OP.2C.02] MECHANISMS OF AGE-DEPENDENT HYPERTENSION

Abstract

Objective: Hypertension is strongly correlated with increased age and elevated sympathetic tone in human subjects. Recent studies have associated excess sympathetic tone with NCC mediated sodium reabsorption. These studies tested the hypothesis that age-dependent hypertension correlates with impaired sympathoinhibitory and natriuretic mechanisms in the Sprague-Dawley rat. Design and method: Two-month, 8-month, and 15-month old male Sprague-Dawley (SD) rats underwent an intravenous (IV) volume expansion (VE; 5% body weight) and mean arterial pressure (MAP), heart rate (HR), natriuresis (UNaV), and paraventricular (PVN) parvocellular neuronal activation (c-Fos expression; IHC) 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, 2 mg/kg), peak depressor response to IV hexamethonium (30 mg/kg), and plasma and renal norepinephrine levels were assessed (n = 4/group). Results: Natriuresis following acute VE was dramatically impaired in aged rats (total % sodium load excreted; 2-month 78 ± 6 vs 8-month 60 ± 7 vs 15-month 22 ± 9, P < 0.05). Significantly, in these rats VE-evoked PVN parvocellular neuronal activation was attenuated (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, NCC activity and renal, global and vascular sympathetic tone increased age-dependently (MAP [mmHg]; 2-month 124 ± 2 vs 8-month 140 ± 1 vs 15-month 146 ± 4, P < 0.05: peak change in UNaV to HCTZ [μeq/min]; 2-month NS 9 ± 0.5 vs 8-month NS 18 ± 2 vs 15-month NS 17 ± 3, P < 0.05l 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 6-month -64 ± 5 vs 15-month -60 ± 3) Conclusions: Age-related hypertension is accompanied by impaired natriuretic and sympathoinhibitory responses to an acute 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 and reductions in dietary salt intake may be particularly useful in older patients with hypertension.