Salt-induced Increase In Blood Pressure Research Articles

Mechanism-based strategies to prevent salt sensitivity and salt-induced hypertension.

High-salt diets are a major cause of hypertension and cardiovascular (CV) disease. Many governments are interested in using food salt reduction programs to reduce the risk for salt-induced increases in blood pressure and CV events. It is assumed that reducing the salt concentration of processed foods will substantially reduce mean salt intake in the general population. However, contrary to expectations, reducing the sodium density of nearly all foods consumed in England by 21% had little or no effect on salt intake in the general population. This may be due to the fact that in England, as in other countries including the U.S.A., mean salt intake is already close to the lower normal physiologic limit for mean salt intake of free-living populations. Thus, mechanism-based strategies for preventing salt-induced increases in blood pressure that do not solely depend on reducing salt intake merit attention. It is now recognized that the initiation of salt-induced increases in blood pressure often involves a combination of normal increases in sodium balance, blood volume and cardiac output together with abnormal vascular resistance responses to increased salt intake. Therefore, preventing either the normal increases in sodium balance and cardiac output, or the abnormal vascular resistance responses to salt, can prevent salt-induced increases in blood pressure. Suboptimal nutrient intake is a common cause of the hemodynamic disturbances mediating salt-induced hypertension. Accordingly, efforts to identify and correct the nutrient deficiencies that promote salt sensitivity hold promise for decreasing population risk of salt-induced hypertension without requiring reductions in salt intake.

Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension.

Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.

Cardiovascular Autonomic Function in Normotensive Men with High Salt and Low Salt Intakes

Background and Aim: The autonomic nervous system may play an important role in saltinduced increases in blood pressure (BP). The aim of this study is to assess and compare the heart rate (HR) responses to Valsalva maneuver, deep breathing and standing and BP responses to standing and sustained handgrip between normotensive men with habitual high salt intake (HSI) and low salt intake (LSI). Methods: Twenty-fourty years old normotensive men (n=34; n=17 for HSI and n=17 for LSI) were recruited by collecting 4 early morning spot urine samples. Average estimated 24-hr sodium (Na+) excretion of 4 urine samples of ≥166 mmol/day was regarded as HSI and <115 mmol/day as LSI. Heart rate responses to Valsalva maneuver, deep breathing and standing (parasympathetic function tests) and BP responses to standing and sustained handgrip (sympathetic function tests) were investigated in both groups. Results: Valsalva ratio (VR) [1.64±0.36 (HSI) vs 1.78±0.49 (LSI)], deep breathing difference (DBD) [24.51±9.56 beats/min (HSI) vs 22.93±6.37 beats/min (LSI)] and 30:15 ratio [1.34 (1.12–1.46) (HSI) vs 1.19 (1.13–1.52) (LSI)] were not significantly different in both groups. Systolic blood pressure (SBP) change from lying to standing [-0.67 (-4.00–9.00) mmHg (HSI) vs 0.00 (-3.34–2.34) mmHg (LSI)] was not significantly different between the two groups whereas diastolic blood pressure (DBP) rise in sustained handgrip [18.20±3.49 mmHg (HSI) vs 14.77±4.71 mmHg (LSI)] was significantly higher in the HSI (p=0.022). Conclusion: Cardiovascular sympathetic activity appears to increase in normotensive men with habitual high salt intake.

Small Amounts of Inorganic Nitrate or Beetroot Provide Substantial Protection From Salt-Induced Increases in Blood Pressure.

To reduce the risk of salt-induced hypertension, medical authorities have emphasized dietary guidelines promoting high intakes of potassium and low intakes of salt that provide molar ratios of potassium to salt of ≥1:1. However, during the past several decades, relatively few people have changed their eating habits sufficiently to reach the recommended dietary goals for salt and potassium. Thus, new strategies that reduce the risk of salt-induced hypertension without requiring major changes in dietary habits would be of considerable medical interest. In the current studies in a widely used model of salt-induced hypertension, the Dahl salt-sensitive rat, we found that supplemental dietary sodium nitrate confers substantial protection from initiation of salt-induced hypertension when the molar ratio of added nitrate to added salt is only ≈1:170. Provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot also conferred substantial protection against salt-induced increases in blood pressure. The results suggest that on a molar basis and a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake. Given that leafy green and root vegetables contain large amounts of inorganic nitrate, these findings raise the possibility that fortification of salty food products with small amounts of a nitrate-rich vegetable concentrate may provide a simple method for reducing risk for salt-induced hypertension.

