Blood Pressure In Dahl Salt-sensitive Rats Research Articles

Adenosine A2A receptors in the rostral ventrolateral medulla participate in blood pressure decrease with electroacupuncture in hypertensive rats.

Acupuncture is increasingly used to manage high blood pressure (BP) as a complementary therapy. However, the mechanisms underlying its hypotensive effects remain unclear. Our previous studies have shown that electroacupuncture (EA) at the ST36-37 acupoints, overlying the deep peroneal nerve, attenuates pressor responses through adenosine A2A receptors (A2AR) in the rostral ventrolateral medulla (rVLM). However, it is uncertain whether rVLM A2AR contributes to EA's BP-lowering effect in sustained hypertension. We hypothesized that a course of EA treatment lowers BP, in part, through the activation of adenosine A2AR in the rVLM in hypertensive rats. To mimic essential hypertension in the clinic, we performed EA in conscious Dahl salt-sensitive hypertensive rats (DSHRs). EA (0.1-0.4 mA, 2 Hz) was applied at ST36-37 for 30 min twice weekly for four weeks, while sham-EA was conducted in a similar manner but without electrical input. In hypertensive rats, BP was reduced by EA (n = 14) but neither by sham-EA (n = 14) nor in the absence of needling (n = 8). Following four weeks of eight treatments and then under anesthesia, EA's modulatory effect on elevated BP was reversed by unilateral rVLM microinjection of SCH 58261 (1 mM in 50 nl; an A2AR antagonist; n = 7; P < 0.05) but not the vehicle (n = 5) in EA-treated DSHRs. Activation of rVLM A2AR in DSHRs treated with sham-EA by an A2AR agonist, CGS-21680 (0.4 mM in 50 nl; n = 8), decreased BP. Unilateral administration of SCH 58261 or CGS-21680 into the rVLM did not alter basal BP in Dahl salt-sensitive rats fed a regular diet with normal BP. The A2AR level in the rVLM after EA was increased compared to the sham-EA and untreated DSHRs (n = 5 in each group; all P < 0.05). These data suggest that a 4-week twice weekly EA treatment reduced BP in salt-sensitive hypertensive rats likely through adenosine-mediated A2AR in the rVLM.

Effects of almonds on ameliorating salt-induced hypertension in dahl salt-sensitive rats.

Excessive dietary salt intake is related to an increased risk of hypertension. Dietary functional foods probably could help to improve salt-induced hypertension. In this study, Dahl salt-sensitive (DSS) rats were used to investigate their metabolic differences from those of salt-resistant SS.13BN rats and determine whether dietary protein-rich almonds could ameliorate salt-induced elevation of blood pressure in DSS rats. After high-salt intake, the systolic blood pressure and mean arterial pressure of the DSS rats increased dramatically. Metabolomics analysis indicated abnormal amino acid metabolism in their kidneys. Their renal nitric oxide (NO) content and nitric oxide synthase activity decreased significantly after high-salt diet. Oxidative stress also occurred in DSS rats. After the DSS rats received almond supplementation, the levels of various amino acids in their kidney increased, and renal arginine and NO contents were upregulated. Their renal hydrogen peroxide and malonaldehyde levels decreased, whereas renal catalase, superoxide dismutase and glutathione peroxidase activities and glutathione levels increased. The renal abnormal amino acid metabolism of DSS rats contributed to the impaired NO production in response to high-salt intake. Together with salt-induced oxidative stress, high-salt diet intake ultimately led to an increase in the blood pressure of DSS rats. Protein-rich almond supplementation might prevent the development of salt-induced hypertension by restoring arginine and NO regeneration and alleviating salt-induced oxidative stress. © 2021 Society of Chemical Industry.

High Fructose-Induced Hypertension and Renal Damage Are Exaggerated in Dahl Salt-Sensitive Rats via Renal Renin-Angiotensin System Activation.

