Targeting the Sympathetic Nervous System

Abstract

Evidence has accumulated during the past several decades, strongly suggesting that abnormalities of the sympathetic nervous system contribute to the development and maintenance of multiple disease states, including hypertension, heart failure, diabetes mellitus, sleep apnea, kidney disease, and atrial fibrillation. 1 The renal nerves have been identified as important contributors to the development of hypertension in both experimental animals and humans.2 Patients with essential hypertension and other disease states often have increased efferent sympathetic drive to the kidneys as demonstrated by elevated rates of renal norepinephrine spillover.1,2 In addition to increased renal efferent nerve activity, there is indirect evidence for increased renal afferent activity in patients with essential hypertension.3 Nonselective surgical sympathectomy has been effectively used as a treatment for severe hypertension, 4 with a remarkable difference in outcomes at 5 years of follow-up. Recently developed endovascular catheter technology has allowed selective denervation of the human kidney using radiofrequency (RF) energy delivered via the renal artery lumen.5 Although the initial clinical trials with this minimally invasive technique have documented the safety and efficacy of such an approach, critical questions have been raised pertaining to long-term safety, mechanisms of action, appropriate patient selection, reductions in ambulatory blood pressure (BP), definition and level of responder rates, need for identification of characteristics that predict nonresponse, phenomenon of a delayed response, and several others. 6 Here, we address several of these key questions. What Are the Mechanisms Responsible for a Decrease in BP After RDN?Catheter-based renal nerve ablation interrupts both efferent and afferent nerves (Figure 1). It is well established that activation of renal sympathetic efferents can decrease renal blood flow, increase tubular sodium and water reabsorption, and increase renin release. 2 However, there is emerging evidence that renal afferent signaling may be as important as renal efferent activity in elevating BP. Activation of renal afferents can cause a reflex increase in sympathetic tone to the kidneys and other organs. 7 Intrarenal infusion of bradykinin in conscious rats 8 or intrarenal infusion of adenosine in conscious dogs with unilateral nephrectomy 9 causes an immediate increase in BP that was abolished by surgical renal denervation (RDN). A role for renal afferents in rats with renovascular hypertension was indicated by a significant drop in BP after dorsal rhizotomy (T8 or T10 to L2) to exclusively interrupt afferent fibers. 10There is also evidence that renal afferents play a role in mediating an increase in sympathetic tone in humans. In 25 patients with treatment-resistant hypertension, RDN significantly decreased multi-and single-unit muscle sympathetic nerve activity at 3-month follow-up, which was accompanied by a significant reduction in BP.11 More recently, it was shown that the reduct...

The renal dopaminergic system: novel diagnostic and therapeutic approaches in hypertension and kidney disease

“…The impaired renal sodium handling in essential hypertension and salt sensitivity could be caused by aberrant counter-regulatory natriuretic and antinatriuretic pathways (49–54). The sympathetic nervous (55, 56) and the renin-angiotensin (50–53) systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway may be afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension (44–49), including that associated with obesity (57–61).…”

Gut microbiota in hypertension

“…The impaired renal sodium handling in essential hypertension and salt sensitivity are caused by aberrant counter-regulatory natriuretic and antinatriuretic pathways. The nervous system, including renal nerves (22–25) and the parasympathetic and sympathetic nervous systems (26), renin-angiotensin-aldosterone system (24, 25, 27–29), and endothelin via the ET A receptor (30) are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal dopaminergic system.…”

Endovascular Renal Denervation in End-Stage Kidney Disease Patients: Cardiovascular Protection—A Proof-of-Concept Study

“… 21 , 55 Though outside the scope of this paper and speculative in those with ESKD, the delayed progressive and evolving pattern observed, may be seen as a result of the time taken to reset central SNA and baroreceptor sensitivity, and for cardiovascular remodeling to manifest. 56 , 57 , 58 …”