Stimulation of renal sympathetic nerves increases the urinary excretion of norepinephrine, which can be inhibited by experimental renal denervation [16, 17]. Renal denervation reduces blood pressure in genetic models of hypertension [18]. In two-kidney one clip rats blood pressure was reduced [19]. In an inherited model of polycystic kidney disease, renal denervation reduced blood pressure and restored renal blood flow [20].

In humans, the first experiences with interventional reduction of sympathetic activity were obtained by thoracolumbar splanchniectomy, which had significant effects on blood pressure in the majority but not all patients with severe hypertension and reduced cardiovascular end organ damage [21–23]. Although mortality was remarkably reduced [23], this technique had serious adverse effects and a high perioprative morbidity and mortality and was abandoned once effective antihypertensive drugs had started to emerge. More recently and applying a similar conceptin patients with resistant hypertension, catheter-based radiofrequency ablation of renal nerves (as schematically illustrated in Fig. 1.2) resulted in significant blood pressure reduction in the Symplicity HTN-1 pilot study [24] and in the randomized controlled Symplicity HTN-2 trial, in which optimal medical therapy + RDN was compared to optimal medical therapy alone ([25], Fig. 1.3). Meanwhile, Symplicity HTN-1 and Symplicity HTN-2 studies provided data to indicate that blood pressure changes that occurred were sustained up to 3 years post-procedure [26, 27]. Data from experienced centers also provided ABPM measurements showing that systolic and diastolic night time, day time and average blood pressure were significantly reduced in resistant hypertensive patients, while in pseudoresistance only office but not ABPM values were diminished [28]. In patients with moderately elevated levels of blood pressure a reduction was also observed [29], albeit the effect was less pronounced. The intriguing finding that after renal denervation not only renal spillover but also a total body spillover is reduced, is strongly arguing in favor of a significant role of both, afferent and efferent denervation [30].

Concerns were raised that renal denervation might producea limitation in exercise tolerance through interference with the sympathetic nervous system [31]. However, a systematic cardiorespiratory exercise testing revealed no evidence for chronotropic incompetence, while exercise tolerance was even slightly increased [32]. Furthermore, exercise blood pressure levels and heart rate responses and recovery were also reduced by renal denervation [32], which might explain the improved exercise tolerance. Furthermore, this finding might provide indirect evidence for potential clinical benefits, because these factors are related to cardiovascular complications including sudden cardiac death [33, 34]. Significant bradycardia was not observed [24–27], probably because heart rate reductions were only reported at higher levels of resting heart rates at baseline with no significant effects on atrioventricular conduction [35]. Interestingly, heart rate reduction and blood pressure reduction showed a dependency on baseline levels, i.e. blood pressure and heart rate effects were most pronounced in those patients with the highest the baseline values (Fig. 1.4, [35]).

Sympathetic nervous activity regulates the increase of heart rate in vasoconstriction to maintain sufficient blood pressure after orthostatic stress. Tilting causes the transfer of thoracic blood into the venous capacitance vessels and promoted fluid filtration into the interstitium resulting in up to 1,500 ml acute volume shifting [36], which has to be counterbalanced by activation of the sympathetic nervous system. Therefore, concerns have been raised on whether hypotensive reactions might limit the clinical benefits of renal denervation [37], which is evidenced by a drop in sympathetic activity and baroreceptor function just before collapse in syncope [38–41]. However, systematic table tilt testing has not shown significant occurrence of syncope or blood pressure drops in patients after renal denervation, in particular no difference between responders and non-responders to blood pressure reduction after renal denervation [42].

Hypertension is often associated with anxiety [43] involving activation of the autonomic nervous system in this condition [44]. Depression is also associated with a dysregulation of the central nervous noradrenergic process [45], but depressed individuals often have an activation of the peripheral sympathetic nervous system [46]. However, renal denervation has been reported to increase quality of life [47] and was not associated with increased depressive symptoms, rather it was associated with reduced anxiety, depression, intensity of headaches and with improved stress tolerance in patients with resistant hypertension [48].