Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats

2009 ◽  
Vol 296 (3) ◽  
pp. R618-R630 ◽  
Author(s):  
Alexander Gabor ◽  
Frans H. H. Leenen
Keyword(s):  
Wistar Rats ◽  
Ouabain Binding ◽  
Short Term ◽  
Receptor Stimulation ◽  
Intracerebroventricular Infusion ◽  
Artificial Cerebrospinal Fluid ◽  
Pressor Responses ◽  
Induced Hypertension

Sympathoexcitatory and hypertensive responses to central infusion of Na+-rich artificial cerebrospinal fluid (aCSF) are enhanced by aldosterone and mediated by mineralocorticoid receptors (MRs) and benzamil-blockable Na+ influx, leading to “ouabain” release and ANG II type 1 (AT1) receptor stimulation. The present study evaluated the functional role of these mechanisms in the paraventricular nucleus (PVN). In conscious Wistar rats, Na+-rich aCSF was infused either directly into the PVN or intracerebroventricularly preceded by aldosterone and blockers. Infusion of Na+-rich aCSF in the PVN caused gradual increases in blood pressure (BP) and heart rate (HR). Aldosterone and a subpressor dose of ouabain in the PVN alone did not affect BP and HR but enhanced responses to Na+. Eplerenone, benzamil, and “ouabain”-binding Fab fragments only blocked the enhancement by aldosterone, whereas losartan blocked all responses to Na+-rich aCSF in the PVN. Increases in BP and HR by intracerebroventricular infusion of Na+-rich aCSF were enhanced by aldosterone infused intracerebroventricularly, but not in the PVN. Telmisartan in the PVN again blocked all responses. In contrast, both eplerenone and benzamil in the PVN did not change the pressor responses to intracerebroventricular infusion of aldosterone and Na+-rich aCSF. These findings indicate that AT1 receptors in the PVN mediate the responses to Na+-rich aCSF and their enhancement by aldosterone, both locally in the PVN or in the general CSF. MRs, benzamil-blockable Na+ channels or transporters, and “ouabain” can be functionally active in the PVN, but in Wistar rats appear not to contribute to the pressor responses to short-term increases in CSF [Na+].

Mechanisms mediating sodium-induced pressor responses in the PVN of Dahl rats

2011 ◽  
Vol 301 (5) ◽  
pp. R1338-R1349 ◽  
Author(s):  
Alexander Gabor ◽  
Frans H. H. Leenen
Keyword(s):  
Wistar Rats ◽  
Mineralocorticoid Receptors ◽  
High Salt Diet ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
Artificial Cerebrospinal Fluid ◽  
Pressor Responses ◽  
No Release ◽  
The Brain

Intracerebroventricular infusion of Na+-rich artificial cerebrospinal fluid (aCSF) causes larger sympathetic and pressor responses in Dahl salt-sensitive (S) than -resistant (R) or Wistar rats. Enhanced activity of the aldosterone-“ouabain” pathway or decreased nitric oxide (NO) release may contribute to this enhanced responsiveness. Where in the brain these mechanisms interact is largely unknown. The present study evaluated whether Na+ in the paraventricular nucleus (PVN) causes larger pressor responses in Dahl S (SS/Mcw) than R (Dahl SS.BN13) rats and whether mineralocorticoid receptors, benzamil-blockable Na+ channels, “ouabain,” angiotensin type 1 receptors, or NO mediates these enhanced responses. Na+-rich aCSF in the PVN caused 30–40% larger increases in blood pressure and heart rate in Dahl S than R or Wistar rats, whereas responses to ouabain, ANG II, or Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) in the PVN were the same. These responses to Na+ were not affected by eplerenone, benzamil, or Fab fragments, whereas they were fully blocked by losartan, in Dahl S and R rats. l-NAME enhanced them more in Dahl R than S rats, thereby equalizing the responses in the two strains. Pressor responses to l-NAME in the PVN were attenuated by a high-salt diet in Dahl S, but not R, rats. The results indicate that acute and chronic increases in Na+ concentration in the PVN inhibit NO release in the PVN of Dahl S, but not R, rats, thereby contributing to the enhanced pressor responses to Na+ in Dahl S rats.

