Aberrant reflex mechanisms contributing to reno‐vascular hypertension: a pain in the neck?

Reno-vascular hypertension has been studied extensively over the course of the last 80 years using the Goldblatt two kidney one clip (2K1C) model. Ample evidence indicates that activation of the renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of this disease (Kopp, 2015). Renal hypoperfusion and ischaemia result in renin release from juxta-glomerular cells and resultant increases in angiotensin II (ANGII) and aldosterone. Depending on the presence of stenosis in one or both kidneys, volume expansion may combine with vasoconstriction to elicit increases in arterial pressure. While the initial phase of reno-vascular hypertension is thought to be primarily dependent on RAAS activation, there is evidence of a strong neurogenic component as well. Directly measured efferent sympathetic nerve activity (SNA) and plasma noradrenaline levels are increased in patients with reno-vascular hypertension as well as in experimental 2K1C animals (Oliveira-Sales et al. 2016). Importantly, recent work suggests that sympathetic overactivity precedes the development of hypertension in this model (Oliveira-Sales et al. 2016). From an aetiological standpoint, global sympathetic activation probably exacerbates systemic vasoconstriction associated with high circulating ANGII and may further increase RAAS activation, resulting in a positive feedback loop. Previous work suggests that sympathetic outflow is altered by peripheral sensors which send afferents to the brainstem (Oliveira-Sales et al. 2016). It has long been appreciated that changes in the function of multiple cardiovascular reflexes contribute to elevated SNA in hypertension. Previous studies have shown that the normally sympatho-inhibitory function of the reno-renal reflex, as well as the arterial baroreflex, are attenuated via ANGII-dependent mechanisms in the spontaneously hypertensive rat (SHR) as well as in the 2K1C model (Kopp, 2015). Chronic intermittent hypoxia, an experimental model used to study the hypertension associated with sleep apnoea, is also characterized by increased SNA and decreased baroreflex sensitivity. In this model, enhanced function of the carotid body chemoreflex (mediated by ANGII/NADPH oxidase-dependent increases in oxidative stress) is required for the genesis and maintenance of autonomic dysfunction and elevated arterial pressure (Marcus et al. 2010). Canonically, the carotid body chemoreceptors are poly-modal receptors that alter ventilation and sympathetic outflow to maintain cardiorespiratory homeostasis in response to perturbations in arterial blood gases. From a teleological perspective it makes sense that repetitive exposure to hypoxia would result in adaptive (or maladaptive) changes in carotid body chemoreceptor function. Interestingly, there is an extensive body of work that indicates that even in the absence of overt hypoxic chemoreceptor stimulation, carotid body chemoreflex activation and plasticity can occur as a result of ANGII/oxidative stress-dependent mechanisms (Schultz et al. 2015). The significance of this relationship to cardiometabolic disease states should not be underestimated. Indeed, recent studies indicate that the carotid body chemoreflex plays an important role in the autonomic dysfunction associated with essential hypertension, heart failure and obesity/metabolic syndrome. Despite the vast amount of research using the 2K1C model, the relative contribution of carotid body activity to increases in SNA and arterial pressure in reno-vascular hypertension has been largely unexplored. Previous studies have shown that carotid body chemoreflex responses to cyanide are enhanced in 2K1C animals concomitant with higher tonic SNA and altered baroreflex function (Oliveira-Sales et al. 2016). Importantly, these previous studies in the 2K1C model, while well-conceived, did not specifically show a contribution of the carotid bodies to the elevated resting SNA or blood pressure. In this issue of The Journal of Physiology, Pijacka et al. (2016) address this association in a more definitive manner with a series of well-executed experiments in conscious 2K1C rats which confirm that carotid body chemoreflex activity contributes to the maintenance and progression of reno-vascular hypertension. In this study, 2K1C animals that underwent carotid sinus denervation (CSD) had a modest but rapid decrease in arterial pressure and further increases in arterial pressure were prevented. SNA was not directly measured; however, CSD had a salutary effect on the progression of autonomic imbalance as assessed by spectral analysis of heart rate variability. The findings of Pijacka et al. (2016) indicate that CSD is an effective means of reducing arterial pressure and improving autonomic balance in the 2K1C model. Reduced afferent activation of autonomic nuclei in the brainstem, as well as decreased reflex increases in renal SNA, and subsequent reduction of RAAS activation and kidney damage, could account for the improvements in arterial pressure. Previous studies in the 2K1C model indicate that restoring renal blood flow via unclipping has a profound salutary effect on arterial pressure, whereas denervation of renal nerves alone results in a smaller reduction in pressure (Kopp, 2015). The incomplete recovery of arterial pressure observed by Pijacka et al. (2016) is consistent with this finding. Thus reductions in SNA per se are probably not sufficient to completely reverse the elevations in arterial pressure without reversal of stenosis and restoration of renal blood flow. Nonetheless, the findings of Pijacka et al. (2016) are encouraging and make a valuable contribution to our understanding of the maintenance and progression of reno-vascular hypertension. Additional studies that carefully dissect the mechanisms by which CSD acts to improve 2K1C hypertension are eagerly anticipated. None declared.