Adaptation of C57BL/6J Mice to High Dietary Salt

Our habitually high salt intake has a detrimental relationship with blood pressure (BP); the more salt consumed per day, the higher the incidences of hypertension within the population (Meneton et al., 2005). This substantial BP effect is an important modifiable risk factor for cardiovascular and renal disease, however the underlying mechanisms responsible remain controversial. Vasodysfunction is proposed as a key event, as the normal decrease in systemic vascular resistance (SVR) is attenuated in salt‐sensitive human subjects (Morris et al., 2016), suggesting impaired vasodilation. Other main theories include a salt‐induced suppression of the acute pressure natriuresis (PN) relationship, in which renal sodium (Na) excretion does not appropriately increase to offset elevated perfusion pressure and rebalance extracellular fluid volume (Hall, 2016). Thus the current study aimed to investigate BP, vasodilatory and PN responses in adult male C57BL/6J mice fed a high salt diet. In the first experiment, mice (n=6–7) had radiotelemetry devices implanted to allow the continuous recording of BP. After 1 week of a standard (0.3% Na) salt intake, mice were fed high salt (3% Na) for a further week. Systolic BP increased significantly by 10.5mmHg during high salt feeding. Next, mice were fed either a standard or high salt diet for 1 week before culling to measure plasma aldosterone and vascular reactivity via isolating mesenteric arteries and administering vasodilatory agents acetylcholine and sodium nitroprusside by wire myography. Plasma aldosterone was substantially lower in mice on the high salt diet. No evidence of intrinsic vasodysfunction was observed: sensitivity to both acetylcholine and sodium nitroprusside did not differ between dietary groups. In the third and final experiment, mice were fed a standard (n=7) or high (n=6) salt diet for 1 week and the acute PN response was measured. This generated a curve expressing the relationship between BP and urinary Na excretion. Mice were anaesthesised with Inactin (120mg/kg) and major arteries were ligated to acutely increase BP. Urine was collected via a bladder catheter. In both groups, there was a significant increase in urinary Na excretion with increasing BP. Glomerular filtration rate (GFR) and renal blood flow also increased, with no differences between cohorts observed. The PN curve was shifted to the left, with a steeper gradient in mice fed high salt compared to those on the standard diet. To conclude, this study reports a salt‐induced increase in BP in C57BL/6J mice. There is no evidence for isolated vasodysfunction, and appropriate adaptation of the renin‐angiotensin‐aldosterone system and the acute PN response was seen to salt challenge. Since BP is a product of cardiac output and SVR, which in turn is influenced by vascular tone, current studies are investigating the contribution of these haemodynamic parameters.Support or Funding InformationThis research was funded by the University of EdinburghThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mouse strains, sex, salt intake, AT1R activity and blood pressure