Ouabain- and central sodium-induced hypertension depend on the ventral anteroventral third ventricle region

1999 ◽  
Vol 276 (1) ◽  
pp. H63-H70 ◽  
Author(s):  
Shereeni J. Veerasingham ◽  
Frans H. H. Leenen
Keyword(s):  
Hypertonic Saline ◽  
Wistar Rats ◽  
Third Ventricle ◽  
Cardiovascular Responses ◽  
Ibotenic Acid ◽  
Air Jet ◽  
Artificial Cerebrospinal Fluid ◽  
Induced Hypertension ◽  
Chronic Infusion

To examine the role of the ventral anteroventral third ventricle (vAV3V) in the hypertension induced by chronic subcutaneous ouabain and intracerebroventricular hypertonic saline, neurons in this area were destroyed by microinjection of an excitotoxin, ibotenic acid. Sham-operated or lesioned Wistar rats were administered ouabain (50 μg/day) or placebo for 3 wk from subcutaneously implanted controlled release pellets or artificial cerebrospinal fluid (CSF) or CSF containing 0.8 mol/l NaCl (5 μl/h) infused intracerebroventricularly for 2 wk. At the end of the experiment, mean arterial pressure (MAP) and heart rate at rest and in response to ganglionic blockade by intravenous hexamethonium (30 mg/kg) were assessed. In rats infused with hypertonic saline, responses to air jet stress were also assessed. Baseline MAP in sham-operated rats receiving intracerebroventricular hypertonic saline or subcutaneous ouabain was significantly higher than in control rats (115 ± 1 vs. 97 ± 3 and 121 ± 3 vs. 103 ± 3 mmHg, respectively). vAV3V lesions abolished the increase in MAP elicited by chronic infusion of hypertonic saline or administration of ouabain. Sham-operated rats treated with hypertonic saline or ouabain exhibited significantly enhanced decreases in MAP to hexamethonium, but lesioned rats did not. Rats infused with hypertonic saline demonstrated enhanced responses to air jet stress that were similar in sham-operated and lesioned rats. These results demonstrate that neurons in the vAV3V are essential for the hypertension induced by intracerebroventricular hypertonic saline and subcutaneous ouabain, possibly by increasing sympathetic tone. Cardiovascular responses to air jet stress appear not to be mediated by the vAV3V.

scholarly journals Possible role of brain salt-inducible kinase 1 in responses to central sodium in Dahl rats

2012 ◽  
Vol 303 (2) ◽  
pp. R236-R245 ◽  
Author(s):  
Bing S. Huang ◽  
Roselyn A. White ◽  
Frans H. H. Leenen
Keyword(s):  
Protein Kinase ◽  
Wistar Rats ◽  
Kinase Inhibitor ◽  
Specific Protein ◽  
Ang Ii ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
Pressor Responses ◽  
Protein Kinase C Inhibitor

In Dahl salt-sensitive (S) rats, Na+ entry into the cerebrospinal fluid (CSF) and sympathoexcitatory and pressor responses to CSF Na+ are enhanced. Salt-inducible kinase 1 (SIK1) increases Na+/K+-ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of CSF [Na+] and responses to Na+ in the brain. SIK1 protein and activity were lower in hypothalamic tissue of Dahl S (SS/Mcw) compared with salt-resistant SS.BN13 rats. Intracerebroventricular infusion of the protein kinase inhibitor staurosporine at 25 ng/day, to inhibit SIK1 further increased mean arterial pressure (MAP) and HR but did not affect the increase in CSF [Na+] or hypothalamic aldosterone in Dahl S on a high-salt diet. Intracerebroventricular infusion of Na+-rich artificial CSF caused significantly larger increases in renal sympathetic nerve activity, MAP, and HR in Dahl S vs. SS.BN13 or Wistar rats on a normal-salt diet. Intracerebroventricular injection of 5 ng staurosporine enhanced these responses, but the enhancement in Dahl S rats was only one-third that in SS.BN13 and Wistar rats. Staurosporine had no effect on MAP and HR responses to intracerebroventricular ANG II or carbachol, whereas the specific protein kinase C inhibitor GF109203X inhibited pressor responses to intracerebroventricular Na+-rich artificial CSF or ANG II. These results suggest that the SIK1-Na+/K+-ATPase network in neurons acts to attenuate sympathoexcitatory and pressor responses to increases in brain [Na+]. The lower hypothalamic SIK1 activity and smaller effect of staurosporine in Dahl S rats suggest that impaired activation of neuronal SIK1 by Na+ may contribute to their enhanced central responses to sodium.

