The Role of Preventing Nitric Oxide Deficiency in the Antihypertensive Effect of Adaptation to Hypoxia

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. The adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5–6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate that the correction of endothelial NO deficiency plays a significant role in the antihypertensive effect of adaptation to hypoxia.     

肾脏和肾神经在应激、钠盐所致高血压中的作用

本工作采用电生理、生化、放免、电镜等方法,探讨了慢性应激和盐致高血压大鼠交感神经系统和肾脏功能的改变。实验在雄性ＳＤ大鼠上进行。结果表明：（１）高盐大鼠肾血浆流量（ＲＰＦ）和尿钠排泄明显增加,而应激大鼠ＲＰＦ显著下降。（２）电镜显示高盐大鼠近曲和远曲小管上皮细胞及线粒体变大,应激则使细胞萎缩、线粒体变小。（３）高盐大鼠肾皮质ＮａＫＡＴＰ酶活性下降,应激可使其恢复。（４）频谱分析显示应激大鼠低频波动（０２～０９Ｈｚ）明显增加。（５）应激导致大鼠肾素活性（ＰＲＡ）及血管紧张素Ⅱ（ＡＮＧⅡ）水平升高,并能使高盐大鼠低ＰＲＡ和ＡＮＧⅡ水平升高。（６）大鼠去除双侧肾神经后,应激无法造成血压升高、ＲＰＦ下降和ＰＲＡ、ＡＮＧⅡ上升。上述结果提示：肾交感神经系统兴奋性增加介导的肾脏机制,可能在应激和／或盐致高血压发病过程中具有重要作用。     

Acetylsalicylic acid provides cerebrovascular protection from oxidant damage in salt-loaded stroke-prone rats

Inflammatory processes may play a pivotal role in the pathogenesis of cerebrovascular injury in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Recent reports revealed that acetylsalicylic acid (aspirin) has anti-oxidative properties and elicits nitric oxide release by a direct activation of the endothelial NO synthase. The present study was designed to determine whether low-dose aspirin might prevent cerebrovascular injury in salt-loaded SHRSP by protecting oxidative damage. Nine-week-old SHRSP were fed a 0.4% NaCl or a 4% NaCl diet with or without treatment by naproxen (20 mg/kg/day), salicylic acid (5 mg/kg/day), or aspirin (5 mg/kg/day) for 5 weeks. Blood pressure, blood brain barrier impairment, mortality, and the parameters of cerebrovascular inflammation and damage were compared among them. High salt intake in SHRSP significantly increased blood brain barrier impairment and early mortality, which were suppressed by treatment with aspirin independent of changes in blood pressure. Salt loading significantly increased superoxide production in basilar arteries of SHRSP, which were significantly suppressed by treatment with aspirin. Salt loading also significantly decreased NOS activity in the basilar arteries of SHRSP, which were significantly improved by treatment with aspirin. At 5 weeks after salt loading, macrophage accumulation and matrix metalloproteinase-9 activity at the stroke-negative area in cerebral cortex of SHRSP were significantly reduced by treatment with aspirin. These results suggest that low-dose aspirin may exert protective effects against cerebrovascular inflammation and damage by salt loading through down-regulation of superoxide production and induction of nitric oxide synthesis.     

Choice of diet impacts the incidence of stroke-related symptoms in the spontaneously hypertensive stroke-prone rat model

The spontaneously hypertensive stroke-prone (SHRSP) rat is a commonly used model of cerebrovascular disease and hypertension. SHRSP rats have been shown to develop stroke-related symptoms (SRS) by age 14 weeks when fed a purified diet, such as AIN-93G, supplemented with 1% NaCl. We conducted a pathology pilot study to compare the incidence of SRS in SHRSP rats fed either AIN-93G (with 1% NaCl in drinking water) or commercially available rat chow (with 4% NaCl in the diet), starting at 8 weeks of age. These results prompted us to analyze data from 5 earlier feeding trials using SHRSP rats. Overall, we found that SHRSP rats fed AIN-93G purified diet for 8 or 17 weeks did not demonstrate SRS (n?= 18), whereas all SHRSP rats fed lab chow exhibited SRS at age 15.1?± 0.6 weeks (n?= 23). In addition, SHRSP rats fed lab chow had decreased mass gain starting at age 13 weeks, as well as decreased feed efficiencies after the first 5 weeks of feeding (p?< 0.05). In conclusion, our data suggest that diet composition is a major contributor to the onset of stroke in SHRSP rats and that diet choice should be critically evaluated based on endpoint measures in the SHRSP model.     

