Aim: The aim of this study was to investigate the effect of a high salt (HS) diet on age-related changes in blood pressure (BP) and the possible role played by regulatory central mechanisms. Methods: Young (5 months) and old (27 months) male Fischer 344 × Brown Norway (F344/BN) rats were fed standard chow or 8% HS diet for 12 days. BP and heart rate (HR) were measured by telemetry. Results: Mean arterial BP (MAP) was significantly elevated in old rats during the day and night when compared with young animals. The HS diet further elevated MAP in both age groups, and the increase was more pronounced in the old animals, while HR was not altered by age or HS diet. In addition, cardiovascular responses to restraint stress were diminished in the old when compared with the young and were unchanged with HS diet in either age group. Both age and the HS diet elevated the adrenomedullary mRNA levels of tyrosine hydroxylase, an indicator for sympathoexcitation. HS diet enhanced intracerebroventricular angiotensin II (AngII)-induced BP and HR elevations in both age groups. AngII type 1 receptor mRNA increased significantly in the hypothalamus with age and HS diet. Furthermore, hypothalamic p22phox mRNA and gp91phox protein, subunits of NADPH oxidase, as well as NADPH oxidase activity increased with the HS diet in the old animals, whereas antioxidant enzymes that decreased with age yet remained unaltered with the HS diet. Conclusion: Our findings indicate that sensitivity of BP to HS diet increases with age, and that central AngII-induced pressor responses are diminished in old rats compared with the young both under control conditions and during HS diet treatment. These changes are paralleled by increases in the expression and NADPH oxidase activity in the hypothalamus, possibly leading to central oxidative stress-mediated sympathoexcitation and high BP.

Keywords:
NADPH oxidase, AngII, Aging, High salt, Blood pressure, Restraint stress
1.
Weinberger MH, Fineberg NS: Sodium and volume sensitivity of blood pressure. Age and pressure change over time. Hypertension 1991;18:67-71.
2.
Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M: The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989;321:580-585.
3.
Cooper R, Van Horn L, Liu K, Trevisan M, Nanas S, Ueshima H, Larbi E, Yu CS, Sempos C, LeGrady D: A randomized trial on the effect of decreased dietary sodium intake on blood pressure in adolescents. J Hypertens 1984;2:361-366.
4.
Weinberger MH: Sodium sensitivity of blood pressure. Curr Opin Nephrol Hypertens 1993;2:935-939.
5.
Folkow B: Critical review of studies on salt and hypertension. Clin Exp Hypertens A 1992;14:1-14.
6.
Luft FC, Fineberg NS, Weinerger MH: The influence of age on renal function and renin and aldosteron responses to sodium volume expansion and contraction in normotensive and mildly hypertensive humans. Am J Hypertension 1992;5:520-528.
7.
Myers J, Morgan T, Waga S, Manley K: The effect of sodium intake on blood pressure related to the age of the patients. Clin Exp Pharmacol Physiol 1982;9:287-289.
8.
Pokkunuri I, Chugh G, Rizvi I, Asghar M: Age-related hypertension and salt sensitivity are associated with unique cortico-medullary distribution of D1R, AT1R, and NADPH-oxidase in FBN rats. Clin Exp Hypertens 2015;37:1-7.
9.
Bellucci A, Wilkes BM: Mechanism of sodium modulation of glomerular angiotensin receptors in the rat. J Clin Invest 1984;74:1593-1600.
10.
Aguilera G, Catt K: Regulation of vascular angiotensin II receptors in the rat during altered sodium intake. Circ Res 1981;49:751-758.
11.
Nickenig G, Strehlow K, Roeling J, Zolk O, Knorr A, Böhm M: Salt induces vascular AT1 receptor overexpression in vitro and in vivo. Hypertension 1998;31:1272-1277.
12.
Campese VM, Romoff MS, Levitan D, Saglikes Y, Friedler RM, Massry SG: Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. Kidney Int 1982;21:371-378.
13.
Koolen MI, Van Brummelen P: Adrenergic activity and peripheral hemodynamics in relation to sodium sensitivity in patients with essential hypertension. Hypertension 1984;6(6 pt 1):820-825.
14.
Wilcox CS: Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regul Integr Comp Physiol 2005;289:R913-R935.
15.
Bayorh MA, Ganafa AA, Socci RR, Silvestrov N, Abukhalaf IK: The role of oxidative stress in salt-induced hypertension. Am J Hypertens 2004;17:31-36.
16.
Matsui H, Shimosawa T, Uetake Y, Wang H, Ogura S, Kaneko T, Liu J, Ando K, Fujita T: Protective effect of potassium against the hypertensive cardiac dysfunction: association with reactive oxygen species reduction. Hypertension 2006;48:225-231.
17.
Taylor NE, Glocka P, Liang M, Cowley AW Jr: NADPH oxidase in the adrenal medulla causes oxidative stress and contributes to salt sensitive hypertension in Dahl S rats. Hypertension 2006;47:692-698.
18.
Kim-Mitsuyama S, Yamamoto E, Tanaka T, Zhan Y, Izumi Y, Izumiya Y, Ioroi T, Wanibuchi H, Iwao H: Critical role of angiotensin II in excess salt-induced brain oxidative stress of stroke-prone spontaneously hypertensive rats. Stroke 2005;36:1083-1088.
19.
Huang BS, Wang H, Leenen FH: Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats. Am J Physiol Heart Circ Physiol 2001;281:H1881-H1889.
20.
Fujita M, Kuwaki T, Ando K, Fujita T: Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain. Hypertension 2005;45:1165-1172.
