Renal Denervation Improves Exaggerated Sympathoexcitation in Rats With Heart Failure

Abstract

Renal denervation (RDN) has been postulated to reduce sympathetic drive during heart failure (HF), but the central mechanisms are not completely understood. The purpose of the present study was to assess the contribution of neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus (PVN) in modulating sympathetic outflow in rats with HF that underwent RDN. HF was induced in rats by ligation of the left coronary artery. Four weeks after surgery, bilateral RDN was performed. Rats with HF had an increase in FosB-positive cells in the PVN with a concomitant increase in urinary excretion of norepinephrine and both of these parameters were ameliorated after RDN. nNOS-positive cells immunostaining, diaphorase staining, and nNOS protein expression were significantly decreased in the PVN of HF rats, findings that were ameliorated by RDN. Microinjection of nNOS inhibitor L-NMMA into the PVN resulted in a blunted increase in lumbar sympathetic nerve activity (ΔLSNA: 11 ± 2 vs. 24 ± 2%) in HF than in sham group. This response was normalized after RDN. Stimulation of afferent renal nerve (ARN) produced a greater activation of PVN neurons in rats with HF. ARN stimulation elicited a greater increase in LSNA in rats with HF compared to sham rats (ΔLSNA: 45 ± 5 vs. 22 ± 2%). These results suggest that intact renal nerves contribute to the reduction of nNOS in the PVN, resulting in activation of the neurons in the PVN of rats with HF. RDN restores nNOS and thus attenuates the sympathoexcitation commonly observed in HF.

Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl- d -Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure

“…Thus, recognizing the contribution of HIF-1α and NMDA receptors represent some new potential therapeutic targets for future clinical interventions to appropriately reduce sympathoexcitation without the detrimental effects. These results provide the insight into the possible underlying mechanisms that result in the beneficial effects of both ExT and RDN 19, 58 .…”

“…Our previous work has identified the PVN and specifically the imbalance between the excitatory glutamatergic and inhibitory NO mechanisms within this site to lead to detrimental sympathoexcitation in HF 6, 53, 55 . Further, our recent studies have utilized the efficacy of ExT (4,5,6) 19, 56, 57 and RDN 58 to reduce sympathoexcitatory drive (interestingly appropriately without the adverse effects such as those observed in the MOXCON trial) to examine the changes in central mechanisms specifically within the PVN to identify a potential therapeutic target. Thus, recognizing the contribution of HIF-1α and NMDA receptors represent some new potential therapeutic targets for future clinical interventions to appropriately reduce sympathoexcitation without the detrimental effects.…”

Integration of renal sensory afferents at the level of the paraventricular nucleus dictating sympathetic outflow

“…Recently, we have shown that ARN stimulation activates RVLM projecting PVN neurons (Xu et al, 2015). Stimulation of ARN also increases sympathetic activity and arterial pressure (Patel et al, 1986; Patel et al, 2016; Xu et al, 2015). Afferent information from the kidney may play an important role in the coordination of neural and humeral activation, concerned with body fluid balance and the regulation of arterial blood pressure in normal and disease conditions such as chronic heart failure (CHF) and hypertension (Caverson et al, 1988; Ciriello et al, 1987; Day et al, 1987; Kopp, 2015; Patel et al, 2016; Solano-Flores et al, 1997).…”

“…Furthermore, an enhanced afferent renal input to the PVN is shown to be intimately involved in processes leading to sympathoexcitation in the CHF condition (Patel et al, 2016; Xu et al, 2012 ).…”

“…Renal sensory afferent nerve activity directly influences sympathetic outflow to the kidneys and other organs such as the heart and peripheral blood vessels, which are also modulated by the PVN (DiBona, 2003). Thus, RDN is likely to be valuable in the treatment of several clinical conditions such as hypertension and CHF characterized by increased sympathetic outflow overall, and particularly RSNA to the kidney (Kline, 1987; Patel et al, 2016; Patel et al, 1996). …”