Effects Of Chronic Salt Loading Research Articles

A11100 Effects of Chronic Salt Loading on Plasma Inflammatory Factors in Normotensive Adults

Objectives: To observe the effects of dietary sodium intake on plasma inflammatory factors tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (CRP) and monocyte chemoattractant protein -1 (MCP-1) in normotensive adults. Methods: Thirty normotensive volunteers, aged 18 to 60, were selected to undergo a baseline survey, a low-sodium diet (51.3 mmol per day) for 7 days, a high-sodium diet (307.8 mmol per day) for an additional 7days. Thirty subjects were classified as salt sensitive group (SS, 10 subjects) or non-salt sensitive group (NSS, 20 subjects) on the basis of their mean arterial blood pressure (MAP) increase more than 10 percent at the end of the high-sodium phase compared with the low-sodium phase. Fasting blood samples were taken on the first day of baseline and on the sixth day of the two intervention phases. Plasma TNF-α and MCP-1 concentration was measured using an enzyme-linked immunosorbent assay system, plasma hsCRP concentration was measured by immune nephelometry. Results: The prevalence of SS is 33%. After salt loading, no significant change was found in the plasma hsCRP concentrations; Whereas plasma TNF-α level increased significantly in both of the two groups [(168.4 ± 67.8 vs. 42.1 ± 26.7)pg/ml, P < 0.01 and (129.8 ± 24.1 vs. 37.7 ± 15.8)pg/ml, P < 0.01, respectively]; Plasma MCP-1 was significantly higher during the high-sodium than the low-sodium phase in both of the two groups[(205.2 ± 64.2 vs. 166.3 ± 48.5)pg/ml, P < 0.01and (212.3 ± 52.2 vs. 143.6 ± 55.9)pg/ml, P < 0.01]. Conclusion: High-sodium diet can induce an inflammatory state, which may be independent of the salt sensitivity.

The Selective A3AR Antagonist LJ-1888 Ameliorates UUO-Induced Tubulointerstitial Fibrosis

Adenosine in the normal kidney significantly elevates in response to cellular damage. The renal A3 adenosine receptor (A3AR) is up-regulated under stress, but the therapeutic effects of A3AR antagonists on chronic kidney disease are not fully understood. The present study examined the effect of LJ-1888 [(2R,3R,4S)-2-[2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl]-tetrahydrothiophene-3,4-diol], a newly developed potent, selective, species-independent, and orally active A3AR antagonist, on unilateral ureteral obstruction (UUO)-induced renal fibrosis. Pretreatment with LJ-1888 inhibited UUO-induced fibronectin and collagen I up-regulation in a dose-dependent manner. Masson's trichrome staining confirmed that LJ-1888 treatment effectively reduced UUO-induced interstitial collagen accumulation. Furthermore, delayed administration of LJ-1888 showed an equivalent therapeutic effect on tubulointerstitial fibrosis to that of losartan. Small-interfering A3AR transfection effectively inhibited transforming growth factor-β1 (TGF-β1)-induced fibronectin and collagen I up-regulation in proximal tubular cells similar to LJ-1888, confirming that the renoprotective effect of LJ-1888 resulted from A3AR blockade. UUO- or TGF-β1-induced c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation decreased significantly after LJ-1888 administration. A3AR blockade reduced UUO- or TGF-β1-induced up-regulation of lysyl oxidase, which induces cross-linking of extracellular matrix, suggesting that LJ-1888 may also regulate extracellular matrix accumulation via post-translational regulation. In conclusion, the present data demonstrate that the A3AR antagonist, LJ-1888, blocked the development and attenuated the progression of renal fibrosis, and they suggest that LJ-1888 may become a new therapeutic modality for renal interstitial fibrosis.

