Hypertension and Sodium Homeostasis in Aging: Impaired Natriuretic Responses to Alterations in Fluid and Electrolyte Balance Accompany Hypertension in Aged Sprague‐Dawley Rats
Authors: Frame Alissa A , Desai Akshay N , Hai Jerry D , Wainford Richard D 
Published: November 2023

AimThe prevalence of hypertension is strongly correlated with increased age and elevated sympathetic tone in human subjects. These studies tested the hypothesis that sodium retention and sympathoexcitation contribute to age‐dependent hypertension in male Sprague‐Dawley (SD) rats.MethodsTwo‐month, 8‐month, and 15‐month old male SD rats underwent an intravenous (IV) volume expansion (VE; 5% body weight) and mean arterial pressure (MAP), heart rate (HR), natriuresis (UNaV), and paraventricular nucleus (PVN) parvocellular neuronal activation (c‐Fos expression) were assessed. In a separate study, naïve 2‐month, 8‐month, and 15‐month old male SD rats were maintained on a normal salt (NS, 0.6% NaCl) or high salt diet (HS, 4% NaCl). On day 21, MAP, HR, NCC activity (peak natriuresis to IV hydrochlorothiazide, HCTZ, 2mg/kg), peak depressor response to IV hexamethonium (30mg/kg), and plasma and renal norepinephrine (NE) levels were assessed (n=4/group).ResultsExcretion of sodium and water following an acute VE was impaired in aged rats (total % sodium load excreted; 2‐month 78±6 vs 8‐month 60±7 vs 15‐month 22±9: total % water load excreted; 2‐month 96±7 vs 8‐month 66±5 vs 15‐month 33±7, P<0.05). PVN parvocellular neuronal activation in response to IV VE was attenuated in aged rats (PVN neuronal activation [c‐fos positive cells]; medial parvocellular 2‐month 59±4 vs 8‐month 42±7 vs 15‐month 13±5, P<0.05).Basal MAP and NCC activity increased with age in rats maintained on a NS diet (MAP [mmHg]; 2‐month 124±2 vs 8‐month 140±1 vs 15‐month 149±3, P<0.05: peak ΔUNaV to HCTZ [μeq/min]; 2‐month NS 9±1 vs 8‐month NS 18±2 vs 15‐month NS 15±5, P<0.05). Measures of sympathetic activity, including global and renal NE levels and peak depressor response to hexamethonium, also increased with age in rats on a NS diet (plasma NE [nmol/L]; 2‐month 44±4 vs 8‐month 55±3, P<0.05: renal NE [pg/mg]; 2‐month 612±36 vs 8‐month 835±48 vs 15‐month 974±39, P<0.05: peak depressor response to hexamethonium [mmHg]; 2‐month −33±4 vs 8‐month −64±5 vs 15‐month −60±3, P<0.05).A chronic HS diet suppressed NCC activity and plasma NE in 2‐month but not 8‐month old rats (peak ΔUNaV to HCTZ [μeq/min]; 2‐month NS 9.2±0.5 vs HS 7.1±0.3, P<0.05: 8‐month NS 17.9±1.8 vs HS 16±1, ns: plasma NE [nmol/L]; 2‐month NS 44±4 vs HS 28±4, P<0.05: 8‐month NS 55±3 vs HS 42±4, P<0.05).ConclusionAge‐related hypertension is accompanied by impaired natriuretic and sympathoinhibitory responses to both acute and chronic challenges to fluid and electrolyte homeostasis. We speculate that in aged animals, elevated sympathetic tone‐ facilitated in part by reduced activation of PVN sympathoinhibitory neurons‐ increases NE‐driven NCC activity, promoting sodium reabsorption and the development of hypertension. These findings suggest that therapies reducing sympathetic outflow and renal sodium retention may be particularly useful in older patients with hypertension given 1) recent evidence from the PATHWAY‐2 trial indicating a primary role of sodium retention in treatment‐resistant hypertension and 2) the excessive dietary sodium intake in the rapidly aging global population.Support or Funding InformationThis work is funded by R01HL107330, K02HL112718 and AHA16MM32090001 to RDW and T32GM008541 to AAF.