Male C57Bl/6J mice are salt‐sensitive while male SJL/J mice are salt‐resistant which is related to the functional state of the renal dopamine D1 receptor (D1R). Angiotensin II may be involved in the decreased renal expression of D1R of salt‐sensitive obese Zucker rats. However, the roles of the duration and amount of dietary salt intake and sex on salt sensitivity are not well known. Therefore, we studied the effect of sodium intake (<0.009, 0.6, 0.8,1.6, 4, 6, % NaCl) on the blood pressure (BP), renal dopamine and angiotensin receptors and sodium transporters in three different strains of male and female mice. We found that 4 or 6% NaCl diet given for 1 or 3 wks increased the BP of male C57Bl/6Jackson but not C57Bl/6Taconic, Balb/c, or SJL/J mice. The male C57Bl/6J mice with NaCl intake equal to or greater than 1.6% had increased BP. Similar to that reported in male C57Bl/6J mice, the BP (telemetry) of female C57Bl/6J mice was also increased by 4% NaCl diet (1 wk) which is associated with a decrease in serum renin but an increase in renal protein expression of angiotensin type 1 (AT1R). The salt‐induced increase in BP was ameliorated by angiotensin type 1 (AT1R) blockade with candesartan (1 mg/kg/day, subcutaneously administered with osmotic mini‐pumps, 1 wk) in both sexes. Except for the lower body weight of female than male mice, as expected, there were no differences in food/water intake, urinary excretions of water and electrolytes, and serum concentrations of creatinine and electrolytes, regardless of diets. In female C57Bl/6J mice on 6% NaCl diet, candesartan increased renal D1R and D5R but not D2R, D3R, or D4R protein expression while male C57Bl/6J mice had increased renal D5R protein expression, only. There was a similar decrease in renal protein expressions of sodium‐hydrogen exchanger isoform 3, sodium‐potassium‐2 chloride cotransporter, sodium‐chloride cotransporter, and α, β and γ epithelial sodium channel (ENaC) but not type 2 sodium phosphate cotransporter and α1Na+K+ATPase, in both male and female mice. We conclude that the salt sensitivity of BP of C57BL6/J mice is not sex‐related. However, the amelioration of high salt induced‐hypertension by AT1R blockade may be mediated by the differential increase in renal dopamine receptor expression and similar reduction in renal apical sodium transporters, leading to a decrease in renal sodium transport in male and female mice.Support or Funding InformationThis work was supported in part by grants from the National Institutes of Health, HL68686, HL23081, HL074940, HL092196, and DK039308. Dr. Xiaoyan Wang was supported, in part, by National Kidney Foundation of Maryland (Professional Development Award, 2014).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The American Heart Association Scientific Statement on salt sensitivity of blood pressure: Prompting consideration of alternative conceptual frameworks for the pathogenesis of salt sensitivity?

: Recently, the American Heart Association (AHA) published a scientific statement on salt sensitivity of blood pressure which emphasized a decades old conceptual framework for the pathogenesis of this common disorder. Here we examine the extent to which the conceptual framework for salt sensitivity emphasized in the AHA Statement accommodates contemporary findings and views of the broader scientific community on the pathogenesis of salt sensitivity. In addition, we highlight alternative conceptual frameworks and important contemporary theories of salt sensitivity that are little discussed in the AHA Statement. We suggest that greater consideration of conceptual frameworks and theories for salt sensitivity beyond those emphasized in the AHA Statement may help to advance understanding of the pathogenesis of salt-induced increases in blood pressure and, in consequence, may lead to improved approaches to preventing and treating this common disorder.

Orchidectomy attenuates high-salt diet-induced increases in blood pressure, renovascular resistance, and hind limb vascular dysfunction: role of testosterone.

Sex hormone-dependent vascular reactivity is an underlying factor contributing to sex differences in salt-dependent hypertension. This study evaluated the role of androgens (testosterone) in high salt-induced increase in blood pressure (BP) and altered vascular reactivity in renal blood flow and perfused hind limb preparation. Weanling male rats (8weeks old, 180-200g) were bilaterally orchidectomised or sham operated with or without testosterone replacement (Sustanon 250, 10mg/kg intramuscularly once in 3weeks) and placed on a normal (0.3%) or high (4.0%) NaCl diet for 6weeks. The high-salt diet (HSD) increased arterial BP, renal vascular resistance (RVR) and positive fluid balance (FB). These changes were accompanied by decreased plasma nitric oxide levels. The increased BP, RVR and FB observed in the rats fed a HSD were reversed by orchidectomy while testosterone replacement prevented the reversal. Phenylephrine (PE)-induced increased vascular resistance in the perfused hind limb vascular bed was enhanced by HSD, the enhanced vascular resistance was prevented by orchidectomy and testosterone replacement reversed orchidectomy effect. Vasorelaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were impaired in HSD groups, orchidectomy attenuated the impairment, while testosterone replacement prevented the orchidectomy attenuation. These data suggested that eNOS-dependent and independently-mediated pathways were equally affected by HSD in vascular function impairment and this effect is testosterone-dependent in male Sprague-Dawley rats.