Effects of chronic salt loading and potassium supplement on blood pressure variability in healthy adults

Objectives: An increasing number of basic and clinical studies indicate that increased variability of blood pressure is associated with target organs damage, reduction in mean blood pressure and variability of blood pressure significantly reduced the cardiovascular morbidity and mortality. In China, hypertension is characterized by high salt and low potassium diet. However, effects of chronic salt loading and potassium supplement on blood pressure variability have not been performed in healthy adults.

Effects of chronic salt loading and potassium supplement on expression of Toll-like receptor4 in peripheral blood mononuclear cells in salt-sensitive normotensive adults

Effects of chronic salt loading and potassium supplement on expression of Toll-like receptor4 in peripheral blood mononuclear cells in salt-sensitive normotensive adults

Effects of chronic salt loading on plasma inflammatory factors in normotensive adults

Objective: To observe the effects of dietary sodium intake on plasma inflammatory factors tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (HS-CRP) and MCP-1 in normotensive adults and to investigate the effect of inflammation induced by salt loading on the development of salt sensitivity. Methods: Thirty normotensive volunteers, aged 16 to 60years, were selected to undergo a baseline survey, a low-sodium diet (51.3mmol per day) for 7days, a high-sodium diet (307.8mmol per day) for an additional 7days.

Effect of chronic salt loading on the remodeling of thoracic aorta in spontaneously hypertensive rats

Objective In addition to its effect on arterial pressure, NaCl affects vascular structure and function. We observe the effect of chronic salt loading on the remodeling of vessels in spontaneously hypertensive rats and investigate the possible mechanism. Methods SHRs (n=80, male, 4–5weeks old) were assigned randomly to receive 4% high salt (HS groups, n=45) and 0.4% low salt (LS groups, n=35) for 16weeks. Body weight, blood pressure, urine volume and urinary sodium excretion were measured every four weeks.

Effects of chronic salt loading on oxidative stress and endothelial dysfunction in spontaneously hypertensive rats

Effects of chronic salt loading on oxidative stress and endothelial dysfunction in spontaneously hypertensive rats

Modulation of adenosine receptor expression in the proximal tubule: a novel adaptive mechanism to regulate renal salt and water metabolism

about 180 liters of filtrate are produced by the human kidneys every day, with more than 99% of the filtered salt and water being subsequently reabsorbed along the nephron. In view of this high level of renal filtration, even slight alterations in the balance between filtration and reabsorption will

Exaggerated Response of Arginine Vasopressin‐Enhanced Green Fluorescent Protein Fusion Gene to Salt Loading without Disturbance of Body Fluid Homeostasis in Rats

We examined the effects of chronic salt loading on the hypothalamic expressions of the enhanced green fluorescent protein (eGFP), arginine vasopressin (AVP) and oxytocin (OXT) genes in AVP-eGFP transgenic rats that expressed eGFP in the hypothalamic AVP-containing neurones. In these rats, salt loading for 5 days caused a marked increase of the eGFP fluorescence in the magnocellular divisions of the paraventricular nucleus (PVN), the supraoptic nucleus (SON) and the internal layer of the median eminence. Expression of the eGFP gene was increased seven- to eight-fold in the PVN and SON of salt-loaded rats in comparison with euhydrated rats. By contrast, none of these changes were observed in the suprachiasmatic nucleus. The expression of the AVP and OXT genes was increased 1.5- to two-fold in the PVN and SON of salt-loaded nontransgenic (control) and transgenic rats. There were no differences in the expression levels of the AVP and OXT genes in the PVN and SON between nontransgenic (control) and transgenic animals under normal conditions and after salt loading. In the posterior pituitary gland, the intensity of the eGFP fluorescence did not change after salt loading for 5 days, but increased after 10 days of salt loading. Upon salt loading, significant increases in the plasma AVP concentrations, plasma osmolality and plasma Na+ were observed. Furthermore, there were no significant differences in changes of water intake, food intake, urine volume, urine osmolality, urine Na+ concentrations, and the body weights in both models under normal or salt-loaded conditions. Our results show that the response of the AVP-eGFP fusion gene to chronic salt loading is exaggerated, and humoral responses such as AVP and OXT and the body fluid homeostasis are maintained in AVP-eGFP transgenic rats. The AVP-eGFP transgenic rat gives us a new opportunity to study the dynamics of the AVP system in vivo.