BackgroundHigh‐fructose diet (HFr) induces hypertension and renal damage. However, it has been unknown whether the HFr‐induced hypertension and renal damage are exaggerated in subjects with salt sensitivity. We tested impacts of HFr in Dahl salt‐sensitive (DS) and salt‐resistant (DR) rats.Methods and ResultsMale DS and DR rats were fed control diet or HFr (60% fructose) with normal‐salt content. After 12 weeks, plasma and urinary parameters, renal histological characteristics, and renal expression of renin‐angiotensin system components were examined. Furthermore, effects of renin‐angiotensin system inhibitors were also examined in DS rats fed the HFr. HFr elevated blood pressure in DS rats but not in DR rats. HFr increased urinary albumin and liver type fatty acid binding protein excretions in both rats, but the excretions were exaggerated in DS rats. HFr increased plasma lipids and uric acid in both rats, whereas HFr increased creatinine clearance in DS rats but not DR rats. Although HFr decreased plasma renin activity in DS rats, HFr‐induced glomerular injury, afferent arteriolar thickening, and renal interstitial fibrosis were exaggerated in DS rats. HFr increased renal expression of angiotensinogen, renin, (pro)renin receptor, angiotensin‐converting enzyme, and angiotensin II type 1 receptor in DS rat, whereas HFr increased only angiotensin‐converting enzyme expression and decreased renin and angiotensin II type 1 receptor expressions in DR rats. Enalapril and candesartan attenuated the HFr‐induced hypertension, albuminuria, glomerular hyperfiltration, and renal damage in DS rats.ConclusionHFr‐induced hypertension and renal damage are exaggerated in DS rats via renal renin‐angiotensin system activation, which can be controlled by renin‐angiotensin system inhibitors.

Renal sympathetic nerve activity regulates cardiovascular energy expenditure in rats fed high salt

We recently reported that a 4% high-salt diet + saline for drinking (HS + saline) leads to a catabolic state, reduced heart rate, and suppression of cardiovascular energy expenditure in mice. We suggested that HS + saline reduces heart rate via the suppression of the sympathetic nervous system to compensate for the high salt intake-induced catabolic state. To test this hypothesis, we directly measured renal sympathetic nerve activity (RSNA) in conscious Sprague-Dawley (SD) rats using a radiotelemetry system. We confirmed that HS + saline induced a catabolic state. HS + saline decreased heart rate, while also reducing RSNA in SD rats. In contrast, Dahl salt-sensitive (DSS) rats exhibited no change in heart rate and increased RSNA during high salt intake. Renal denervation significantly decreased heart rate and attenuated the catabolic state independent of blood pressure in DSS rats fed HS + saline, suggesting that salt-sensitive animals were unable to decrease cardiovascular energy consumption due to abnormal renal sympathetic nerve activation during high salt intake. These findings support the hypothesis that RSNA mediates heart rate during high salt intake in SD rats. However, the insensitivity of heart rate and enhanced RSNA observed in DSS rats may be additional critical diagnostic factors for salt-sensitive hypertension. Renal denervation may benefit salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure.

The mechanism of RNA oxidation involved in the development of heart failure

Heart failure (HF) has become a global public health problem due to its unclear pathogenesis. Our previous studies have found that RNA oxidation is associated with the occurrence and development of a variety of chronic diseases in the elderly, but whether RNA oxidation is related to the pathogenesis of HF remains unclear. Male Dahl salt-sensitive rats (DSSR) were divided into 8% NaCl groups and 0.3% NaCl groups. The blood pressure of DSSR, HE staining of cardiac tissue, cardiac function index of colour Doppler echocardiography and plasma N-terminal probrain Natriuretic Peptide (NT-ProBNP) were used to evaluate the model making. The levels of 8-hydroxyguanosine (8-oxoGsn) and 8-hydroxydeoxyguanosine (8-oxodGsn) in myocardium and urine of DSSR were determined by high-performance liquid chromatography–mass spectrometry (LC-MS/MS). The expression of ERK-MAPK pathway and MTH1 was detected by Western blot (WB). Rats in the 8% NaCl group developed heart failure symptoms such as increased blood pressure, myocardial hypertrophy, decreased diastolic function, and increased plasma NT-ProBNP. The content of 8-oxoGsn in urine and heart tissue also increased, which was positively correlated with the related indicators of heart failure. This process is also accompanied by the sequential activation of ERK-MAPK pathway molecules and the increase of MTH1. The mechanism of RNA oxidation and inhibition is related to the occurrence and development of HF, which may be involved through ERK-MAPK pathway.