Estrogen promotes microvascular pathology in female stroke-prone spontaneously hypertensive rats

Estrogen produces both beneficial and adverse effects on cardiovascular health via mechanisms that remain unclear. Stroke-prone spontaneously hypertensive rats (SHRSP) maintained on Stroke-Prone Rodent Diet and 1% NaCl drinking water (starting at 8 wk of age) rapidly develop stroke and malignant nephrosclerosis that can be prevented, despite continued hypertension, by drugs targeting angiotensin II and aldosterone actions. This study evaluated estrogen's effects in the SHRSP model. Female SHRSP that were sham operated (SHAM), ovariectomized (OVX) at 4 wk of age, or OVX and treated with estradiol benzoate (E2,30 microg x kg-1 x wk-1) were studied. In a survival protocol, OVX rats lived significantly longer (15.1 +/- 0.3 wk) compared with SHAM (13.6 +/- 0.2 wk) or OVX+E2 rats (12.4 +/- 0.2 wk). In a protocol in which animals were matched for age, at 11.5 wk, terminal systolic blood pressure and urine protein excretion were elevated in SHAM and OVX+E2 rats compared with OVX rats; blood urea nitrogen, renal microvascular and glomerular lesions, and plasma renin concentration were elevated in OVX+E2 relative to SHAM or OVX rats. In a survival protocol using intact female SHRSP, treatment with an antiestrogen (tamoxifen, 7 mg.kg-1.wk-1) prolonged survival by >2 wk compared with controls (P < 0.01). The data indicate that estrogen promotes microangiopathy in the kidney and stroke in saline-drinking SHRSP.     

Is there a link between salt-intake and atrial natriuretic peptide system during hypertension induced by nitric oxide blockade?

Long-term nitric oxide (NO) blockade is known to induce a severe and progressive hypertension. The influence of the salt-intake on atrial natriuretic peptide (ANP) system in this hypertension model is unknown. The aim of this study was to evaluate ANP plasma levels, content and mRNA in atria of male Wistar rats chronically treated with oral Nomega-nitro-L-arginine methyl ester (L-NAME) after 4 weeks of high-salt diet. The high-salt diet induced an increase (P < 0.05) in ANP plasma levels in normotensive rats and no significant changes in hypertensive animals. We observed a significant increase in the ANP content in the left and right atria of hypertensive rats (P < 0.001) when compared to normotensive ones. However, no significant changes were observed during high-salt diet in normotensive and hypertensive animals. Northern blot analysis revealed that ANP gene expression is higher in the right and left atria of hypertensive rats when compared to normotensive rats. However, we found no significant changes in ANP mRNA of rats treated with high-salt diet in normotensive and hypertensive rats when compared to low-salt diet. The present observations indicate no interaction between salt-intake and activation of the ANP system during chronic nitric oxide synthase (NOS) inhibition.     

Prevention of hypertension and maintenance of normotension in spontaneously hypertensive rats is dependent on continuous severe dietary sodium restriction

Spontaneously hypertensive rats were placed on a very low (9 mumol/g) or control (101 mumol/g) sodium diet at birth or 4 weeks of age. These diets were continued to 16 weeks of age, or at 10 weeks were increased from 9 to 26 or 101 mumol/g. Sodium restriction initiated up to 4 weeks of age and continued to 16 weeks of age severely retarded growth, prevented the development of hypertension, and reduced effective sympathetic activity as assessed by the response of blood pressure to ganglionic blockade. Only a small increase in sodium intake at 10 weeks of age (to 26 mumol/g or more) resulted in a marked increase in growth rate, an elevation of blood pressure, and a return of the response to ganglionic blockade towards normal. These data indicate that very severe sodium restriction must be continuous to maintain decreased sympathetic activity and normal blood pressure in spontaneously hypertensive rats. It appears that severe dietary sodium restriction suppresses one or more of the mechanisms involved in normal growth and development of hypertension in spontaneously hypertensive rats, but these mechanisms may still proceed once the sodium intake is increased.     