Upregulation of synapsin IIa and IIb mRNAs in the paraventricular and supraoptic nuclei in chronic salt loaded and lactating rats.

The effects of chronic salt loading (2% saline to drink for 5 and 10 days), gestation, lactation and adrenalectomy on the expression of synapsin IIa and IIb genes were examined in the rat paraventricular (PVN) and supraoptic nuclei (SON), using in situ hybridization histochemistry. In each control, synapsin IIa and IIb genes were moderately expressed in the magnocellular division of the PVN and SON, while few transcripts of synapsin IIa and IIb were observed in the parvocellular division of the PVN. Chronic salt loading, gestation on day 21 and lactation on day 10 caused significant increases in synapsin IIa and IIb transcripts in the magnocellular division of the PVN and SON, compared to each control. Although corticotropin-releasing hormone transcripts in the parvocellular division of the PVN were significantly increased in the adrenalectomized rats, no changes in the transcripts of synapsin IIa and IIb were observed throughout the PVN. These results suggest that physiological stimuli such as osmotic challenge and lactation potently increase synapsin IIa and IIb mRNAs in the magnocellular neurons of the PVN and SON.

Effect of chronic salt loading on adenosine metabolism and receptor expression in renal cortex and medulla in rats.

Previous studies have shown that chronic salt loading increased renal interstitial adenosine concentrations and desensitized renal effects of adenosine, a phenomenon that could facilitate sodium excretion. However, the mechanisms responsible for the increased adenosine production and decreased adenosine response are poorly understood. This study examined the effects of the dietary high salt intake on adenosine metabolism and receptor expression in the renal cortex and medulla in Sprague Dawley rats. Fluorescent high-performance liquid chromatography analyses were performed to determine adenosine levels in snap-frozen kidney tissues. Comparing rats fed a normal (1% NaCl) versus high salt (4% NaCl) diet, renal adenosine concentrations in rats fed a high salt diet were significantly higher (cortex: 43+/-3 versus 85+/-4, P<0.05; medulla: 183+/-4 versus 302+/-8 nmol/g wet tissue, P<0.05). Increased adenosine concentrations were not associated with changes in the 5'-nucleotidase or adenosine deaminase activity, as determined by quantitative isoelectric focusing and gel electrophoresis. Western blot analyses showed that a high salt diet (4% NaCl for 3 weeks) downregulated A1 receptors (antinatriuretic type), did not alter A2A and A2B receptors (natriuretic type), and upregulated A3 receptors (function unknown) in both renal cortex and medulla. The data show that stimulation of adenosine production and downregulation of A1 receptors with salt loading may play an important role in adaptation in the kidney to promote sodium excretion.

Effect of chronic salt loading on kidney function in early and established diabetes mellitus in rats