Upregulation of Orexin in the Paraventricular Nucleus Contributes to Salt Sensitive Hypertension

Orexin and orexin receptors are extensively expressed in the hypothalamic paraventricular nucleus (PVN) and the hyperactivity of PVN orexin contributes to increased sympathetic nerve activity (SNA) and elevated blood pressure in several animal models. However, the role of PVN orexin in the development of salt sensitive hypertension (SSHTN) is unknown. In this study, we tested the hypothesis that PVN orexin expression is increased in SSHTN and contributes to the development of SSHTN via regulating vasopressin secretion. Eight‐week‐old Dahl salt sensitive (DS) rats were divided into two groups and were fed either a high salt (HS, 8% NaCl) or normal salt (NS, 0.4% NaCl) diet. Six weeks following diet treatment, rats were anesthetized and their mean arterial pressure (MAP) and sympathetic nerve activity (SNA) response to orexin receptor blockade were recorded. In a separate group of rats PVN orexin mRNA levels were measured. The results showed that HS intake induced significant increases in MAP (HS: 146±2 vs. NS: 112±5; n=5; P&lt;0.05) and PVN orexin mRNA levels (HS: 3.8±0.37 vs. NS: 1.0±0.68; n=3; P&lt;0.05). Bilateral PVN microinjection of orexin receptor 1 (OX1R) antagonist SB408124 (30 pmol/50nl) resulted in a greater reduction in arterial blood pressure in DS rats with a HS intake compared to their cohorts with a NS diet (HS: −16±5 vs. NS: −4±4 mmHg; n=5–6; P&lt;0.05). OX1R blockade also increased splanchnic SNA (HS: 48.2±12.6%) vs. NS: 35.82±9%; P=0.2) and renal SNA (HS: 26.7±7.5% vs. NS: 17.4±9.5%; P=0.2) in DS rats with either HS or NS diet. Incubation of orexin A resulted in a dose‐dependent increase in vasopressin mRNA levels (100nM: 2.9‐fold; 1μM; 5.6 fold; 10μM: 18‐fold) in primary cultured neurons from the hypothalamus containing the PVN of neonatal Sprague Dawley rats. These orexin A‐induced increases of vasopressin mRNA were abolished by OX1R blockade. These results coupled with the evidence that plasma vasopressin is upregulated in DS rats under the condition of HS‐induced hypertension suggest that increased PVN orexin expression may be involved in the development of SSHTN through regulating vasopressin secretion.Support or Funding InformationThis study is supported by AHA 11SDG7420029 and NIH R15‐HL122952.

Abstract P248: Changes in Dipping Pattern of Blood Pressure During the Progression of Renal Injury in Dahl Salt-sensitive Hypertensive Rats

A growing body of clinical evidence has indicated that non-dipper pattern of circadian rhythm of blood pressure (BP) is a great risk of cardiovascular disease, which is accompanied by impaired renal function and proteinuria. Here, we aimed to investigate the circadian rhythm of BP during the progression of renal injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were treated with a high salt diet (HS; 8% NaCl) for 10 weeks (n=10). Before starting a HS diet, the difference in mean arterial pressure (MAP) between dark and light period was 6.46±0.61 mmHg in normal salt (0.3% NaCl)-fed DSS rats. Treatment with a HS diet for 5 days did not change renal function, but blood pressure was increased. Furthermore, the difference in MAP between dark and light period was significantly increased (11.05±0.87 mmHg, P&lt;0.05), suggesting extreme dipping type of circadian BP. However, further HS diet feeding for 10 weeks induced the development of hypertension, renal tissue injury and proteinuria, which were associated with non-dipper pattern of BP. Namely, the MAP was similar between dark and light period (180.47±6.26 vs.177.92±6.33 mmHg). After switching to normal salt diet for 4 weeks, MAP was significantly decreased and circadian rhythm of BP was returned to normal dipper type (157.27±3.96 vs. 149.93±4.11 for MAP in dark and light period, respectively). In conclusion, the present study has demonstrated that treatment with HS diet initially showed extreme dipping pattern of BP in DSS rats, whereas it changed to non-dipping pattern of BP during the progression of renal tissue injury and proteinuria. These data support the hypothesis that non-dipping pattern of BP is associated with the progression of renal injury during the development of salt-dependent hypertension, which may contribute to the cardiovascular events.

