Potential Role for Renal Nerves in Mediating Hypertension in Male ETB‐deficient Rats
Authors: Becker Bryan K , Feagans Amanda C , Chen Daian , Jin Chunhua , Speed Joshua S , De Miguel Carmen , Pollock Jennifer S , Pollock David M 
Published: November 2023

Over activation of the sympathetic nervous system and alterations in endothelin (ET) signaling are independent contributors to several cardiovascular diseases such as heart failure and hypertension. However, it is incompletely understood how ET and the sympathetic nervous system interact during these disease states. Previous findings suggest that ETB receptors increase sympathetic neuron activity, but the contribution of this interaction to long‐term control of blood pressure, end organ damage, and sensitivity to dietary salt is unknown. We hypothesized that denervation of renal sympathetic nerves would attenuate the hypertension and associated renal damage in a salt‐sensitive model of ET system dysfunction. Rats deficient of ETB receptors on all tissues except sympathetic nerves (ETB ‐def) and transgenic (TG) controls underwent bilateral renal denervation (Dnx) (n = 6 ETB ‐def; n = 5 TG) or sham surgery (n = 7 ETB ‐def; n = 6 TG). Following recovery, animals were fed normal salt (0.49% NaCl) or 14 days of high salt (4.0% NaCl) diet, and blood pressure was measured via telemetry. Water intake, urine output, and urine electrolytes did not differ across groups. ETB ‐def rats with renal Dnx had lower 24‐hr systolic blood pressure (SBP) compared to sham (147.3 ± 2.6 vs. 161.7 ± 1.9 mmHg; p < 0.0001) and there was no significant effect of Dnx on TG controls (132.1 ± 3.1 vs. 139.3 ± 1.4 mmHg; p = 0.10) during normal salt. ETB ‐def rats had elevated sympathetic to parasympathetic tone compared to TG controls as indicated by higher low frequency to high frequency ratio (LF/HF) in the heart rate frequency domain during normal salt (1.32 ± 0.03 vs. 1.03 ± 0.02; p < 0.0001). Denervation reduced LF/HF in ETB ‐def rats (1.13 ± 0.02; p < 0.0001) but had little effect on TG controls (p = 0.65). Denervation did not influence the SBP sensitivity to high salt in ETB ‐def rats (+19.2 ± 1.7 vs. +15.4 ± 2.1 mmHg change in 24‐hr SBP from normal salt to high salt; p = 0.4), although denervated rats continued to have lower SBP during high salt feeding compared to sham (p = 0.003). High salt had no significant effect on SBP in TG controls. Renal production of ET‐1 as measured by urinary excretion of ET‐1 tended to be increased in ETB ‐def rats compared to TG controls (6.3 ± 2.0 vs. 2.2 ± 0.4 pg/d; p = 0.06), and Dnx attenuated this effect in ETB ‐def rats (1.74 ± 0.5 pg/d; p = 0.03) during normal salt. Urinary excretion of ET‐1 increased in all groups following high salt diet, and no group differences were observed. On high salt diet, sham ETB ‐def rats had elevated urinary albumin excretion relative to TG controls (1.52 ± 0.26 vs. 0.31 ± 0.03 mg/12 hr; p < 0.0001). Denervation tended to attenuate the albuminuria in ETB ‐def (0.91 ± 0.12 mg/12 hr; p = 0.06 vs. ETB ‐def Sham) and had no effect on TG controls (0.32 ± 0.05 mg/12 hr; p > 0.99 vs. TG Sham). We conclude that the renal sympathetic nerves are important mediators of hypertension in the ETB ‐def rat model but do not contribute to the salt‐sensitivity of blood pressure, and renal denervation may provide protection against renal damage in this model.

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5P01HL069999 to DMP; 5T32HL00745735 of which BKB is a trainee