21.
Erdos B, Cudykier I, Woods M, Basgut B, Whidden M, Tawil R, Cardounel AJ, Tumer N: Hypertensive effects of central angiotensin II infusion and restraint stress are reduced with age. J Hypertens 2010;28:1298-1306.
22.
Basgut B, Woods ME, Cudykier I, Whidden MA, Rodriguez M, Erdos B, Tumer N: The role of central AT1 receptors in age related changes of hypothalamic redox signaling and adrenomedullary tyrosine hydroxylase expression. FASEB J 2009;23:abstr 606.8.
23.
Woods ME, Basgut B, Cudykier I, Rodriguez M, Whidden M, Erdos B, Tumer N: Effects of high-fat diet and age on hypothalamic redox balance and central blood pressure regulation. FASEB J 2009;23:abstr 792.7.
24.
Zimmerman MC, Dunlay RP, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, Davisson RL: Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res 2004;95:532-539.
25.
Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH: Sympathoexcitation by central ANG II: roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM. Am J Physiol Heart Circ Physiol 2005;288:H2271-H2279.
26.
Erdös B, Broxson CS, King MA, Scarpace PJ, Tümer N: Acute pressor effect of central angiotensin II is mediated by NAD(P)H-oxidase-dependent production of superoxide in the hypothalamic cardiovascular regulatory nuclei. J Hypertens 2006;24:109-116.
27.
Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS: Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 1986;8(suppl II):127-134.
28.
Carlson SH, Roysomutti S, Peng N, Wyss JM: The role of the central nervous system in NaCl-sensitive hypertension in spontaneously hypertensive rats. Am J Hypertens 2001;14:155S-162S.
29.
Huang BS, Leenen FH: Brain “ouabain” and angiotensin II in salt-sensitive hypertension in spontaneously hypertensive rats. Hypertension 1996;28:1005-1012.
30.
Dahl LK, Knudsen KD, Heine MA, Leitl GJ: Effects of chronic excess salt ingestion. Modification of experimental hypertension in the rat by variations in the diet. Circ Res 1968;22:11-18.
31.
Dobesová Z, Kunes J, Zicha J: Body fluid alterations and organ hypertrophy in age-dependent salt hypertension of Dahl rats. Physiol Res 1995;44:377-387.
32.
Nedvídek J, Zicha J: Baroreflex control of heart rate in young and adult salt hypertensive inbred Dahl rats. Physiol Res 2000;49:323-330.
33.
Ono A, Kuwaki T, Kumada M, Fujita T: Differential central modulation of the baroreflex by salt loading in normotensive and spontaneously hypertensive rats. Hypertension 1997;29:808-814.
34.
Huang BS, Leenen FH: Both brain angiotensin II and “ouabain” contribute to sympathoexcitation and hypertension in Dahl S rats on high salt intake. Hypertension 1998;32:1028-1033.
35.
Koga Y, Hirooka Y, Araki S, Nozoe M, Kishi T, Sunagawa K: High salt intake enhances blood pressure increase during development of hypertension via oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats. Hypertens Res 2008;31:2075-2083.
36.
Deter HC, Buchholz K, Schorr U, Schächinger H, Turan S, Sharma AM: Psychophysiological reactivity of salt-sensitive normotensive subjects. J Hypertens 1997;15:839-844.
37.
Turkkan JS, Goldstein DS: Chronic effects of high salt intake and conflict stress on blood pressure in primates. A progress report. Integr Physiol Behav Sci 1991;26:269-281.
38.
Ruan X, Wagner C, Chatziantoniou C, Kurtz A, Arendshorst WJ: Regulation of angiotensin II receptor AT1 subtypes in renal afferent arterioles during chronic changes in sodium diet. J Clin Invest 1997;99:1072-1081.
39.
Schmid C, Castrop H, Reitbauer J, Della Bruna R, Kurtz A: Dietary salt intake modulates angiotensin II type 1 receptor gene expression. Hypertension 1997;29:923-929.
40.
Wang DH, Du Y: Regulation of vascular type 1 angiotensin II receptor in hypertension and sodium loading: role of angiotensin II. J Hypertens 1998;16:467-475.
41.
Akasaki T, Ohya Y, Kuroda J, Eto K, Abe I, Sumimoto H, Iida M: Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system. Hypertens Res 2006;29:813-820.
42.
Nozoe M, Hirooka Y, Koga Y, Sagara Y, Kishi T, Engelhardt JF, Sunagawa K: Inhibition of Rac1-derived reactive oxygen species in nucleus tractus solitarius decreases blood pressure and heart rate in stroke-prone spontaneously hypertensive rats. Hypertension 2007;50:62-68.
43.
Campese VM, Shaohua Y, Huiquin Z: Oxidative stress mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 2005;46:533-539.
44.
Hirooka Y: Role of reactive oxygen species in brainstem in neural mechanisms of hypertension. Auton Neurosci 2008;142:20-24.
45.
Kishi T, Hirooka Y, Kimura Y, Ito K, Shimokawa H, Takeshita A: Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation 2004;109:2357-2362.
46.
Fujita M, Ando K, Nagae A, Fujita T: Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension. Hypertension 2007;50:360-367.
47.
Chugh G, Asghar M, Patki G, Bohat R, Jafri F, Allam F, Dao AT, Mowrey C, Alkadhi K, Salim S: A high-salt diet further impairs age-associated declines in cognitive, behavioral, and cardiovascular functions in male Fischer Brown Norway rats. J Nutr 2013;143:1406-1413.
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