Effect of dipeptidyl peptidase-4 inhibition on circadian blood pressure during the development of salt-dependent hypertension in rats.

A growing body of evidence has indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors have antihypertensive effects. Here, we aim to examine the effect of vildagliptin, a DPP-4-specific inhibitor, on blood pressure and its circadian-dipping pattern during the development of salt-dependent hypertension in Dahl salt-sensitive (DSS) rats. DSS rats were treated with a high-salt diet (8% NaCl) plus vehicle or vildagliptin (3 or 10 mg kg(-1) twice daily by oral gavage) for 7 days. Blood pressure was measured by the telemetry system. High-salt diet for 7 days significantly increased the mean arterial pressure (MAP), systolic blood pressure (SBP) and were also associated with an extreme dipping pattern of blood pressure in DSS rats. Treatment with vildagliptin dose-dependently decreased plasma DPP-4 activity, increased plasma glucagon-like peptide 1 (GLP-1) levels and attenuated the development of salt-induced hypertension. Furthermore, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern of blood pressure. In contrast, intracerebroventricular infusion of vildagliptin (50, 500 or 2500 μg) did not alter MAP and heart rate in DSS rats. These data suggest that salt-dependent hypertension initially develops with an extreme blood pressure dipping pattern. The DPP-4 inhibitor, vildagliptin, may elicit beneficial antihypertensive effects, including the improvement of abnormal circadian blood pressure pattern, by enhancing urinary sodium excretion.

Differential Effect of Renal Cortical and Medullary Interstitial Fluid Calcium on Blood Pressure Regulation in Salt-Sensitive Hypertension.

Hypercalciuria is a frequent characteristic of hypertension. In this report we extend our earlier studies investigating the role of renal interstitial fluid calcium (ISF(Ca))(2+) as a link between urinary calcium excretion and blood pressure in the Dahl salt-sensitive (DS) hypertensive model. Dahl salt-sensitive and salt-resistant (DR) rats were placed on control (0.45%) and high (8%) salt diets to determine if changes in renal cortical and medullary ISF(Ca)(2+)correlated with changes in urinary calcium excretion and blood pressure. We observed that renal ISFCa(2+) was predicted by urinary calcium excretion (P < 0.05) in DS rats but not DR rats. Renal cortical ISF(Ca)(2+) was negatively associated with blood pressure (P < 0.03) while renal medullary ISF(Ca)(2+) was positively associated with blood pressure in DS rats (P < 0.04). In contrast, neither urinary calcium excretion nor renal ISF(Ca)(2+) was associated with blood pressure in the DR rats under the conditions of this study. We interpret these findings to suggest that decreased renal cortical ISF(Ca)(2+) plays a role in the increase in blood pressure following a high salt diet in salt hypertension perhaps by mediating renal vasoconstriction; the role of medullary calcium remains to be fully understood. Further studies are needed to determine the mechanism of the altered renal ISF(Ca)(2+) and its role in blood pressure regulation.

Abstract 533: Effect of Dipeptidyl Peptidase-4 Inhibition on Blood Pressure and Its Dipping Pattern in Dahl Salt-Sensitive Rats