Glomerular hyperfiltration and renal hypertrophy are among the events that characterize the early course of diabetes mellitus in rats and human patients. Previous studies from this laboratory demonstrated that salt restriction paradoxically reduces total renal vascular resistance (RVR) and increases glomerular filtration rate (GFR) in diabetic rats (J Am Soc Nephrol 1995;5: 1761-7). In the present study we examined the converse condition by testing the effects of chronic salt loading on kidney function in moderately hyperglycemic insulin-treated rats with early and restablished streptozotocin diabetes. Salt loading was accomplished by adding 1% NaCl to the drinking water 1 day or 35 days after diabetes was induced. The high-salt diet appropriately increased salt excretion in diabetic rats and nondiabetic controls. GFR and renal plasma flow were determined by inulin and para-amino hippuric acid (PAH) clearance 7 days after salt loading was started. Diabetic rats receiving tap water exhibited hyperfiltration with no change in renal blood flow (RBF). In nondiabetic rats, salt loading caused a reduction in total RVR and proportional increases in RBF, GFR, and kidney weight (KW). Salt loading in early diabetes did not affect RVR, RBF, or KW and caused a paradoxical reduction in GFR. In established diabetes, salt loading reduced RVR and increased RBF, similar to results in nondiabetic rats, but as in rats with early diabetes, it did not increase GFR or KW. In summary, although the response in RVR and RBF to chronic salt loading depends on the duration of diabetes, the increase in GFR and KW as seen in nondiabetic rats is blunted in the early and established state of insulin-treated diabetes in rats. These findings further support the notion that the renal response to variation in salt intake is altered in insulin-treated diabetes in rats.

Increase of urocortin-like immunoreactivity in the rat hypothalamo-neurohypophysial system after salt loading and hypophysectomy

The effect of chronic salt loading on urocortin-like immunoreactivity (Ucn-IR) was investigated in the rat hypothalamo-neurohypophysial system. In control rats a few Ucn-IR neurons were observed scattered throughout the supraoptic nucleus (SON) and few in the paraventricular nucleus (PVN). A small number of Ucn-IR fibers were observed scattered in the median eminence (ME) and the posterior pituitary. However, after 5 days of chronic administration of 2% saline, a marked increase in the number of Ucn-IR perikarya and fibers was observed in the PVN and the SON. Additionally, Ucn-IR varicosities and fibers were found in the internal zone of the ME and in the posterior pituitary. To confirm the findings and examine the possible involvement of anterior pituitary function in synthesis of Ucn, surgical hypophysectomized rats were used. Five days after hypophysectomy, a marked increase in Ucn-IR was observed in the PVN, the SON, and both the internal and the external zone of the ME. These results suggest that Ucn in the hypothalamo-neurohypophysial system may be involved in the regulation of salt balance, and possibly in the stimulation of ACTH release from the anterior pituitary.

Up-regulation of calretinin in the supraoptic nucleus of the rat after chronic salt loading

We immunocytochemically examined the effect of chronic salt loading on the content of calretinin, a calcium-binding protein, in both the supraoptic nucleus and the magnocellular parts of the hypothalamic paraventricular nucleus. In control rats that were given water for drinking, the supraoptic nucleus contained a cluster of calretinin-stained cells. Drinking 2% sodium chloride solution for 7 days resulted in an increase of the staining intensity of calretinin in cells of the supraoptic nucleus. In both the control and salt-loaded rats, the magnocellular parts of the paraventricular nucleus were almost devoid of calretinin-labeled cells. It is suggested that expression of calretinin in cells of the supraoptic nucleus is up regulated by chronic salt loading.

Involvement of renal dopaminergic system in experimental neurogenic arterial hypertension.

The effect of chronic salt loading (10 g of NaCl for a period of 7 days) on urinary dopamine release has been investigated in 3 groups of beagle dogs: normotensive dogs (group 1: n = 7), and 2 groups of dogs made hypertensive by chronic sinoaortic denervation [group 2: (n = 6) during the first 4 months after sinoaortic denervation i.e. a model of arterial hypertension with high levels of plasma catecholamines and group 3: (n = 6) one year after denervation i.e. a model of arterial hypertension with normal sympathetic tone]. In normal dogs (group 1), salt loading induced an increase in urinary dopamine excretion during the two first days after salt loading. The rise in urinary dopamine was blunted in group 2. It was not observed in group 3. Salt loading failed to change arterial pressure and heart rate in the three groups of animals. These data show an alteration of the renal dopaminergic system in hypertensive sinoaortic denervated dogs suggesting that a dopaminergic impairment can appear during the development of arterial neurogenic hypertension.

