scholarly journals Chronic high-NaCl intake prolongs the cardiorenal responses to central N/OFQ and produces regional changes in the endogenous brain NOP receptor system

2009 ◽  
Vol 296 (2) ◽  
pp. R280-R288 ◽  
Author(s):  
Richard D. Wainford ◽  
Daniel R. Kapusta
Keyword(s):  
G Protein ◽  
Urine Output ◽  
Salt Intake ◽  
Ventrolateral Medulla ◽  
Receptor Density ◽  
Nop Receptor ◽  
Sprague Dawley ◽  
Receptor System ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake

Intracerebroventricular nociceptin/orphanin FQ (N/OFQ) produces cardiovascular depressor, diuretic, and renal sympathoinhibitory responses in conscious rats. These studies examined how a chronic high-NaCl intake alters these peptide-evoked responses and the activity of the endogenous central N/OFQ peptide (NOP) receptor system. In normotensive Sprague-Dawley rats fed a chronic (3-wk) high (8%)-NaCl diet, intracerebroventricular N/OFQ (5.5 nmol) produced prolonged bradycardic, hypotensive, and diuretic responses but failed to suppress renal sympathetic nerve activity. In a separate group of rats maintained on a high-NaCl diet, intracerebroventricular infusion of the NOP receptor antagonist UFP-101 significantly decreased urine output. At the tissue level, high-NaCl treatment of rats significantly increased NOP receptor density, without altering endogenous N/OFQ peptide levels in whole hypothalamus (control, 712 ± 35 fmol/mg vs. 8% NaCl, 883 ± 49 fmol/mg, P < 0.05) and paraventricular nucleus. Furthermore, in the hypothalamus, basal GTPγS binding was increased without altering the sensitivity of N/OFQ-stimulated G protein coupling. In contrast, in whole medulla and the ventrolateral medulla (VLM), high-NaCl treatment decreased NOP receptor density (medulla: control, 1,473 ± 131 fmol/mg vs. 8% NaCl, 327 ± 31 fmol/mg, P < 0.05) and endogenous N/OFQ peptide levels (medulla: control, 35.3 ± 2 fmol/mg vs. 8% NaCl, 11.9 ± 3 fmol/mg, P < 0.05), while increasing the sensitivity of G protein signaling pathways to N/OFQ stimulation. Together, these findings suggest that during a chronic high-salt intake, regional changes in the activity of the N/OFQ-NOP system in the brain may contribute to the tonic regulation of cardiovascular function and urine output and to the altered physiological responses to exogenous central N/OFQ.

Abstract 445: Increased Dietary Salt Intake Enhances Sympathetic and Cardiovascular Responses to Various Stressors

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Sean D Stocker ◽  
Sarah S Simmonds
Keyword(s):  
Salt Intake ◽  
Sympathetic Neurons ◽  
Cardiovascular Responses ◽  
Ventrolateral Medulla ◽  
Cardiovascular Reflexes ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Dietary Salt Intake ◽  
Intracerebroventricular Infusion ◽  
Arterial Blood

Previous studies indicate that increased dietary salt intake enhances sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses evoked from sympathetic neurons of the rostral ventrolateral medulla. The present study sought to extend these findings and determine whether dietary salt intake enhances SNA and ABP responses various sympathetic reflexes that depend on RVLM neurotransmission. Male Sprague-Dawley rats were fed 0.1% (n=6-8) or 4.0% (n=6-8) NaCl diets for 14-21 days. Then, animals were anesthetized with Inactin. Electrical stimulation (1-20 Hz, 1 ms pulse, 500 uA) of sciatic afferents produced frequency-dependent changes in SNA and ABP in both groups. However, rats ingesting 4% versus 0.1% NaCl displayed significantly larger increases in lumbar SNA (5Hz: 213±25 vs 146±25%, P<0.05), renal SNA (5Hz: 187±24 vs 120±11%), splanchnic SNA (5Hz: 203±21 vs 136±9%), and mean ABP (5Hz: 28±2 vs 12±2 mmHg). Rats ingesting 4% vs 0.1% NaCl also displayed greater increases in lumbar SNA (24±6 vs 13±2%, P<0.05) and mean ABP (12.1±0.9 vs 8.2±1.3mmHg, P<0.05) during increases in cerebrospinal fluid sodium concentration produced by intracerebroventricular infusion of 1M NaCl (5ul/10min). Lastly, hypercapnia (7% CO2, 33% O2, 63% N2, 60s) produced greater increases in lumbar SNA in rats ingesting 4% versus 0.1% NaCl (24±2% versus 9±3%, respectively; P<0.01). These findings suggest increased dietary salt intake enhances several sympathetic and cardiovascular reflexes.