Several studies have indicated that treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors decreases blood pressure. We aimed to examine the effects of vildagliptin, a specific DPP-4 inhibitor, on blood pressure and its dipping pattern in Dahl salt-sensitive (DSS) rats. Male DSS rats were treated with a high salt (8% NaCl) diet and vehicle (0.5% carboxymethylcellulose) or vildagliptin (3 or 10 mg/kg, twice daily, p.o.) for 7 days (n = 7 per group). Mean arterial pressure (MAP) was measured by telemetry. High salt diet for 7 days significantly increased MAP with an extreme dipping pattern of blood pressure in DSS rats. Vildagliptin dose-dependently inhibited DPP-4 enzymatic activity and increased plasma GLP-1 levels. Furthermore, vildagliptin dose-dependently attenuated the development of salt-induced hypertension. Interestingly, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern. In anesthetized high salt-diet DSS rats, acute intra-cerebroventricular infusion of vildagliptin (50, 500 or 2500 μg in 10 μl solution) did not alter MAP or heart rate (n = 4). These data suggest that treatment with the DPP-4 inhibitor, vildagliptin, attenuates the extreme dipping pattern of blood pressure and development of salt sensitive hypertension by increasing urinary sodium excretion. These effects of vildagliptin may not be mediated through the central nervous system.

Female sex hormones protect against salt-sensitive hypertension but not essential hypertension.

Initial studies found that female Dahl salt-sensitive (DS) rats exhibit greater blood pressure (BP) salt sensitivity than female spontaneously hypertensive rats (SHR). On the basis of the central role played by NO in sodium excretion and BP control, we further tested the hypothesis that blunted increases in BP in female SHR will be accompanied by greater increases in renal inner medullary nitric oxide synthase (NOS) activity and expression in response to a high-salt (HS) diet compared with DS rats. Gonad-intact and ovariectomized (OVX) female SHR and DS rats were placed on normal salt (NS; 0.4% salt) or HS (4% salt) diet for 2 wk. OVX did not alter BP in SHR, and HS diet produced a modest increase in BP. OVX significantly increased BP in DS rats on NS; HS further increased BP in all DS rats, although OVX had a greater increase in BP. Renal inner medullary NOS activity, total NOS3 protein, and NOS3 phosphorylated on serine residue 1177 were not altered by salt or OVX in either strain. NOS1 protein expression, however, significantly increased with HS only in SHR, and this corresponded to an increase in urinary nitrate/nitrite excretion. SHR also exhibit greater NOS1 and NOS3 protein expression than DS rats. These data indicate that female sex hormones offer protection against HS-mediated elevations in BP in DS rats but not SHR. We propose that the relative resistance to HS-mediated increases in BP in SHR is related to greater NOS expression and the ability to increase NOS1 protein expression compared with DS rats.

Effects of Angiotensin II AT1–Receptor Blockade on High Fat Diet–Induced Vascular Oxidative Stress and Endothelial Dysfunction in Dahl Salt-Sensitive Rats

We examined the effects of angiotensin II AT1–receptor blockade with olmesartan on high fat (HF) diet–induced vascular oxidative stress and endothelial dysfunction in normal salt (NS) diet–fed Dahl salt-sensitive (DSS) rats. Treatment with NS + HF diet (32% crude fat, 0.3% NaCl) for 20 weeks significantly increased blood pressure in DSS rats. NS + HF diet–fed DSS rats also showed higher plasma levels of thiobarbituric acid–reactive substances, aortic superoxide production, and mRNA levels of p22phox and gp91phox in aortic tissues than NS diet–fed DSS rats. Furthermore, acetylcholine-induced vasorelaxation of aorta from NS + HF diet–fed DSS rats was significantly reduced. In NS + HF diet–fed DSS rats, treatment with olmesartan medoxomil (10 mg/kg per day, p.o.) and hydralazine (25 mg/kg per day, p.o.) similarly decreased blood pressure. However, in these animals, only olmesartan normalized plasma levels of thiobarbituric acid–reactive substances, vascular superoxide in aortic tissues, and acetylcholine-induced vasorelaxation. These data indicate that HF diet–induced hypertension is associated with vascular oxidative stress and endothelial dysfunction in NS diet–treated DSS rats. Inhibition of angiotensin II AT1 receptors may elicit beneficial effects on HF-induced hypertension and vascular injury in subjects that have genetically enhanced sodium-sensitive blood pressure.