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.

Abstract 422: Role of Brain Salt-inducible Kinase 1 in Responses to Central Sodium in Salt-induced Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Bing S Huang ◽  
Roselyn A White ◽  
Frans H Leenen
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Specific Protein ◽  
Feedback Mechanism ◽  
Ang Ii ◽  
High Salt Diet ◽  
Pressor Responses ◽  
Induced Hypertension ◽  
Protein Kinase C Inhibitor

In Dahl salt sensitive (S) rats, sympatho-excitatory and pressor responses to CSF Na + are enhanced. Salt-inducible kinase 1 (SIK1) increases Na + /K + -ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of sympatho-excitatory and pressor responses to Na + in the brain. Icv injection of the protein kinase inhibitor staurosporine (staur, 5ng) to inhibit SIK1 similarly enhanced renal sympathetic nerve activity (RSNA), BP and HR responses to icv infusion of Na + -rich aCSF in Wistar and salt-resistant Dahl SS.BN13. The enhancement in Dahl S rats was only 1/3 of that in other strains. Staur had no effect on BP responses to icv Ang II or carbachol, whereas the specific protein kinase C inhibitor GF109203X attenuated pressor responses to icv Na + -rich aCSF or Ang II. Hypothalamic SIK1 protein and activity, measured by Western blot and phosphocellulose binding technique, were lower in Dahl S vs SS.BN13 rats after high salt diet for 2 weeks. Staur at 5-50 nM inhibited SIK1 activity in a dose-related manner. These data suggest that the SIK1 -Na + /K + -ATPase network in neurons acts as a feedback mechanism to attenuate sympatho-excitatory and pressor responses to increases in brain [Na + ]. Lower neuronal SIK1 protein expression and activity in Dahl S rats may contribute to enhanced responses to CSF Na + and thereby to their salt-induced hypertension. Data= means±SE (n=4-7). * p<0.05, vs. SS.BN13 or Wistar rats.

Chronic central infusion of aldosterone leads to sympathetic hyperreactivity and hypertension in Dahl S but not Dahl R rats

2005 ◽  
Vol 288 (2) ◽  
pp. H517-H524 ◽  
Author(s):  
Bing S. Huang ◽  
Hao Wang ◽  
Frans H. H. Leenen
Keyword(s):  
Salt Intake ◽  
Baroreflex Control ◽  
Renal Sympathetic Nerve Activity ◽  
Intracerebroventricular Infusion ◽  
Artificial Cerebrospinal Fluid ◽  
Pressor Responses ◽  
High Salt Intake ◽  
Adrenoceptor Agonists ◽  
Rat Strain ◽  
Excitatory Responses

Six-week-old Dahl salt-sensitive (S) and -resistant (R) rats received for 2 wk an intracerebroventricular infusion of aldosterone (Aldo) (22.5 ng/h) or vehicle containing artificial cerebrospinal fluid (aCSF) with 0.15 M Na+. At 8 wk, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in conscious rats at rest, in response to air stress, and to an intracerebroventricular injection of the α2-adrenoceptor agonists guanabenz or ouabain. Baroreflex control of RSNA and HR was estimated by using intravenous phenylephrine and nitroprusside. In Dahl S but not Dahl R rats, Aldo raised resting MAP by 20–25 mmHg, doubled sympathoexcitatory and pressor responses to air stress and sympathoinhibitory and depressor responses to guanabenz, and impaired baroreflex function. In Dahl S but not Dahl R rats, Aldo significantly increased content of ouabain-like compounds (OLC) in the hypothalamus and attenuated excitatory responses to ouabain. Aldo did not affect water intake, plasma electrolytes, or OLC in plasma and adrenal glands. In another set of three groups of Dahl S rats, Aldo dissolved in aCSF containing 0.16, 0.15, or 0.14 M Na+ was infused intracerebroventricularly for 2 wk. CSF Na+ concentration ([Na+]) showed only a nonsignificant increase, but resting MAP increased from 111 ± 3 mmHg in rats with Aldo in 0.14 M Na+ to 131 ± 3 and 147 ± 3 mmHg with Aldo in 0.15 and 0.16 M Na+, respectively ( P < 0.05 for both). These findings indicate that in Dahl S rats, intracerebroventricular infusion of Aldo causes similar central responses as high salt intake, i.e., increases in brain OLC content, sympathetic hyperreactivity, and hypertension. The extent of the increase in blood pressure (BP) by intracerebroventricular Aldo depends on the [Na+] in the vehicle. In Dahl R rats, intracerebroventricular Aldo did not increase brain OLC, sympathetic reactivity, and BP, suggesting that in this rat strain, a decrease in central responsiveness to mineralocorticoids may contribute to its salt-resistant nature.