Abstract 138: High Salt Intake Augments Excitability of Pre-sympathetic PVN Neurons Through Dysfunction of the Endoplasmic Reticulum Ca2+ ATPase

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Robert A Larson ◽  
Andrew D Chapp ◽  
Michael J Huber ◽  
Zixi Cheng ◽  
Zhiying Shan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Salt Intake ◽  
Sympathetic Neurons ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Atpase Inhibitor ◽  
High Salt Intake ◽  
Significant Difference

High salt (HS) intake sensitizes pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) leading to augmented neuronal excitability. Recently, we reported that dysfunction of Ca 2+ dependent K + channels in the PVN contributes to HS intake induced sympathoexcitation. The endoplasmic reticulum (ER) acts as a Ca 2+ store and plays an important role in regulating intracellular Ca 2+ homeostasis. The ER Ca 2+ ATPase is responsible for maintaining the high level of ER Ca 2+ and loss of function would deplete the Ca 2+ store contributing to the reduced activity of Ca 2+ dependent K + channels. We hypothesized that a 2% (NaCl) HS diet for 5 weeks would reduce function of the ER Ca 2+ ATPase and augment excitability of PVN neurons with axon projections to the rostral ventrolateral medulla (PVN-RVLM) identified by retrograde label. In whole cell current-clamp recordings from PVN-RVLM neurons, graded current injections evoked graded increases in spike frequency. Maximum discharge was evoked by +200 pA injections and averaged 22±2 Hz (n=6) in normal salt (NS) control and was significantly augmented (p<0.05) by HS diet 34±5 Hz (n=8). Bath application of thapsigargin (TG) (0.5 μM), the ER Ca 2+ ATPase inhibitor, augmented excitability of PVN-RVLM neurons in NS (32±4 Hz, n=5, p<0.05), yet had no significant effect in HS rats (32±6 Hz, n=6). ER Ca 2+ ATPase function was assessed in whole animal preparations by bilateral PVN microinjection of TG in anesthetized rats. PVN microinjection of TG (0.15, 0.3 0.75 and 1.5 nmol/100nl) increased sympathetic nerve activity (SNA) and mean arterial pressure (MAP) in a dose-dependent manner in NS rats. Maximum increases in splanchnic SNA (SSNA), renal SNA (RSNA) and MAP elicited by PVN TG (0.75 nmol/100nl; n=5) were 93±7%, 75±7%, and 11±2mmHg, respectively. In contrast, sympathoexcitatory responses to PVN TG (0.75 nmol/100nl; n=5) were attenuated in HS treated rats (SSNA 41±8%, RSNA 22±5%, p<0.05 vs. NS) while MAP responses demonstrated no significant difference (+8±2 mmHg, p>0.05 vs NS). Our data indicate that a HS diet reduces ER Ca 2+ ATPase activity and augments excitability of PVN-RVLM neurons in vitro. Altered ER Ca 2+ homeostasis may contribute to sympathoexcitation through loss of Ca 2+ dependent K + channel activity in the PVN.