Chronic Activation of Heme Free Guanylate Cyclase Leads to Renal Protection in Dahl Salt-Sensitive Rats.

The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophasphate (cGMP)-signalling pathway is impaired under oxidative stress conditions due to oxidation and subsequent loss of the prosthetic sGC heme group as observed in particular in chronic renal failure. Thus, the pool of heme free sGC is increased under pathological conditions. sGC activators such as cinaciguat selectively activate the heme free form of sGC and target the disease associated enzyme. In this study, a therapeutic effect of long-term activation of heme free sGC by the sGC activator cinaciguat was investigated in an experimental model of salt-sensitive hypertension, a condition that is associated with increased oxidative stress, heme loss from sGC and development of chronic renal failure. For that purpose Dahl/ss rats, which develop severe hypertension upon high salt intake, were fed a high salt diet (8% NaCl) containing either placebo or cinaciguat for 21 weeks. Cinaciguat markedly improved survival and ameliorated the salt-induced increase in blood pressure upon treatment with cinaciguat compared to placebo. Renal function was significantly improved in the cinaciguat group compared to the placebo group as indicated by a significantly improved glomerular filtration rate and reduced urinary protein excretion. This was due to anti-fibrotic and anti-inflammatory effects of the cinaciguat treatment. Taken together, this is the first study showing that long-term activation of heme free sGC leads to renal protection in an experimental model of hypertension and chronic kidney disease. These results underline the promising potential of cinaciguat to treat renal diseases by targeting the disease associated heme free form of sGC.

Abstract 535: Impaired Natriuresis and Increased Salt Sensitivity in Response to Acute Salt Load During Western Diet-intake: Role of Trpv1

Western diet (WD) intake increases morbidity of obesity, diabetes, and salt sensitive hypertension albeit mechanisms are largely unknown. We tested the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channels are activated during WD intake to protect against salt-induced increases in blood pressure possibly via enhancing natriuresis. Wild-type (WT, C57BL/6) or gene-targeted TRPV1-null mutant (TRPV1 -/- ) mice were fed a normal (CON) or Western (WD) diet for 16-18 weeks. Mean arterial pressure (MAP), determined by radiotelemetry after acute sodium loading (NS, 0.9% NaCl) or vehicle (C) by gavage with or without treatment with Nω-nitro-l-arginine methyl ester ( L - NAME, 10mg/kg, ip. ) or a TRPV1 agonist, N-oleoyldopamine ( OLDA, 0.1mg/kg, ip ), was not different between two strains fed a CON diet. WT or TRPV1-/- mice fed a WD diet had increased MAP after NS, with a greater magnitude in TRPV1-/- mice (p<0.05). OLDA decreased while L-NAME increased MAP in WT-WD-NS but not TRPV1-/-WD-NS mice (p<0.05). The urinary nitrates plus nitrites excretion (UNOx, umol*4h urine/kg BW), an indicator of renal nitric oxide (NO) production, was increased in both strains fed a CON diet after NS (p<0.05). OLDA further increased while L-NAME prevented NS-induced increases in UNOx in WT-CON-NS only or in both strains, respectively. TRPV1 ablation with WD intake decreased UNOx levels before NS and abolished NS-induced increment in UNOx (WT-WD-C: 0.3 ±0.06 vs. TRPV1-/-WD-C: 0.2 ±0.05; and WT-WD-NS: 0.7 ±0.1 vs. TRPV1-/-WD-NS: 0.3 ±0.1; p<0.05). OLDA further increased while L-NAME prevented NS-induced increment in UNOx in WT-WD-NS mice only (p<0.05). Urinary sodium excretion was increased in both strains fed a CON diet after NS (p<0.05), which was unaffected by OLDA or L-NAME. UNa was increased in WT-WD-NS but not TRPV1-/-WD-NS after NS. OLDA further increased while L-NAME prevented NS-induced increases in UNa in WT-WD-NS only. Thus, TRPV1 ablation increases salt sensitivity during WD intake possibly via impaired NS-induced renal NO production and sodium excretion. Activation of TRPV1 with OLDA enhances renal NO production and sodium excretion, resulting in prevention of increased salt sensitivity during WD intake.

