation of the sympathetic nervous system. Angiotensin II reduces activation of the A2 cell group, leading to attenuation of the baroreceptor reflex. Normally, activation of the A2 cell group would restrain sympathetic activation. The paper by Jancovski et al. (2014) also further defines the mechanisms for the effects of the global deletion of the AT1AR from catecholamine-containing cells to attenuate the development of hypertension in response to Ang II infusion. The improved salt and water excretion associated with less increase in noradrenaline excretion is of particular interest in the animals with deletion of the AT1AR from all catecholaminergic cells. Information on urinary salt, water and catecholamines in the animals with C1-specific AT1AR deletion is needed for a better understanding of the contribution of renal mechanisms to blood pressure control in the presence of that more selective intervention. This question is particularly relevant to the differences in time course observed in response to the Ang II infusion in the two models of AT1AR deficiency. The knockdown of the AT1AR on catecholamine-containing neurons globally was associated with lower levels of reactive oxygen species (ROS) only in the rostral ventrolateral medulla, but not in forebrain sites of action. One implication is that the increase in ROS at forebrain sites is occurring in non-catecholaminergic neurons that respond to peripherally administered Ang II. Alternatively, other transmitters and factors released from the vasculature or glial cells in response to circulating Ang II, but independent of catecholaminergic neurons, may indirectly influence ROS generation within the catecholamine-containing neurons. In contrast, the lower ROS in the rostral ventrolateral medulla of the animals with the global catecholaminergic neuron AT1AR deletion may result from a loss of the direct actions of Ang II on the C1 neurons. Unfortunately, in the present study the authors did not measure ROS in the C1 neurons following Ang II infusions in the animals with targeted disruption of the AT1AR in C1 neurons. Therefore, it will be important to determine in future studies whether Ang II activation of descending pathways leads to ROS activation in the C1 cells independent of local direct actions of Ang II. Further study is also required to understand the connections between the different signalling pathways and the myriad effects of Ang II at both forebrain and medullary sites of action, perhaps using similar technology to that used by Jancovski et al. (2014). The study by Jancovski et al. (2014) clearly shows that AT1ARs on both catecholamine neurons in general and C1 neurons in particular participate in the pressor responses to infusions of Ang II. They also note that we gain insight into the subpopulations of receptors participating in the pressor response to Ang II from differences in the time course of interference with the pressor responses between their two models of disrupted expression of the AT1AR and the information gleaned from studies by Northcott et al. (2010) revealing a role for the paraventricular nucleus in the acute effects of Ang II. Moreover, they appropriately address the fact that brain sites are not the only location for AT1ARs responsible for the increase in blood pressure in response to elevated systemic levels of Ang II, given that approaches using targeted overexpression or deletion of the AT1AR on specific cells within the kidney and immune system have identified receptors at these locations as important to the full expression of Ang II-induced hypertension and related tissue injury (Crowley et al. 2006; Gurley et al. 2011; Guzik et al. 2007; Li et al. 2011; Zhang et al. 2014). This is in contrast to the observed lack of effect of targeted deletion of AT1ARs in smooth muscle of large vessels, such as the aorta, on vascular remodelling (Sparks et al. 2011). In some respects, the findings presented by Jancovski et al. (2014) are not unexpected, given that catecholamines are known to participate in the central and peripheral nervous system actions of Ang II relevant to vasopressin release, drinking behaviour and pressor responses. Global deletion of the AT1AR on catecholaminergic cells might be expected to be similar to intraventricular or systemic infusions of agents that deplete catecholamines, which have been shown to limit the actions of Ang II administered centrally. However, interpretation of the data from the older approaches to the question of the involvement of catecholamine pathways in the pressor actions of Ang II is complicated by the fact that depletion of catecholamines will impact activation of these pathways by other agents as well. A concern with the present approach is that Ang II–catecholamine interactions relevant to affective behaviour and attention/cognitive pathways may be disrupted along with the blood pressure and fluid balance pathways. However, the benefits of the studies by Jancovski et al. (2014) are that they leave intact the direct actions of the peptide on non-catecholamine neurons and pathways. Thus, we eagerly await further insights from the next chapter in this series of studies. None declared. The author's research is supported by National Institutes of Health grants HL-51952 and HD-47584.