Abstract 142: A Fructose-but Not a Glucose-enriched Diet, Induces a Salt-dependent Increase in Blood Pressure and Enhances NKCC2 Phosphorylation in Normal Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keyona N King-Medina ◽  
Emily Henson ◽  
Pablo Ortiz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Salt Intake ◽  
Caloric Intake ◽  
High Salt ◽  
Human Consumption ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
High Fructose ◽  
High Salt Intake

Human consumption of fructose as a sweetener has increased in the past 30 years. High fructose intake has been implicated in the development of hypertension, diabetes, and obesity. In the US, the upper 10th percentile of the population consumes up to 40% of their caloric intake from added sugars, in which fructose represents half of these. Fructose metabolism is strikingly different from that of glucose. Yet, the effect of a fructose or glucose-enriched diet in salt handling by the kidney, affecting blood pressure, and its interaction with high salt intake has been poorly studied. In genetic models of salt-sensitive hypertension, the activity of the Na + /K + /2Cl - cotransporter (NKCC2) in the thick ascending limb (TAL) is abnormally enhanced. We hypothesized that chronic fructose in drinking water induces a salt-dependent increase in blood pressure and stimulates NKCC2 during high salt intake in normal rats. Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt (HS) diet (4% Na + in chow) was started for 3 weeks. When we measured systolic blood pressure (SBP) by tail cuff plethysmography in fructose-fed and glucose-fed rats on a HS diet, only the fructose-fed rats had an increased SBP from 120±10 to 132±6 mmHg on day 7 of HS (p<0.01). SBP continued to increase up to 144±18 mmHg after 3 weeks (p<0.01 vs glucose). Fructose or glucose alone did not increase SBP after 4 weeks. We then repeated the protocol using radiotelemetry to monitor the blood pressure (BP). In rats fed fructose, by day 5 of HS the SBP increased by 12±3 mmHg (p<0.02) and SBP remained elevated for 3 weeks (delta: 10±2.5 mmHg, n=3). In rats fed glucose, a HS diet did not significantly change SBP for 3 weeks (n=5). Moreover, NKCC2 activity in the TAL is enhanced by phosphorylation at Thr96, 101. We found that NKCC2 phosphorylation was higher in rats fed fructose plus HS (p<0.02) but not in rats fed glucose plus HS for 3 weeks (HS: 100, fructose+HS: 250±40%, glucose+HS: 95±10%). Therefore, we conclude that a high fructose (but not a glucose) diet in normal rats induces a salt-dependent increase in BP independently from caloric intake. Thus, the increase in BP may in part be due to the stimulation of NKCC2 phosphorylation in the TAL by fructose.

scholarly journals Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats

2017 ◽  
Vol 114 (2) ◽  
pp. 233-246 ◽  
Author(s):  
Jiao Lu ◽  
Hong-Wei Wang ◽  
Monir Ahmad ◽  
Marzieh Keshtkar-Jahromi ◽  
Mordecai P Blaustein ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adrenal Cortex ◽  
Salt Intake ◽  
Plasma Corticosterone ◽  
High Salt ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake ◽  
Endogenous Ouabain ◽  
Salt Hypertension

AbstractAimsHigh salt intake markedly enhances hypertension induced by angiotensin II (Ang II). We explored central and peripheral slow-pressor mechanisms which may be activated by Ang II and salt.Methods and resultsIn protocol I, Wistar rats were infused subcutaneously with low-dose Ang II (150 ng/kg/min) and fed regular (0.4%) or high salt (2%) diet for 14 days. In protocol II, Ang II-high salt was combined with intracerebroventricular infusion of mineralocorticoid receptor (MR) blockers (eplerenone, spironolactone), epithelial sodium channel (ENaC) blocker (benzamil), angiotensin II type 1 receptor (AT1R) blocker (losartan) or vehicles. Ang II alone raised mean arterial pressure (MAP) ∼10 mmHg, but Ang II-high salt increased MAP ∼50 mmHg. Ang II-high salt elevated plasma corticosterone, aldosterone and endogenous ouabain but not Ang II alone. Both Ang II alone and Ang II-high salt increased mRNA and protein expression of CYP11B2 (aldosterone synthase gene) in the adrenal cortex but not of CYP11B1 (11-β-hydroxylase gene). In the aorta, Ang II-high salt increased sodium-calcium exchanger-1 (NCX1) protein. The Ang II-high salt induced increase in MAP was largely prevented by central infusion of MR blockers, benzamil or losartan. Central blockades significantly lowered plasma aldosterone and endogenous ouabain and markedly decreased Ang II-high salt induced CYP11B2 mRNA expression in the adrenal cortex and NCX1 protein in the aorta.ConclusionThese results suggest that in Ang II-high salt hypertension, MR-ENaC-AT1R signalling in the brain increases circulating aldosterone and endogenous ouabain, and arterial NCX1. These factors can amplify blood pressure responses to centrally-induced sympatho-excitation and thereby contribute to severe hypertension.

Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats

2001 ◽  
Vol 281 (5) ◽  
pp. H1881-H1889 ◽  
Author(s):  
Bing S. Huang ◽  
Hao Wang ◽  
Frans H. H. Leenen
Keyword(s):  
Wistar Rats ◽  
Salt Intake ◽  
Baroreflex Control ◽  
Renal Sympathetic Nerve Activity ◽  
Intracerebroventricular Infusion ◽  
Air Jet ◽  
Adrenoceptor Agonist ◽  
Pressor Responses ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

An enhanced responsiveness to increases in cerebrospinal fluid (CSF) Na+ by high salt intake may contribute to salt-sensitive hypertension in Dahl salt-sensitive (S) rats. To test this hypothesis, sympathetic and pressor responses to acute and chronic increases in CSF Na+were evaluated. In conscious young (5–6 wk old) and adult (10–11 wk old) Dahl S and salt-resistant (R) rats as well as weight-matched Wistar rats, hemodynamic [blood pressure (BP) and heart rate (HR)] and sympathetic [renal sympathetic nerve activity (RSNA)] responses to 10-min intracerebroventricular infusions of artificial CSF (aCSF) and Na+-rich aCSF (containing 0.2–0.45 M Na+) were evaluated. Intracerebroventricular Na+-rich aCSF increased BP, RSNA, and HR in a dose-related manner. The extent of these increases was significantly larger in Dahl S versus Dahl R or Wistar rats and young versus adult Dahl S rats. In a second set of experiments, young Dahl S and R rats received a chronic intracerebroventricular infusion of aCSF or Na+-rich (0.8 M) aCSF (5 μl/h) for 14 days, with the use of osmotic minipumps. On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular α2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function. The infusion of Na+-rich aCSF versus aCSF increased CSF Na+ concentration to the same extent but caused severe versus mild hypertension in Dahl S and Dahl R rats, respectively. After central Na+ loading, hypothalamus “ouabain” significantly increased in Dahl S and only tended to increase in Dahl R rats. Moreover, sympathoexcitatory and pressor responses to intracerebroventricular exogenous ouabain were attenuated by Na+-rich aCSF to a greater extent in Dahl S versus Dahl R rats. Responses to air-jet stress or intracerebroventricular guanabenz were enhanced by Na+-rich aCSF in both strains, but the extent of enhancement was significantly larger in Dahl S versus Dahl R. Na+-rich aCSF impaired arterial baroreflex control of RSNA more markedly in Dahl S versus R rats. These findings indicate that genetic control of mechanisms linking CSF Na+ with brain “ouabain” is altered in Dahl S rats toward sympathetic hyperactivity and hypertension.

Central infusion of aliskiren prevents sympathetic hyperactivity and hypertension in Dahl salt-sensitive rats on high salt intake

2012 ◽  
Vol 302 (7) ◽  
pp. R825-R832 ◽  
Author(s):  
Bing S. Huang ◽  
Roselyn A. White ◽  
Li Bi ◽  
Frans H. H. Leenen
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Sympathetic Hyperactivity ◽  
Direct Renin Inhibitor ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake ◽  
The Brain