Salt-Induced Renal Injury in Spontaneously Hypertensive Rats: Effects of Nebivolol

Background: We investigated renal effects of nebivolol, a selective β₁-receptor blocker with additional antioxidative ability, in spontaneously hypertensive rats (SHR) where increased salt intake induces oxidative stress and worsens renal function as a result of further activation of the renin-angiotensin and sympathetic nervous systems. Methods: Male SHR were given an 8% salt diet (HS; n = 22) for 5 weeks; their age-matched controls (n = 9) received standard chow. Nebivolol was given at a dose of 10 mg/kg/day for 5 weeks in 11 HS rats. Results: HS increased blood pressure, plasma renin concentration, urinary protein excretion, and renal nitroxidative stress while decreasing renal blood flow and angiotensin 1–7 receptor (mas) protein expression. There was no change in angiotensin II type 1 receptor expression among the experimental groups. Nebivolol did not alter the salt-induced increase in blood pressure but reduced urinary protein excretion, plasma renin concentration, and nitroxidative stress. Nebivolol also increased neuronal NOS expression while preventing the salt-induced decrease in renal blood flow and mas protein expression. Conclusion: Nebivolol prevented salt-induced kidney injury and associated proteinuria in SHR through a blood pressure-independent mechanism. Its protective effects may be related to reduction in oxidative stress, increases in neuronal NOS and restoration of angiotensin II type 1/mas receptor balance.

Salt Intake Augments Hypotensive Effects of Transient Receptor Potential Vanilloid 4

To test the hypothesis that activation of the transient receptor potential vanilloid 4 (TRPV4) channel conveys a hypotensive effect that is enhanced during salt load, male Wistar rats fed a normal-sodium (0.5%) or high-sodium (HS; 4%) diet for 3 weeks were given 4α-phorbol 12,13-didecanoate (4α-PDD), a specific TRPV4 activator, in the presence or absence of capsazepine, a selective TRPV1 blocker, ruthenium red, a TRPV4 blocker, or TRPV4 small hairpin RNA that selectively knockdowns TRPV4. 4α-PDD (1, 2.5, or 5 mg/kg IV) dose-dependently decreased mean arterial pressure ( P <0.05). HS enhanced 4α-PDD–induced depressor effects as well as 4α-PDD–mediated release of calcitonin gene–related peptide and substance P ( P <0.001). Ruthenium red markedly blunted ( P <0.001), whereas capsazepine slightly attenuated ( P <0.05) 4α-PDD–induced depressor effects in HS and normal-sodium diet rats. Ruthenium red alone increased baseline mean arterial pressure in both HS and normal-sodium diet rats with a greater magnitude in the former ( P <0.05). Western blot analysis showed that HS increased TRPV4 expression in dorsal root ganglia and mesenteric arteries ( P <0.05) but not the renal cortex and medulla. Gene-silencing approach revealed that TRPV4 small hairpin RNA downregulated TRPV4 expression leading to blunted 4α-PDD–induced hypotension ( P <0.05). Thus, TRPV4 activation decreases blood pressure in rats given a normal-sodium diet. HS enhances TRPV4 expression in sensory nerves/mesenteric arteries and TRPV4-mediated depressor effects and calcitonin gene–related peptide/substance P release such that HS causes a greater increase in blood pressure when TRPV4 is blocked. Our data indicate that TRPV4 activation may constitute a compensatory mechanism in preventing salt-induced increases in blood pressure.

