A Sympathetically Mediated α1‐Adrenoceptor Dependent Pathway Promotes Renal Sodium Chloride Cotransporter Activity in Age‐Related Hypertension

Abstract

AimHypertension is positively correlated with age and sympathetic tone in human subjects. These studies tested the hypothesis that sodium chloride cotransporter (NCC)‐mediated sodium retention and sympathoexcitation contribute to age‐related hypertension.MethodsThree‐month, 8‐month, and 16‐month old male Sprague‐Dawley (SD) rats underwent one of three studies. In the first study, MAP, HR, NCC activity (peak natriuresis to IV hydrochlorothiazide, HCTZ, 2 mg/kg), and measures of sympathetic tone [peak depressor response to IV hexamethonium (30 mg/kg), and plasma and renal norepinephrine (NE) levels] were assessed. In the second study, renal histology was evaluated and total protein expression of the NCC, with‐no‐lysine 1 (WNK1), and STE‐20 Alanine/Proline kinase (SPAK), and phosphorylated SPAK/oxidative stress response 1 (OxSR1) normalized to β‐actin was assessed in renal cortical tissue. In the third study, rats underwent chronic antagonism of the NCC (s.c. HCTZ, 4 mg/kg/d, 14d) or α1‐adrenoceptors (s.c. terazosin, 10 mg/kg/d, 14d) and MAP, HR, and NCC activity were assessed (n=4–5/group).ResultsBasal MAP and NCC activity increased with age (MAP [mmHg]; 3‐month 124±2 vs 8‐month 140±1 vs 16‐month 149±3, P<0.05: peak ΔUNaV to HCTZ [μeq/min]; 3‐month 9±1 vs 8‐month 18±2 vs 16‐month 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 (plasma NE [nmol/L]; 3‐month 44±4 vs 8‐month 55±3, P<0.05: renal NE [pg/mg]; 3‐month 612±36 vs 8‐month 835±48 vs 16‐month 974±39, P<0.05: peak depressor response to hexamethonium [mmHg]; 3‐month −33±4 vs 8‐month −64±5 vs 15‐month −60±3, P<0.05).Renal cortical expression of total WNK1 and phosphorylated SPAK/OxSR1 increased with age (WNK1 [ODU/mm2]; 3‐month 0.49±0.07 vs 8‐month 0.62±0.05 vs 16‐month 0.78±0.08, P<0.05: pSPAK/OxSR1 [ODU/mm2]; 3‐month 0.81±0.1 vs 8‐month 0.95±0.14 vs 16‐month 1.37±0.17, p<0.05). Total NCC, SPAK, and OxSR1 expression did not change with age. No gross changes in renal histology were observed in aging rats.Chronic α1‐adrenoceptor antagonism abolished the age‐related increase in NCC activity and attenuated age‐related hypertension (peak ΔUNaV to HCTZ [μeq/min]; 16‐month 15±5 vs. s.c. terazosin 10±3, P<0.05: MAP [mmHg]; 16‐month 149±3 vs s.c. terazosin 134±4, P<0.05). Chronic NCC antagonism attenuated age‐related hypertension (MAP [mmHg] 16‐month 149±3 vs s.c. HCTZ 136±5, P<0.05).ConclusionAge‐related hypertension is accompanied by global and renal sympathoexcitation and increased renal NCC activity. We speculate that in aged animals, elevated sympathetic tone increases NE‐driven renal NCC activity via an α1‐adrenoceptor‐WNK1‐SPAK/OxSR1 dependent pathway, promoting NCC‐mediated sodium reabsorption and the development of age‐related hypertension. Our data suggest that therapies targeting renal sympathetic outflow and α1‐adrenoceptors may be particularly well suited to the elderly hypertensive patient population.Support or Funding InformationThis work was supported by NIH grants R01HL107330 and K02HL112718 and AHA grants 16MM32090001 and AHA17GRNT3367002 to RDW and NIH grant F31DK116501 to AAF.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.