Central ANG II-receptor antagonists impair cardiovascular and vasopressin response to hemorrhage in rats

1995 ◽  
Vol 268 (6) ◽  
pp. R1500-R1506 ◽  
Author(s):  
W. J. Lee ◽  
E. K. Yang ◽  
D. K. Ahn ◽  
Y. Y. Park ◽  
J. S. Park ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Physiological Role ◽  
Ang Ii ◽  
Vasopressin Release ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Artificial Cerebrospinal Fluid ◽  
Wistar Kyoto ◽  
Different Strains

The role of brain angiotensin II (ANG II) in mediating cardiovascular, vasopressin, and renin responses to hemorrhage was assessed in conscious spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) and Wistar rats. Intracerebroventricular administration of losartan (10 micrograms) and saralasin (1 microgram.microliter-1.min-1) produced a markedly greater fall in blood pressure and a reduced tachycardia during and after hemorrhage (15 ml/kg) compared with the artificial cerebrospinal fluid control in SHR and Wistar rats but not in WKY rats. Vasopressin release after hemorrhage was also impaired, but renin release was enhanced by intracerebroventricular ANG II antagonists in SHR and Wistar rats but not in WKY rats. Losartan and saralasin produced remarkably similar effects on the cardiovascular, vasopressin, and renin responses to hemorrhage. These data suggest that brain ANG II acting through AT1 receptors plays an important physiological role in mediating rapid cardiovascular regulation and vasopressin release in response to hemorrhage. The relative importance of brain angiotensin system may vary in different strains of rate.

scholarly journals Brain sodium channels and ouabainlike compounds mediate central aldosterone-induced hypertension

2003 ◽  
Vol 285 (6) ◽  
pp. H2516-H2523 ◽  
Author(s):  
Hao Wang ◽  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Sodium Channels ◽  
Sympathetic Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Intracerebroventricular Infusion ◽  
Artificial Cerebrospinal Fluid ◽  
Induced Hypertension ◽  
Salt Sensitive Hypertension ◽  
Cns Effects ◽  
The Brain ◽  
Renal Sympathetic

Central nervous system (CNS) effects of mineralocorticoids participate in the development of salt-sensitive hypertension. In the brain, mineralocorticoids activate amiloride-sensitive sodium channels, and we hypothesized that this would lead to increased release of ouabainlike compounds (OLC) and thereby sympathetic hyperactivity and hypertension. In conscious Wistar rats, intracerebroventricular infusion of aldosterone at 300 or 900 ng/h in artificial cerebrospinal fluid (aCSF) with 0.145 M Na+ for 2 h did not change baseline mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), or heart rate (HR). Intracerebroventricular infusion of aCSF containing 0.16 M Na+ (versus 0.145 M Na+ in regular aCSF) did not change MAP or RSNA, but significant increases in MAP, RSNA, and HR were observed after intracerebroventricular infusion of aldosterone at 300 ng/h for 2 h. Intracerebroventricular infusion of aCSF containing 0.3 M Na+ increased MAP, RSNA, and HR significantly more after intracerebroventricular infusion of aldosterone versus vehicle. After intracerebroventricular infusion of aldosterone, the MAP, RSNA, and HR responses to intracerebroventricular infusion of aCSF containing 0.16 M Na+ were blocked by blockade of brain OLC with intracerebroventricular infusion of Fab fragments or of brain sodium channels with intracerebroventricular benzamil. Chronic intracerebroventricular infusion of aldosterone at 25 ng/h in aCSF with 0.15 M Na+ for 2 wk increased MAP by 15–20 mmHg and increased hypothalamic OLC by 30% and pituitary OLC by 60%. Benzamil blocked all these responses to aldosterone. These findings indicate that in the brain, mineralocorticoids activate brain sodium channels, with small increases in CSF Na+ leading to increases in brain OLC, sympathetic outflow, and blood pressure.

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