Neural Control of Blood Pressure: Focusing on Capsaicin-Sensitive Sensory Nerves

Hypertension is a major risk factor leading to devastating cardiovascular events such as myocardial infarction, stroke, heart failure, and renal failure. Despite intensive research in this area, mechanisms underlying essential hypertension remain to be defined. Accumulating evidence indicates that neural components including both sympathetic and sensory nerves innervating the cardiovascular and renal tissues play a key role in regulating water and sodium homeostasis and blood pressure, and that abnormalities in these nervous systems contribute to increased salt sensitivity and development of hypertension. In contrast to relatively well-defined sympathetic nervous system, the role of sensory nerves in the control of cardiovascular homeostasis is largely unknown. Data from our laboratory show that degeneration of capsaicin-sensitive sensory nerves renders a rat salt sensitive in terms of blood pressure regulation. Evidence is also available indicating that sensory nerves, in interacting with other neurohormonal systems including the sympathetic nervous system, the renin-angiotensin aldosterone system, the endothelin system, and superoxide, regulate cardiovascular and renal function in such that they play a counter-balancing role in preventing salt-induced increases in blood pressure under pathophysiological conditions. Altered activity of the sensory nervous system, a condition existed in both genetic and experimental models of hypertension, contributes to the development of hypertension. This article focuses on reviewing the current knowledge regarding the possible role of sensory nerves in regulating blood pressure homeostasis as well as the function and regulation of novel molecules expressed in sensory nerves.

Endocannabinoid Regulates Blood Pressure via Activation of the Transient Receptor Potential Vanilloid Type 1 in Wistar Rats Fed a High-Salt Diet

This study was designed to examine the role of the endocannabinoids in blood pressure regulation during high sodium (HS) intake. HS (4% Na+ by weight) intake for 3 weeks increased baseline mean arterial pressure (MAP, mm Hg) compared with normal sodium (NS, 0.4% Na+ by weight)-treated male Wistar rats. Capsazepine (3 mg/kg), a selective transient receptor potential vanilloid type 1 (TRPV1) antagonist, caused a greater increase in MAP (mm Hg) in HS-treated compared with NS-treated rats (13+/-3 versus 4+/-2, p<0.05), whereas calcitonin gene-related peptide (CGRP) dose-dependently decreased MAP in both HS- and NS-treated rats with a more profound effect in the former. HS increased plasma anandamide levels analyzed by liquid chromatography/electrospray tandem mass spectrometry (NS, 2.40+/-0.31 versus HS, 4.05+/-0.47 pmol/ml, p<0.05) and plasma CGRP levels determined by radioimmunoassay (NS, 36.6+/-3.8 versus HS, 55.7+/-6.4 pg/ml, p<0.05). Methanandamide, a metabolically stable analog of anandamide, caused a greater CGRP release in mesenteric arteries isolated from HS-treated compared with NS-treated rats. Western blot showed that expression of receptor activity-modifying protein 1, a subunit of the CGRP receptor, in mesenteric arteries was greater in HS-treated compared with NS-treated rats. These results show that HS intake increases production of anandamide, which may serve as an endovanilloid to activate TRPV1, leading to release of CGRP to blunt salt-induced increases in blood pressure. These data support the notion that TRPV1 may act as a molecular target for salt-induced elevation of endovanilloid compounds to regulate blood pressure.

α2B‐Adrenergic receptor deficiency modulates DOCA‐salt hypertension

Studies suggest central nervous system (CNS) α2B-adrenoceptors (α2B-AR) regulate blood pressure (BP), renal sympathetic nervous system activity (SNSA) and salt balance. However, it is not clear whether CNS α2B-AR subtypes lower BP and SNSA or contribute to salt-induced increases in BP and SNSA. Infusing nonselective α2-AR agonists centrally attenuates DOCA-salt-induced hypertension and renal SNS (RSN) activation. RSN ablation in rats also attenuates DOCA-salt hypertension. Therefore we hypothesized that α2B-AR activate RSNA and contribute to DOCA-salt-induced increases in BP. HET and WT α2B-AR KO mice were given DOCA-salt (50 mg implant sc, 1% NaCl, 1% KCl drinking water) or high-salt treatment (1% NaCl drinking water). BP and heart rate (HR) were recorded using telemetry for 4 control and 14 DOCA-salt or high-salt days. BP was significantly increased from control on days 1 to 14 of DOCA treatment in both WT and HET mice (p=0.02). High-salt only had no effect in either group. In contrast, HR was elevated in HET compared to control days and to WT mice during DOCA treatment (p<0.05). Urinary norepinephrine (NE) decreased with DOCA treatment in WT but not HET mice (p<0.05). Thus α2B-AR appear necessary for the reflex decrease in HR and NE excretion during the development of DOCA-salt hypertension suggesting that CNS α2B-AR modulate SNSA responses to salt loading and increased BP.

