A selective impairment in the mechanosensitive afferent renal nerve‐mediated sympathoinhibitory reno‐renal reflex contributes to age‐related hypertension

Abstract

AimThe afferent renal nerves (ARN) mediate reno‐renal reflexes that influence efferent renal sympathetic nerve activity, sodium homeostasis, and blood pressure. These studies tested the hypothesis that impairments in the sympathoinhibitory reno‐renal reflex contribute to age‐related hypertension (HTN).MethodsThree‐month (mo), 8mo, and 16mo male (M) Sprague Dawley (SD) rats on a normal salt (NS; 0.6% NaCl) diet underwent an acute isotonic saline volume expansion (VE; 5% body weight – mechanoreceptor stimulus) or an acute isovolumetric 1M NaCl infusion (20μL/min, 2hr – chemoreceptor stimulus) and mean arterial pressure (MAP), natriuresis (UNaV), and paraventricular nucleus (PVN) neuronal activation (c‐Fos expression) were assessed. Three and 8mo female SD rats also underwent acute VE. N=6/gp.In 3mo, 8mo and 16mo M SD rats, 1) sympathetic tone (plasma and renal norepinephrine [NE] content) or 2) ex vivo ARN activity (substance P [SP] release in response to 1250pM NE [general stimulus] or 450mM NaCl [chemoreceptor stimulus]) were assessed on day 21 of NS or high salt (HS; 4% NaCl) diet. N=6/gp.In 3mo and 16mo M SD rats on a NS diet, MAP and sodium balance were assessed on day 10 after selective ARN ablation (33mM capsaicin) or total bilateral renal denervation (RDNX; 10% phenol). N=6/gp.ResultsAged rats develop HTN (MAP [mmHg] 3mo 124 ± 2 vs 8mo 135 ± 4 vs 16mo 150 ± 3, p<0.05) and exhibit blunted natriuretic and PVN sympathoinhibitory parvocellular neuronal responses to an acute VE (% sodium load excreted 3mo 78 ± 6 vs 8mo 60 ± 7 vs 16mo 22 ± 9, p<0.05; medial parvocellular neuronal activation [c‐fos+ cell count] 3mo 59 ± 4 vs 8mo 42 ± 7 vs 16mo 13 ± 5, p<0.05). There are no sex differences in VE responses in 3 or 8mo rats. The natriuretic and PVN neuronal responses to a 1M NaCl infusion are intact in aged rats.Aged rats exhibit reduced NE‐evoked ARN activity during NS intake and fail to increase NE‐evoked ARN activity during HS intake (SP release [pg/min] 3mo NS 14 ± 2 vs HS 23 ± 4, p<0.05; 8mo NS 8 ± 2 vs HS 6 ± 3, ns; 16mo NS 2 ± 7 vs HS 2 ± 6, ns). Age and diet did not alter 450mM NaCl‐evoked ARN activity.Aged rats exhibit elevated basal plasma and renal sympathetic tone and impaired HS‐evoked suppression of sympathetic tone (renal NE content [pg/mg] 3mo NS 612 ± 36 vs HS 368 ± 32; 8mo NS 835 ± 48 vs HS 722 ± 44, p<0.05; 16mo HS 974 ± 13 vs NS 1019 ± 34, ns).Bilateral RDNX attenuates MAP and improves sodium balance in aged rats (MAP [mmHg] 15mo intact 150 ± 3 vs RDNX 140 ± 2, p<0.05; 24hr sodium balance [mEq] 15mo intact 0.51 ± 0.13 vs RDNX 0.08 ± 0.13, p<0.05). Selective ARN ablation has no impact on MAP or sodium balance.ConclusionsAge‐related HTN is characterized by a selective impairment in the mechanosensitive ARN. We speculate that a decrease in ARN‐mediated sympathoinhibitory reno‐renal reflex activity promotes sympathoexcitation, perhaps due to reduced PVN parvocellular neuronal activity, driving sodium retention and HTN. Critically, RDNX attenuates age‐related HTN and may do so via an improvement in sodium balance.Support or Funding InformationThis work was supported by NIH R56 AG057687, R01 HL139867, R01 HL141406 and 17GRNT33670023 to RDW and NIH F31 DK116501 to AAF.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.