The mechanism of sympathetic stimulation in hypertension is complex but perhaps involves both baroreceptor and chemoreceptor pathways. Both central and peripheral baroreceptors are reset at higher blood pressures in hypertension; and returns to normal as blood pressure is lowered with treatment (Chapleau et al. 1988; Guo et al. 1983; Xie et al. 1990). Factors implicated in sympathetic stimulation are summarised in Box 1.

Reproduced with permission of Springer: The role of the kidney and the sympathetic nervous system in hypertension. Paediatric Nephrology 2015 (Thomas and Dasgupta 2015).

Renal nerves are the ‘communication link between the central nervous system and the kidney’. The major structural and functional components of the kidney, the vessels, glomeruli, and tubules are innervated. In response to various stimuli, both mechanical and chemical, the efferent renal sympathetic nerves are activated. Activation of the efferent renal sympathetic nerves leads to reduction in renal blood flow and glomerular filtration rate, increase in renal tubular sodium and water reabsorption, and increase in renin release. Inhibition of these nerves has the functionally opposite effects. The afferent renal sympathetic nerves generally, in response to stretch, exert an inhibitory effect through facilitating sodium and water excretion. This reno-renal reflex plays an important role in maintaining sodium and water homeostasis in various physiological and pathological states. However, in states of kidney disease and injury the excitatory fibres in the afferent sympathetic nerves are stimulated which leads to increased peripheral and renal sympathetic nerve activity leading to peripheral vasoconstriction, increased cardiac output, renal vasoconstriction, increased renin release and tubular salt retention all of which contribute to elevation of systemic blood pressure. It is postulated that it is the activation of these fibres that contribute to initiation and maintenance of essential hypertension (DiBona and Sawin 1999; DiBona and Kopp 1995, 1997).

The evidence for the important role that the renal sympathetic nerve play in the pathogenesis and maintenance of hypertension come from animal experiments. There is a suggestion that the association between the SNS and the kidney starts in utero. In rodents, glial cell line-derived neurotrophic factor (GDNF) is essential to the normal development of renal sympathetic innervation and glomerular morphogenesis (Sainio et al. 1997). Deletion of a single GDNF gene in mice results in abnormal renal morphogenesis with the kidneys developing fewer, larger glomeruli and higher arterial pressures (~20 mmHg) compared to control animals with two copies of the gene (Cullen-McEwen et al. 2003). In spontaneously hypertensive rats (SHR), neonetal sympathectomy reduce blood pressure long-term (Gattone et al. 1990; Head 1989). This is further confirmed when kidneys from neonatally sympathectomised SHR are transplanted into untreated SHR. Mean arterial pressure is lower in these animals compared to the control group in which kidneys from hydralazine treated animals are transplanted into untreated SHR. This suggests that neonatal sympathectomy induces chronic changes to SHR kidney function leading to reduction of mean arterial pressure even when extrarenal sympathetic tone is restored (Grisk et al. 2002). It is suggested that it is the impairment of the reno-renal reflex mentioned above that contributes to the development of hypertension in SHR. Furthermore, there is a lot of evidence demonstrating renal denervation can delay development and attenuate several different types of experimental hypertension (Stella and Zancetti 1991).

Experiments in both rat models and humans have demonstrated that the SNS exhibits preferential activation of renal sympathetic fibres in response to baroreceptor unloading (Scislo et al. 1998; Johansson et al. 2003). In the human experiment enalaprilat, an intravenous angiotensin-converting enzyme inhibitor, was administered to healthy individuals. There was a minor drop in mean arterial pressure, but renal noradrenaline spillover increased to 26 % and 49 % in response to low and high dose enalaprilat respectively, whilst the cardiac and total body noradrenaline spillover remained constant. These findings suggest that in healthy individuals without activated renin angiotensin system, there is selective stimulation of renal sympathetic nerve activity in response to baroreceptor unloading (Johansson et al. 2003). Purported mediators of baroreflex resetting include angiotensin II and oxygen free radicals (Abboud 1974; Li et al. 1996).

On the basis of the vasoconstrictor and cardioaccleratory properties of the sympathetic nervous system, a number of therapies have been developed in an attempt to modify the effect of the sympathetic nervous system on blood pressure (BP) control. Efficacy of these therapies further support the important role the SNA plays in hypertension. In 1923, Fritz Bruening performed the first surgical sympathectomy for hypertension based on the hypothesis that reduction of sympathetic outflow will lead to reduction in blood pressure (Freis 1990). This original concept was further developed by other surgeons such as Peet and Smithwick (Peet 1947; Smithwick and Thompson 1953) who performed more extensive operations termed splanchnicectomy which was offered to those with severe hypertension with evidence of cardiovascular damage. These procedures resulted in impressive reduction in blood pressure but were associated with significant surgical morbidities and complicated by orthostatic symptoms. With the availability of effective medical therapy these procedures were abandoned. However, the success of surgical sympathectomy in reducing high blood pressure led to the development of drugs producing chemical sympathectomy. A number of ganglion blocking agents were developed to treat hypertension like hexamethonium and tetraethylammonium chloride (Lyons et al. 1947; Paton and Zaimis 1948). These agents were the first pharmacological agents to block sympathetic outflow from the ganglion and also one of the earliest medical therapies for hypertension. Alpha-methyldopa a centrally acting anti-hypertensive agent which acts by inhibiting sympathetic outflow through binding to α₂ adrenoreceptors became available in the 1960s (Oates et al. 1960). Use of this drug is uncommon nowadays except in the context of hypertension in pregnancy. The role of sympathetic nervous system in the pathogenesis of hypertension is mediated by the alpha and beta adrenergic receptors. Beta-blockers were shown to be beneficial in the management of hypertension in 1964 (Prichard and Gillam 1964). The alpha-1 receptors present in the blood vessels are responsible for peripheral resistance. Selective alpha-1 receptor blockers were developed with a view to treating hypertension by reducing elevated total peripheral resistance (Nash 1990). However, in practice these agents have been found to have very modest blood pressure lowering effect (Heran et al. 2012).

Another example of sympathetic modulation to achieve blood pressure control is bilateral nephrectomy that used to be carried out in dialysis patients with refractory hypertension (Zazgornik et al. 1998). The improvement in blood pressure control in this situation is likely to be due to removal of the sympatho-excitatory effects of the damaged kidneys.

A greater understanding of the role of the sympathetic nervous system in the pathogenesis and maintenance of primary hypertension and the lessons learnt from modulation of sympathetic activity in hypertension control has led to a number of novel device based therapies of which catheter based renal denervation (RDN) is the foremost. Initial encouraging results from clinical studies led to more than 10,000 procedures being carried out in treatment resistant hypertension (TRH) across the world in the last few years.