Abstract 081: Renal Sensory Nerves Increase Blood Pressure and Sympathetic Nerve Activity in 2-Kidney 1-Clip Hypertensive Mice

Abstract

Renal denervation lowers arterial blood pressure (ABP) in multiple clinical trials and some experimental models of hypertension. These antihypertensive effects have been attributed to the removal of renal afferent nerves. The purpose of the present study was to determine whether renal sensory nerves contributed to the 2-Kidney-1-Clip (2K1C) model of hypertension. 2K1C hypertension was produced in male C57Bl6 mice (12-14 weeks, Jackson Laboratories) by placement of a 0.5mm length of PTFE tubing (ID: 0.008” x OD: 0.014”) around the left renal artery. 2K1C mice (n=6) displayed an elevated ABP measured via telemetry (Day 0: 96±4mmHg vs Day 14: 115±3mmHg, P<0.05). Ganglionic blockade with hexamethonium (30mg/kg, ip) produced a greater fall in mean ABP at Day 14 vs Day 0 (Day 0: -38±4mmHg vs Day 14: -51±4mmHg, P<0.05). Ipsilateral vs contralateral kidneys of 2K1C mice had lower mass (0.072±0.01g vs 0.163±0.02g, respectively; P<0.05) and higher mRNA levels of several pro-inflammatory cytokines (IL1B, IL2, IL10, TNFa; P<0.05). Both total renal denervation (10% phenol) or selective denervation of renal afferent nerves (periaxonal application of 33mM capsaicin) at time of clipping resulted in a lower ABP than 2K1C mice at Day 14 (2K1C: 115±3mmHg, phenol: 104±2mmHg, capsaicin: 105±3mmHg; P<0.05). Direct recording of renal afferent nerve activity showed significantly greater discharge in 2K1C versus control mice (control: 2.2±1.3Hz vs 2K1C: 61±12Hz, n=3/group; P<0.05). Furthermore, electrical stimulation of renal afferent nerves in control mice produced a frequency-dependent increase in ABP (5Hz: 3±1mmHg, 10Hz: 7±1mmHg, 20Hz: 12±2mmHg, n=4/group; P<0.05). These responses were eliminated after ganglionic blockade with 5mg/kg chlorisondamine (5Hz: 1±1mmHg, 10Hz: 1±1mmHg, 20Hz: 1±1mmHg; P<0.05). Stimulus-triggered averaging of SNA during stimulation of renal afferent nerves (1 Hz, 200uA) revealed significant (P<0.05, n=4/group) increases in splanchnic (221±28%), renal (195+15%), and lumbar (234±32%) SNA. Interestingly, the latency to the peak SNA (142±10ms) suggests supraspinal pathways mediate the sympathoexcitatory response. These findings suggest 2K1C hypertension depends on renal sensory nerves and elevated SNA via supraspinal pathways.