Regulation of atrial natriuretic peptide receptors in glomeruli during chronic salt loading

The effects of chronic salt loading on atrial natriuretic peptide (ANP) receptor density and affinity were studied in isolated renal glomeruli of male Sprague-Dawley rats, which received 0.9% saline as drinking fluid (NaCl-rats) and a normal rat chow diet for 35 days (N = 12). Animals on a low sodium intake received the same diet, but deionized water and served as controls (C) (N = 12). After 35 days blood pressure was only slightly increased to 136 +/- 9 in NaCl-rats versus 120 +/- 2 mm Hg in C (NS). Glomerular filtration rate, plasma cGMP and plasma ANP remained unaltered. Determination of total ANP receptor characteristics in these rats indicated a significant down-regulation of ANP receptors in salt loaded rats. Since ANP-stimulated cGMP formation was not affected by salt loading, the roles of clearance (C) and of biologically active (B) receptors were further evaluated at 21 degrees C on freshly isolated and acid washed (pH 5) glomeruli in seven animals after 35 days of salt loading and in seven animals on a low sodium intake. B-receptors were assessed by blocking C-receptors with 4-23 cANP. C-receptor numbers were lower in NaCl-rats (97 +/- 8 vs. 184 +/- 14 fmol/mg protein in C; N = 7; P less than 0.02), while C-receptor affinity was increased (Kd: 12 +/- 3 pM in NaCl-rats vs. 22 +/- 5 pM in C; P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic salt loading and adrenergic mechanisms in the Sprague-Dawley rat.

The effect of chronic salt loading on adrenergic mechanisms was evaluated in Sprague-Dawley rats (and NMRI mice) maintained on a high sodium (8%) or normal sodium (0.3%) regime for 4 weeks. The basal blood pressure (carotid artery) was not influenced by the high salt diet but the heart rate and blood pressure increases to mental stress (jet air) were larger in the salt loaded rats. There were indications of an increased sympathetic tone in rats on the high salt diet since in these rats sympathoinhibitory treatment with ganglionic blockade or clonidine induced larger falls in blood pressure and heart rate than in the controls. Central catecholamines (brain stem, striatum, hemispheres) were determined spectrofluorimetrically after cation exchange chromatography. The high salt diet influenced neither the endogenous levels of noradrenaline nor central noradrenaline turnover (disappearance of noradrenaline after synthesis inhibition by alpha-methyltyrosine and accumulation of dihydroxyphenylalanine after decarboxylase inhibition by 3-hydroxybenzylhydrazine). There were no changes in central alpha 2-adrenoceptor responsiveness when assessed as clonidine-induced deceleration of noradrenaline turnover in the brain and in central alpha 1-adrenoceptor responsiveness (clonidine-induced increase of flexor reflex in spinalized rats and clonidine-induced increase of motor activity in reserpinized mice). Peripheral sympathetic function was assessed in pithed rats. The pressor responses to intravenously administered noradrenaline (0.01-10 micrograms/kg) and electrical stimulation of the spinal sympathetic nerves (SNS, 0.25-2 Hz) were similar in the two groups, suggesting that salt did not influence vascular alpha-adrenoceptor responsiveness or transmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic salt loading on plasma atrial natriuretic peptide (ANP) in the spontaneously hypertensive rat.

Plasma concentrations of immunoreactive atrial natriuretic peptide (ANP) was measured in spontaneously hypertensive rats (SHR) during chronic salt loading (1.5% NaCl in drinking water). During the 3-week experimental period mean arterial blood pressure, heart rate, urinary sodium excretion and body weight was assessed in salt-loaded as well as in control rats. The sodium excretion was more than 10-fold increased in the rats on the high salt diet. The plasma ANP concentration was significantly increased only 24 h after the start of the high salt intake. Thereafter plasma ANP concentrations were not significantly different from values obtained in control rats. The blood pressure was significantly increased after 3 weeks on the high salt diet. At the end of the 3-week experimental period the rats were subjected to a 10 and 20% acute volume expansion with homologous whole blood. During this intervention the increase in plasma ANP concentrations was blunted in the high salt rats compared to the control group. It is concluded that during chronic salt loading in SHR there is an initial rise in plasma ANP levels and that other hormonal and neuronal systems are more important in the long term maintenance of fluid and electrolyte balance.

