Pathophysiology of age-dependent hypertension in male Sprague-Dawley rats
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BACKGROUND: Hypertension is a major health concern with a myriad of possible causes. Sodium is a major component of blood pressure regulation implicated in the maintenance of fluid volume. The blood pressure response to changes in salt intake varies considerably among individuals; salt-sensitive individuals exhibit increases in blood pressure parallel to elevated sodium intake, whereas salt-resistant individuals maintain constant blood pressure regardless of variations in sodium intake. Salt-Sensitive Hypertension (SSH) develops due to an impairment of normal mechanisms that react to an elevated sodium load. Aging is another major risk factor for the development of hypertension. The effects of aging have a profound impact on the cardiovascular, renal, and nervous systems, which work together to regulate blood pressure. The development of SSH and impact of aging on blood pressure have been well-established, but the neurophysiological mechanisms implicated in SSH and aging, have only been recently explored. OBJECTIVE: To provide mechanistic insight regarding the integrated roles of the renal and nervous systems in age-dependent hypertension in male Sprague-Dawley (SD) rats. METHODS: Male SD rats of various ages were randomly assigned to various experimental protocols. 3-month-old male SD rats were randomly assigned to receive Renal-Capsaicin surgery (Renal-CAP) to ablate the afferent renal nerve (ARN) or sham surgery, followed by an acute 5% body weight i.v.-isotonic volume expansion protocol (5%-VE) in which natriuretic response and cardiovascular functions (HR/MAP) were continuously monitored and analyzed for the duration of the experimental period. 3/8/16-month-old male SD rats without Renal-CAP surgery were similarly exposed to the 5%-VE protocol. C-fos immunohistochemistry (c-Fos IHC) was performed on brain slides prepared from rats assigned to the 5%-VE protocol to assess PVN parvocellular neuronal activation, as a marker for ARN activity. 3/8/16-month-old male SD rats on normal-salt and high-salt (NS/HS; 0.6%/4% sodium chloride respectively) diets were assigned to an amiloride and hydrochlorothiazide protocol (AM-HCTZ) to evaluate NCC activity, and exposed to i.p. hexamethonium to account for the sympathetic contribution to blood pressure. Renal/plasma NE content was assessed via ELISA to further account for sympathetic tone. Immunoblotting was performed on 3-month-old control saline-infused, s.c.-norepinephrine (NE), and s.c.-norepinephrine+terazosin/propranolol male SD rats to assess NCC, phosphorylated NCC (pNCCT58), SPAK, WNK1, OxSR1, and phosphorylated OxSR1 protein levels, to evaluate the roles of the α1/β-adrenoceptors in the NCC-implicated ARN-mediated sympathoinhibitory pathway. RESULTS: In response to the 5%-VE protocol, the natriuretic response was attenuated in Renal-Cap rats. Renal-CAP rats also experienced a significant increase in MAP in response to 5%-VE, while sham Renal-CAP rats did not. Both Renal-CAP and sham Renal-CAP rats experienced a significant increase in the mean number of PVN Fos-positive cells (Fos+) post-expansion, although the increase in Fos+ cells in Renal-CAP rats was smaller in magnitude in comparison to their sham Renal-CAP counterpart. An increase in MAP and decrease in urinary volume/sodium excretion was observed in male SD rats of increasing age in response to 5%-VE. An increase in the mean number of Fos+ cells was observed post-expansion in all age groups, while 3-month-old rats experienced a larger increase in Fos+ cell count relative to 8-month-old rats. An increase in MAP was observed in rats of increasing age on NS-intake. An increase in MAP was also observed in rats of the same age with an increase in dietary salt intake from a NS to HS-intake. An increase in MAP drop due to hexamethonium was observed in rats on HS-intake and of older age. An increase in renal/plasma NE content was observed in rats of increasing age on NS-intake, and increases in salt intake in the same age group led to a significant increase in NE content. An increase in NCC activity was observed in s.c.-NE/Renal-CAP 3-month-old rats in response to HS-intake, and in rats of increasing age on NS-intake. In response to HS-intake, a decrease in NCC activity occurred in rats treated with terazosin but not propranolol. Furthermore, a decrease in NCC/pNCC/WNK1/pOxSR1 expression was observed in rats treated with terazosin in response to HS-intake, whereas protein levels in rats treated with propranolol varied independently of dietary salt intake. CONCLUSION: This present study has provided abundant evidence regarding the integrated roles of renal sodium handling and the ARN-mediated sympathetic tone in the pathophysiology of age-dependent hypertension in male SD rats. Through the demonstration of a hypertensive mechanism, involving an impairment of fluid and electrolyte homeostasis that implicates the renal, cardiovascular, and nervous systems, this study provides a crucial stepping stone for the development of mechanistic treatments for age-dependent hypertension in elderly individuals with elevated sympathetic tone.