Renal Deafferentation Prevents Progression of Hypertension and Changes to Sympathetic Reflexes in a Rabbit Model of Chronic Kidney Disease

There is increasing evidence that renal denervation is effective in alleviating hypertension associated with elevation of renal sympathetic nerve activity (RSNA) in chronic kidney disease (CKD), but whether this is due to reduction in renal afferent signaling is unclear. We determined the cardiovascular and sympathetic effects of total renal denervation or afferent renal denervation (topical capsaicin) on CKD induced by glomerular layer lesioning of the left kidney and right nephrectomy in conscious rabbits. CKD increased blood pressure by 18±2 mmHg and plasma creatinine by 40% over 2 to 4 weeks (both P <0.001), while RSNA (43%) and total norepinephrine spillover (28%) were elevated in CKD compared with sham (both P =0.04). After total or afferent renal denervation blood pressure, RSNA and norepinephrine spillover were similar or lower than non-CKD (sham) rabbits. While plasma creatinine in CKD rabbits was not affected by total renal denervation, deafferented rabbits had lower levels ( P =0.017). The greater hypotensive response to pentolinium in CKD was also normalized after total or afferent denervation. Heart rate and RSNA baroreflex gain were similar in all groups. The RSNA response to airjet stress was greater in CKD compared with sham but not after total or afferent renal denervation. By contrast, the sympathetic response to hypoxia was similar in sham and CKD intact or deafferented groups but elevated in total denervated CKD animals. We conclude that the elevated sympathetic activity and blood pressure in this model of CKD is predominantly driven by renal afferents.

A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes

Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPR). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor α1 (GFRα1) in DRGs. Here we report that increased GDNF/GFRα1 signaling to sensory neurons from ischemia/reperfusion affected muscle modulated nociceptive-like behaviors, increased EPRs, and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased CREB/CREB-binding protein mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may play an important dual role in nociception and sympathetic reflexes and could provide a novel therapeutic target for treating complications from ischemic injuries.

Intrathecal melanin-concentrating hormone reduces sympathetic tone and blocks cardiovascular reflexes

Melanin-concentrating hormone (MCH) is a neuropeptide that acts to increase feeding behavior and decrease energy expenditure. The role of MCH in central cardiorespiratory regulation is still poorly understood. Experiments were conducted on urethane-anesthetized, vagotomized, and artificially ventilated male Sprague-Dawley rats ( n = 22) to ascertain whether MCH modulates sympathetic vasomotor tone, as well as barosympathetic, chemosympathetic, and somatosympathetic reflexes at the level of the spinal cord. Intrathecal injection of 10 μl of MCH produced a dose-dependent hypotension, bradycardia, and sympathoinhibition. Peak response was observed following administration of 1 mM MCH, causing a decrease in mean arterial pressure of 39 ± 2 mmHg ( P < 0.001), splanchnic sympathetic nerve activity of 78 ± 11% ( P < 0.001), and heart rate of 87 ± 11 beats per minute (bpm) ( P < 0.01). The two peaks of the somatosympathetic reflex were decreased by intrathecal MCH, 7 ± 3% ( P < 0.01) and 31 ± 6% ( P < 0.01), respectively, and the spinal component of the reflex was accentuated 96 ± 23% ( P < 0.05), with respect to the baseline for MCH, compared with the two peaks and spinal component of the somatosympathetic reflex elicited following saline injection with respect to the baseline for saline. MCH decreased the sympathetic gain to 120 s of hyperoxic hypercapnea (10% CO2 in 90% O2) and to 10–12 s poikilocapneic anoxia (100% N2) from 0.74 ± 0.14%/s to 0.23 ± 0.04%/s ( P < 0.05) and 16.47 ± 3.2% to 4.35 ± 1.56% ( P < 0.05), respectively. There was a 34% decrease in gain and a 62% decrease in range of the sympathetic baroreflex with intrathecal MCH. These data demonstrate that spinal MCH blunts the central regulation of sympathetic tone and adaptive sympathetic reflexes.