Biochemical aspects of salt-induced, pressure-independent left ventricular hypertrophy in rats.

In an attempt to investigate the effect of chronic salt loading on heart size and biochemical composition, sixty 3-month-old male Wistar-Kyoto rats (WKY) were equally divided into two groups: One group was given 1% NaCl in drinking water, and the other group was given tap water as the control. After 7 months, five randomly selected rats from each group were examined for body weight (BW), indirect blood pressure (BP), hematocrit (Hct), and organ weights. Ventricles of the heart, aorta, and mesenteric arteries were biochemically analyzed for collagen (C) and noncollagenous protein NC) and deoxyribonucleic acid (DNA). Although here was no difference between the salt and control groups in BP (129 +/- 3 mmHg vs. 125 +/- 4 mmHg, mean +/- SE), BW (376 +/- 8 g vs. 372 +/- 5 g) and Hct (42.8% +/- 1.0% vs. 44.3% +/- 0.8%), left ventricular weight (857 +/- 19 mg vs. 788 +/- 8 mg) and kidney weight (2.59 +/- 00.9 g vs 2.31 +/- 0.05 g) were both significantly (P less than 0.01) greater in the salt group, whereas the weights of the right ventricle, aorta, and adrenal glands were equal. Biochemical analysis showed significant increase in NC/DNA ratio and total collagen content as well as decreased DNA concentration in the left ventricle of the salt group compared with the control, suggesting hypertrophy rather than hyperplasia of myocardial cells with concomitant activation of collagen synthesis. Since the manner of reactive collagen production appeared different from that reported for spontaneously hypertrophic rats (SHR) or in hypoxia- or aortic constriction-induced cardiac hypertrophy, some unique mechanism may be involved in salt-induced cardiac hypertrophy.

Chronic salt loading and central adrenergic mechanisms in the spontaneously hypertensive rat.

The effects of chronic salt loading on central adrenergic mechanisms were evaluated in spontaneously hypertensive rats maintained on tap water or 1.2% sodium chloride drinking water for 4 weeks. Basal blood pressure was increased by 10% in the high salt group. Central catecholamines were measured spectrofluorimetrically after cation exchange chromatography. Endogenous levels of noradrenaline (NA) were not influenced by salt loading but the NA turnover (disappearance of NA following synthesis inhibition by alpha-methyltyrosine) was increased in the hemisperes. Central alpha 2-adrenoceptor sensitivity was assessed as the clonidine-induced reduction in blood pressure and as the clonidine-induced deceleration of NA turnover and locus coeruleus (LC) NA cell firing rate (single unit recording). The results were slightly disparate but the unchanged sensitivity of clonidine to reduce LC NA cell firing suggests that there were no alterations in central alpha 2-adrenoceptor sensitivity following a salt load. There were also no changes in alpha 1-adrenoceptor function, which was assessed semiquantitatively as the clonidine-induced increase in flexor reflex activity in spinalized rats. In salt loaded rats there was an enhanced blood pressure and heart rate reduction following ganglionic blockade which may be interpreted as an increased basal sympathetic tone. In the periphery the pressor responses to phenylephrine were increased whereas the chronotropic response to isoprenaline was unchanged. In conclusion, in the spontaneously hypertensive rat on a high salt intake the aggravated development of hypertension was not associated with major changes in central alpha 1 and alpha 2-adrenoceptor mediated functions or in neuronal activity of brain stem NA neurons. There were indications of an increased basal sympathetic tone and increased blood pressure response to pressor substances.