A Novel Mechanism Contributing to Development of Dahl Salt–Sensitive Hypertension

To determine the role of the transient receptor potential vanilloid type 1 (TRPV1) channels in development of hypertension in Dahl salt-sensitive (DS) rats fed a high-salt diet (HS), male DS and Dahl salt-resistant (DR) rats were maintained on a low-salt diet (LS) or HS for 3 weeks. HS significantly increased systolic blood pressure in DS+HS rats compared with DS+LS, DR+HS, and DR+LS rats. Intravenous bolus injection of capsazepine (3 mg/kg), a selective TRPV1 antagonist, significantly increased mean arterial pressure in conscious DR+HS rats compared with DR+LS, DS+/-HS, and DS+/-LS rats. In contrast, capsaicin (10 or 30 microg/kg), a selective TRPV1 agonist, dose-dependently decreased mean arterial pressure in all of the groups with the most profound magnitude in DR+HS rats compared with the other 3 groups. TRPV1 expression in mesenteric resistance arteries and the renal cortex and medulla, calcitonin gene-related peptide levels in dorsal root ganglia, and calcitonin gene-related peptide-positive sensory nerve density in mesenteric resistance arteries were significantly decreased in DS+HS rats compared with DS+LS, DR+HS, and DR+LS rats. Taken together, our data indicate that the TRPV1 receptor is activated and its expression upregulated during HS intake in DR rats, which acts to prevent salt-induced increases in blood pressure. In contrast, TRPV1 expression and function are impaired in DS rats, which renders DS rats sensitive to salt load in terms of blood pressure regulation.

ETA receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation

To test the hypothesis that activation of the endothelin type A (ET(A)) receptor contributes to decreased renal excretory function and increased blood pressure in sensory nerve-degenerated rats fed a high-salt diet, neonatal Wistar rats were given vehicle or capsaicin (CAP, 50 mg/kg s.c.) on the first and second day of life. After being weaned, vehicle or CAP-treated rats were fed a normal (NS, 0.5%) or a high- (HS, 4%) sodium diet for 2 wk with or without ABT-627 (5 mg x kg(-1) x day(-1), a selective ET(A) receptor antagonist). Systolic blood pressure increased in CAP-treated rats fed a HS diet (CAP-HS) compared with vehicle-treated rats fed a HS diet (CON-HS, 145 +/- 7 vs. 89 +/- 5 mmHg, P < 0.05). Creatinine clearance and fractional sodium excretion (FE(Na)) decreased in CAP-HS rats compared with CON-HS rats (creatinine clearance, 0.54 +/- 0.05 vs. 0.81 +/- 0.09 ml x min(-1) x 100 g body wt(-1); FE(Na), 8.68 +/- 0.99 vs. 12.53 +/- 1.47%, respectively; P < 0.05). Water and sodium balance increased in CAP-HS rats compared with CON-HS (water balance, 20.2 +/- 1.5 vs. 15.5 +/- 1.9 ml/day; sodium balance, 11.9 +/- 3.1 vs. 2.4 +/- 0.3 meq/day, respectively; P < 0.05). The endothelin (ET)-1 levels in plasma and isolated glomeruli increased by about twofold in CAP-HS rats compared with CON-HS rats (P < 0.05). ABT-627 prevented the decrease in creatinine clearance and FE(Na), the increase in water and sodium balance, and the increase in blood pressure in CAP-HS rats (P < 0.05). Therefore, the blockade of the ET(A) receptor ameliorates the impairment of renal excretory function and prevents the elevation in blood pressure in salt-sensitive hypertension induced by degeneration of sensory nerves, indicating that the activation of the ET(A) receptor impairs renal function and contributes to the development of a salt-induced increase in blood pressure in this model.