Natriuretic response to renal medullary endothelin B receptor activation is impaired in Dahl‐salt sensitive rats on a high‐caloric diet

Renal medullary endothelin B receptors (ETB) mediate sodium excretion and blood pressure (BP) control. Several animal models of hypertension including the Dahl salt sensitive (DS) rat on a high salt diet have impaired renal medullary endothelin system. Our lab has recently reported that the DS rat becomes hypertensive on a normal salt, high‐caloric diet. Thus we hypothesized that renal medullary ETB function is dysfunctional in DS rats fed a high‐caloric diet. The diuretic and natriuretic response to intramedullary infusion of ETB agonist sarafotoxin 6c (S6c) was determined in DS rats fed either a normal (14% fat; 3.93 kcal/g) or high‐caloric diet (59% fat; 5.45 kcal/g) for 4 weeks. We found that 4‐week high‐caloric diet elevated systolic BP in DS rats (126±2 vs. 143±3 mmHg, p&lt;0.05). In DS rats fed a regular diet, intramedullary infusion of S6c (0.45 μg/kg/hr) increased urine flow (3.6±0.5 μl/min during baseline vs. 7.0±0.5 μl/min after S6c; p&lt;0.05) and sodium excretion (0.42±0.09 vs. 0.97±0.08 μmol/min; p&lt;0.05). However, DS rats fed a high‐caloric diet did not display an increase in urine flow (2.8±0.3 vs. 4.3±0.5 μl/min) or sodium excretion (0.35±0.07 vs. 0.48±0.12 μmol/min) upon S6c infusion. These data demonstrate that renal medullary ETB function is impaired in DS rats fed a high‐caloric diet, which may contribute to the elevation of blood pressure during high‐caloric feeding in this model.

Relaxin ameliorates salt-sensitive hypertension and renal fibrosis

Although relaxin (RLX) has potent vasodilatory and anti-fibrotic properties, there is no information on its effects on salt-sensitive hypertension. We investigated the effects of short-term treatment with RLX on blood pressure (BP) and nitric oxide synthase (NOS) protein in the kidneys of male Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats after 1 week consumption of an 8% NaCl diet. We also evaluated the inhibitory effects of each specific NOS inhibitor on BP during 1-week RLX treatment under high-salt diet. Next, we examined the long-term effects of RLX treatment for 6 weeks on renal histology and transforming growth factor-beta1 (TGF-β1) expression in male DS and DR rats placed on the 8-week high-salt diet. The short-term RLX treatment significantly attenuated the high-salt diet-induced rise in BP in DS rats with increasing neuronal NOS and endothelial NOS protein in kidneys. Selective inhibition of each of the three NOS isoforms significantly blocked the anti-hypertensive effects of RLX in DS rats after 1-week high-salt diet. The long-term treatment of DS rats with RLX for 6 weeks significantly reduced systolic BP, lessened glomerular and tubulointerstitial changes and reduced TGF-β signaling compared to saline-treated controls. The results suggested that RLX converted salt sensitivity to salt resistance, at least in part, by up-regulating NOS. RLX is a potentially useful therapeutic agent for salt-sensitive hypertension.

Rosiglitazone Decreases Blood Pressure in Female Dahl Rats: Role of Nitric Oxide and Oxidative Stress

In women the prevalence of hypertension (HT) and salt‐sensitivity of blood pressure (BP) increases after menopause (PM). The peroxisome proliferator activator receptor gamma agonist, rosiglitazone (RO), reduces BP in humans and animals, including male Dahl salt‐sensitive rats (DS). We tested the hypothesis that RO decreases BP in intact (Int) and ovariectomized (Ovx) female DS by increasing nitric oxide (NO) and decreasing oxidative stress (OS). Int and Ovx DS (10 weeks; n=15/group) received low salt diet (LS: 0.3% NaCl) or LS+RO (100mg/kg diet) for 1 week and then challenged for 1 week to high salt (HS: 8% NaCl) or HS+RO. Urinary Nitrate/nitrite (N/N) and F2‐isoprostanes (F2Ip) were assessed on HS. On LS, telemetric BP was similar in Int and Ovx, and RO decreased BP to similar levels. On HS, BP increased to higher levels in Ovx than Int and RO decreased BP to similar levels in Int and Ovx. RO increased N/N only in Ovx. F2Ip were lower in Ovx than Int and not affected by RO. Our data suggest that in Ovx on HS, RO protects against the greater increase in BP, possibly by increasing NO bioavailability, and that OS plays no role in salt‐sensitivity of BP in female DS. RO may be a new therapeutic approach for treating HT in PM women (supported by NIH HL 66072, AHA 0725561B)

