Renal denervation based on experimental rationale

Abstract

Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension and heart failure. Within the central nervous system, the paraventricular nucleus (PVN) of the hypothalamus and the rostral ventrolateral medulla in the brain stem play critical roles in the regulation of sympathetic outflow to peripheral organs. Information from the peripheral circulation, including serum concentrations of sodium and angiotensin II, is conveyed to the PVN via adjacent structures with a weak blood-brain barrier. In addition, signals from baroreceptors, chemoreceptors and cardiopulmonary receptors as well as afferent input via the renal nerves are all integrated at the level of the PVN. The brain renin-angiotensin system and the balance between nitric oxide and reactive oxygen species in these brain areas also determine the final sympathetic outflow. Additionally, brain inflammatory responses have been shown to modulate these processes. Renal denervation interrupts both the afferent inputs from the kidney to the PVN and the efferent outputs from the PVN to the kidney, resulting in the suppression of sympathetic outflow and eliciting beneficial effects on both hypertension and heart failure.

Keywords: Heart failure; Hypertension; Paraventricular nucleus; Renal denervation; Sympathetic nervous system.

Figure 1.

Proposed model for the integration of afferent information to the PVN and the subsequent sympathetic outflow regulating the heart, peripheral arterioles and the kidney. SFO: subfornical organ; OVLT: organum vasculosum lamina terminalis; MnPO: median preoptic nucleus; PVN: paraventricular nucleus; RVLM: rostral ventrolateral medulla; IML: intermediolateral cell column; NTS: nucleus tractus solitarius; CVLM: caudal ventrolateral medulla; Ang II: angiotensin II.

Figure 2.

A schematic of the brain renin-angiotensin system, which affects various central nervous system sites involved in the regulation of cardiovascular function.

Figure 3.

Activation of afferent renal nerve activity (ARNA) from the renal pelvis. ARNA response to intrapelvic injection of capsaicin (activating the transient receptor potential vanilloid 1, i.e., the non-selective cation channel) is shown. A: Raw tracings and integrated signals of ARNA from Sham and HF rats. The ARNA was recorded before and after intrapelvic injection of capsaicin 100 μM to determine the peak level of ARNA (ARNAmax). B: Summary data for basal ARNA expressed as a percentage of ARNAmax in the two groups of rats. Data are presented as mean ±SE. n=6. *P < 0.05 vs. Sham.

Figure 4.

Proposed model for the potential therapeutic effects of RDN in HF on cardiac function, changes in the CNS and fluid retention. Red arrows indicate the effects of HF on these parameters. Green arrows indicate the effects of T-RDN on these parameters in HF. Blue arrows indicate the effects of A-RDN on these parameters in HF. CNS: central nervous system; NO: nitric oxide; nNOS: neuronal NO synthase; T-RDN: total renal denervation; A-RDN: afferent renal denervation; ENaC: epithelial sodium channels; AQP2: water channel aquaporin 2; GLP-1: glucagon-like peptide-1.