Central infusion of an angiotensin type 1 (AT1) receptor blocker prevents sympathetic hyperactivity and hypertension in Dahl salt-sensitive (S) rats on high salt. In the present study, we examined whether central infusion of a direct renin inhibitor exerts similar effects. Intracerebroventricular infusion of aliskiren at the rate of 0.05 mg/day markedly inhibited the increase in ANG II levels in the cerebrospinal fluid and in blood pressure (BP) caused by intracerebroventricular infusion of rat renin. In Dahl S rats on high salt, intracerebroventricular infusion of aliskiren at 0.05 and 0.25 mg/day for 2 wk similarly decreased resting BP in Dahl S rats on high salt. In other groups of Dahl S rats, high salt intake for 2 wk increased resting BP by ∼25 mmHg, enhanced pressor and sympathoexcitatory responses to air-stress, and desensitized arterial baroreflex function. All of these effects were largely prevented by intracerebroventricular infusion of aliskiren at 0.05 mg/day. Aliskiren had no effects in rats on regular salt. Neither high salt nor aliskiren affected hypothalamic ANG II content. These results indicate that intracerebroventricular infusions of aliskiren and an AT1 receptor blocker are similarly effective in preventing salt-induced sympathetic hyperactivity and hypertension in Dahl S rats, suggesting that renin in the brain plays an essential role in the salt-induced hypertension. The absence of an obvious increase in hypothalamic ANG II by high salt, or decrease in ANG II by aliskiren, suggests that tissue levels do not reflect renin-dependent ANG II production in sympathoexcitatory angiotensinergic neurons.

Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation

2015 ◽  
Vol 308 (5) ◽  
pp. H530-H539 ◽  
Author(s):  
Koji Ito ◽  
Yoshitaka Hirooka ◽  
Kenji Sunagawa
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Salt Intake ◽  
Receptor Activation ◽  
High Salt ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake ◽  
Tnf Α ◽  
Excitatory Responses

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na+ channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na+, we performed an intracerebroventricular infusion of high Na+-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.

scholarly journals Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

2008 ◽  
Vol 31 (2) ◽  
pp. 62 ◽  
Author(s):  
Sowndramalingam Sankaralingam ◽  
Kaushik M Desai ◽  
Thomas W Wilson
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
And Oxidative Stress ◽  
Hypotensive Response

Purpose: High salt intake causes hypertension and endothelial dysfunction in young Sprague-Dawley rats. Clofibrate (clof) prevents this salt induced hypertension. We asked whether clof can prevent salt-induced endothelial dysfunction, and if so, its mechanism. We also questioned whether high salt intake can induce endothelial dysfunction without hypertension in older animals. Methods: Young (Y, 5 weeks) and old (O, 53 weeks) male Sprague-Dawley rats were given either vehicle (Con, 20 mM Na2CO3) or 0.9% NaCl (Sal) to drink for three weeks. Some young rats received clof (80 mg/d) in their drinking fluid. After three weeks, we measured mean arterial pressure (MAP), endothelial function, by comparing hypotensive responses to acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent), plasma total nitrite+nitrate levels (PNOx), by the Griess reaction, and aortic superoxide production by lucigenin chemiluminescence. Results: Carotid artery MAP did not change in O. Sal-Y developed hypertension: 133±3 vs. 114±2 mmHg, P < 0.001, which was prevented by clof: 105±2 mmHg. ACh induced a similar dose dependent hypotensive response in Con-O and Sal-O that was inhibited by L-NAME (100mg/kg i.v.). Responses to ACh were blunted in Sal-Y but not in Con-Y. Further, L-NAME inhibited ACh responses only in Con-Y. The response to SNP was similar in all animals. Importantly, the ACh-induced hypotensive response was potentiated in clof+Sal-Y, an effect which was attenuated by blocking calcium-activated potassium channels (KCa) with a combination of apamin (50 ug/kg i.v.) + charybdotoxin (50 ug/kg i.v.), but not by L-NAME. PNOx was reduced in Sal-Y compared to Con-Y (2.09±0.26 vs. 4.8±0.35 µM, P < 0.001), but not in Sal-O. Aortic superoxide production was higher (P < 0.001) in Sal-Y (2388±40 milliunits/mg/min) than Sal-O (1107±159 milliunits/mg/min), but was reduced by clof (1378±64 milliunits/mg/min; P < 0.001). Conclusions: High salt intake increases oxidative stress in young animals, leading to impaired nitric oxide activity and endothelial dysfunction. Clofibrate prevents endothelial dysfunction partly through reduced O2?- formation but mainly via selective activation of KCa channels. Older animals are resistant to both salt induced hypertension and oxidative stress.

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