Assessment of Mitochondrial DNA Polymorphisms in Salt-Sensitive Hypertension in Dahl Salt-Sensitive Rats

The Dahl salt-sensitive (DS) rat is the most prevalently used animal model of salt-sensitive hypertension. The purpose of the present study was to test the hypothesis that mitochondrial DNA (mtDNA) polymorphisms influence blood pressure in DS rats. We produced two strains of female F1 rats, one from female DS and male Lewis rats (DL) and the other from Lewis female and DS male rats (LD). These two strains had the same autosomal genetic background, but their mitochondria had different origins. The DL and LD rats had DS and Lewis mitochondria, respectively. A high-salt diet was started at 4 weeks of age. Radiotelemetry devices were implanted into the lower abdominal aorta of these F1 rats at 9 weeks of age. Blood pressure was monitored for 24 h at 11, 12, 13, 14, and 19 weeks of age. No significant differences were observed in blood pressure levels between the strains. Although more than 100 polymorphisms were detected between DS and Lewis rats, it is unlikely that polymorphisms in mtDNA contribute to hypertension in DS rats. Moreover, we found no difference between DS and Lewis rats in the mtDNA copy number in the kidneys, the liver, and the ventricles of the heart before and after salt loading. Thus, it is unlikely that mitochondrial dysfunction due to high blood pressure exacerbated target organ damage. Intriguingly, the time course of body weight gain differed significantly between DL and LD F1 rats, suggesting the influence of mitochondrial polymorphisms on body composition.

Challenged sodium balance and expression of angiotensin type 1A receptor mRNA in the hypothalamus of Wistar and Dahl rat strains

The present study investigates the influence of a chronic high Na + diet (8% Na +) on the expression of the angiotensin type 1A (AT 1A) receptor gene in the lamina terminalis and paraventricular nucleus of the hypothalamus (PVH) in normotensive Wistar (W) rats, as well as in Dahl salt-resistant (DR) and Dahl salt-sensitive (DS) rats. Three weeks of 8% Na + diet led to a higher blood pressure in DS rats compared to DR and W rats. Moreover, the high Na + diet was correlated with a decreased expression of AT 1A receptor mRNA in the median preoptic nucleus (MnPO) and in the PVH of DS rats, compared to DR and W rats. Contrastingly, the AT 1A receptor mRNA expression was not altered by the high Na + diet in the forebrain circumventricular organs of all the rat strains. Interestingly, a furosemide-induced Na + depletion was correlated with an increased expression of AT 1A receptor mRNA in the PVH, MnPO and SFO of both the DS and DR rats. It is concluded that chronic high Na + diet did differently regulate the expression of AT 1A receptor mRNA in two hypothalamic integrative centers for hydromineral and cardiovascular balance (the PVH and MnPO) in DS rats, compared to DR and W rats. However, the AT 1A receptor mRNA expression was similarly regulated in DS and DR rats in response to an acute Na + depletion, suggesting a distinct high Na +-induced regulation of the AT 1A receptor gene in the PVH and MnPO of DS rats.

PPARα agonist protects against salt‐mediated increases in endogenous carbon monoxide production and blood pressure in Dahl salt‐sensitive rats

Heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme-derived CO inhibits nitric oxide synthase and promotes hypertension in Dahl salt-sensitive rats (DS). Peroxisome proliferator-activated receptor α (PPARα) agonists confer cardiovascular protection during hypertension and lower blood pressure in DS. The current study tests the hypothesis that the PPARα agonist fenofibrate prevents the high salt (HS)-diet induced increase in endogenous CO production and blood pressure in DS. Male DS were placed on low (0.3% NaCl, LS) or HS (8% NaCl) diets and some received 90mg/kg/day fenofibrate in the drinking water. Respiratory CO excretion and blood pressure were measured weekly via solid-phase gas chromatography and tail-cuff plethysmography. CO excretion (HS: Δ +0.57±0.07 μmol/hr per kg) and systolic blood pressure (HS: 132±4 to 251±5 mmHg) increased markedly in HS rats. Fenofibrate treatment attenuated the HS diet induced increase in CO excretion (Δ+0.07±0.01 μmol/hr per kg) and blood pressure (145±4 to 172±8 mmHg). These data show that a PPARα agonist protects from HS diet-induced increases in CO production and blood pressure in DS. These results suggest that PPARα agonists might exert their blood pressure lowering effect by “normalizing” endogenous CO production in DS. Supported by NIH/NCRR grant P20 RR017659 (FKJ), NIH/NHLBI RO1 grants HL76187 (RAJ), HL59976 (WD) and HL74966 (WD).

Dietary lipoic acid supplementation attenuates hypertension in Dahl salt sensitive rats

There is strong evidence that excess dietary salt (NaCl) is a major factor contributing to the development of hypertension. Salt sensitive humans and rats develop hypertension even on a normal salt diet. Salt sensitivity is associated with glucose intolerance and insulin resistance in both humans and animal models, including Dahl salt sensitive (DSS) rats. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes. These aldehydes bind sulfhydryl groups of membrane proteins, altering calcium channels, increasing cytosolic free calcium ([Ca2+]i) and blood pressure. Treatment with lipoic acid, an endogenous sulfur-containing fatty acid, normalizes insulin resistance and lowers tissue aldehyde conjugates, cytosolic [Ca2+]i, and blood pressure in spontaneously hypertensive rats (SHR). The objective of this study was to investigate the effects of a normal salt diet on tissue aldehyde conjugates, cytosolic [Ca2+]i and blood pressure in DSS rats and to determine whether lipoic acid supplementation prevents the increase in blood pressure and biochemical changes. Starting at 7 weeks of age, DSS rats were divided into three groups of six animals each and treated for 6 weeks with diets as follows: DSS-low salt, 0.4% NaCl; DSS-normal salt, 0.7% NaCl, and; DSS-normal salt + lipoic acid, 0.7% NaCl + lipoic acid 500 mg/kg feed. At completion, animals in the normal salt group had elevated systolic blood pressure, cytosolic [Ca2+]i and tissue aldehyde conjugates as compared to the low salt group. They also showed smooth muscle cell hyperplasia in small arteries and arterioles of the kidney. Dietary lipoic acid supplementation attenuated the increase in systolic blood pressure and associated biochemical and histopathological changes.

Dietary Vitamin E Supplementation Attenuates Hypertension in Dahl Salt-Sensitive Rats

There is strong evidence that excess dietary salt (NaCl) is a major factor contributing to the development of hypertension. Salt-sensitive humans and rats develop hypertension even on a normal-salt diet. Salt sensitivity is associated with glucose intolerance and insulin resistance in both humans and animal models, including Dahl salt-sensitive (DSS) rats. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes that bind sulfhydryl groups of membrane proteins, altering calcium channels, and increasing cytosolic free calcium ([Ca2+]i) and blood pressure. Vitamin E lowers tissue aldehyde conjugates, cytosolic [Ca2+]i, and blood pressure in spontaneously hypertensive rats and fructose-induced hypertensive Wistar Kyoto rats, models of insulin resistance. This study investigated the effect of a normal-salt diet on tissue aldehyde conjugates, cytosolic [Ca2+]i, and blood pressure in DSS rats and the effect of vitamin E supplementation on blood pressure and associated biochemical changes in these animals. Seven-week-old DSS rats were divided into 3 groups of 6 animals each and treated for 6 weeks with diets as follows: low-salt (0.4% NaCl); normal-salt (0.7% NaCl) and normal salt (0.7% NaCl) plus vitamin E (34 mg/kg feed). At completion, animals in the normal-salt group had significantly elevated systolic blood pressure, cytosolic [Ca2+]i, and tissue aldehyde conjugates compared with the low-salt group. They also showed smooth muscle cell hyperplasia in small arteries and arterioles of the kidney. Dietary vitamin E supplementation significantly attenuated the increase in systolic blood pressure and associated biochemical and histopathologic changes.