High-salt-induced increase in blood pressure: role of capsaicin-sensitive sensory nerves.

To test the hypothesis that sensory afferents are significant functional components in preventing salt-induced increases in blood pressure. Neonatal Wistar rats were subcutaneously injected with 50 mg/kg capsaicin or vehicle on the first and second days of life. After weaning, male rats were divided into three groups and treated for 4 weeks with: control plus normal (0.5%, CON-NS) or high (4%, CON-HS) sodium diet, and capsaicin pretreatment plus HS diet (CAP-HS). Mean arterial pressure (MAP) and its response to bolus injection of calcitonin gene-related peptide (CGRP) and its antagonist, CGRP(8-37), were measured by carotid arterial catheterization. Radioimmunoassay was used to measure CGRP levels in plasma and dorsal root ganglia (DRG). Expression of components of the CGRP receptor, calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1), was determined by the use of Western blot analysis. Baseline MAP was increased in CAP-HS compared with CON-HS and CON-NS rats, and it was higher in CON-HS than in CON-NS rats. MAP response to exogenous CGRP was enhanced in CAP-HS and CON-HS than in CON-NS rats, but MAP response to CGRP(8-37) was increased only in CON-HS rats. Plasma CGRP levels were not different among three groups, but CGRP content in DRG was decreased in CAP-HS compared with CON-HS and CON-NS rats. CRLR expression in mesenteric resistance arteries was upregulated in CAP-HS and CON-HS compared with CON-NS rats, but RAMP1 content was not different among these groups. Chronic high-salt intake upregulates expression of mesenteric CGRP receptors without altering CGRP levels in plasma and DRG. Increased expression of mesenteric CGRP receptors may play a counter regulatory role in attenuating salt-induced increases in blood pressure.

Salt intake, endothelial dysfunction, and salt-sensitive hypertension.

Numerous epidemiologic and clinical studies have demonstrated a clear relationship between high salt intake and blood pressure. However, the mechanisms of a salt-induced increase in blood pressure--a phenomenon known as salt sensitivity--and the heterogeneity of this effect are far from being completely understood. Endothelial dysfunction, and especially the nitric oxide system, is implicated in both experimental and clinical hypertension. Animal studies indicate that endogenous nitric oxide plays an important role in renal hemodynamics and sodium homeostasis, inducing renal vasodilation and natriuresis. Studies of essential hypertensive patients have also suggested that both high salt intake and salt sensitivity are associated with impaired endothelial function. Although there are many hypotheses concerning the nature of salt sensitivity, clinical data indicate that salt-sensitive patients may be unable to up-regulate the production of nitric oxide in response to salt intake. This endothelial dysfunction, which is more frequent in salt-sensitive than in salt-resistant essential hypertensive patients, may partially explain the blood pressure increase in response to salt intake and may underlie the more pronounced target organ damage and cardiovascular risk in salt-sensitive patients.

Corticosteroid synthesis in the central nervous system.

The possibility that adrenocorticosteroids might be synthesized in the central nervous system was assessed by RT-PCR using primers for the CYP11B1 gene which codes for 11 beta-hydroxylase, the enzyme responsible for corticosterone and cortisol formation in the zona fasciculata, incubation of minces of several areas of the brain with 3H-DOC and measuring steroid metabolites, and determining the effect of the intracerebroventricular infusion of the 11 beta-hydroxylase mechanism-based inhibitor 19-ethynyldeoxycorticosterone upon the salt-induced increase in blood pressure in SS/jr rats. Significant, though small relative to the adrenal, amounts of mRNA for 11 beta-hydroxylase was found in the aorta, cerebrum, cerebellum, hippocampus, hypothalamus and amygdala, but not in the heart. Brain minces converted 3H-DOC to corticosterone and 11-dehydrocorticosterone to a greater degree than to 18-OH-DOC. The effect of 19-ethynyldeoxycorticosterone was dose dependent, with the lower doses preventing salt-induced hypertension and the higher doses having no effect or increasing the blood pressure.