Dietary docosahexaenoic acid ameliorates, but rapeseed oil and safflower oil accelerate renal injury in stroke-prone spontaneously hypertensive rats as compared with soybean oil, which is associated with expression for renal transforming growth factor-beta, fibronectin and renin

We have noted that n-3 fatty acid-rich oils, such as fish oil, perilla oil and flaxseed oil as well as ethyl docosahexaenoate (DHA) prolonged the survival time of stroke-prone spontaneously hypertensive rats (SHRSP) rats by approximately 10% as compared with linoleate (n-6)-rich safflower oil. Rapeseed oil with a relatively low n-6/n-3 ratio unusually shortened the survival time by approximately 40%, suggesting the presence of minor components unfavorable to SHRSP rats. This study examined the effects of dietary oils and DHA on renal injury and gene expression related to renal injury in SHRSP rats. Rats fed rapeseed oil- and safflower oil-supplemented diets developed more severe proteinuria than those fed soybean oil-supplemented diet used as a control, but there were no significant differences in blood pressure. In contrast, the DHA-supplemented diet inhibited the development of proteinuria and suppressed hypertension. The mRNA levels for renal TGF-beta, fibronectin and renin were higher in the rapeseed oil and safflower oil groups after 9 weeks of feeding of the experimental diet than in the soybean oil and DHA groups. The fatty acid composition of kidney phospholipids was markedly affected by these diets. These results indicate that the renal injury observed in the groups fed safflower oil with a high n-6/n-3 ratio and rapeseed oil with presumed minor components is accompanied by increased expression of the TGF-beta, renin and fibronectin genes, and that dietary DHA suppresses renal injury and gene expression as compared with soybean oil.     

Fenofibrate lowers blood pressure in two genetic models of hypertension

Fenofibrate, a commonly used lipid lowering drug, induces the expression of the gene coding for cytochrome P450-4A, whose major product is 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a potassium channel antagonist, could increase or decrease blood pressure (BP). We studied the effects of four weeks of oral fenofibrate on BP, urine output (UVol), plasma renin activity (PRA), and urine protein excretion in young (4-5 weeks) stroke prone spontaneously hypertensive rats (SHRSP), older (25 weeks) SHRSP, Dahl salt sensitive rats (Dahl S) on a high salt diet, Dahl S rats on a normal salt diet, and normotensive Sprague-Dawley (SD) rats. Fenofibrate prevented the increase in BP in 4-5 week old SHRSP, reduced BP in 25 week old SHRSP, but had no effect on BP in normotensive SD rats. Similarly, fenofibrate prevented the increase in BP in Dahl S rats on a high salt diet, but had no effect in Dahl S rats on a low salt diet. Fenofibrate increased UVol (and reduced weight gain) in young SHRSP and tended to increase it in other groups. It also increased PRA 2 to 5-fold in all groups except older SHRSP. Young SHRSP receiving fenofibrate excreted significantly less urine protein than control rats. The drug reduced proteinuria in Dahl S rats on high salt diet, but had no significant effect on proteinuria in other groups. In summary, fenofibrate reduced blood pressure and weight gain, increased UVol and PRA, and reduced urine protein excretion in young SHRSP. Other groups of animals showed these changes to a variable, but directionally similar extent. These findings are consistent with a natriuretic effect of fenofibrate.     

The effects of maternal mild protein restriction on stroke incidence and blood pressure in stroke-prone spontaneously hypertensive rats (SHRSP)

The effect of maternal protein restriction during pregnancy on the offspring's blood pressure was assessed in stroke-prone spontaneously hypertensive rats (SHRSP) which are genetically predisposed to hypertension and stroke. After the confirmation of pregnancy, the control group was given a 20% casein diet, and the low-protein group was fed a 9% casein diet. After the confirmation of delivery, commercial feed was given to both of the groups. No differences were seen between the control and low-protein offspring in regard to body weight, blood pressure elevation, or life span. One percent saline solution was put in the control and low-protein groups after the age of 11 weeks. Blood pressure increased markedly in the low-protein group, on the blood pressure level in the low-protein group on week 2 after salt loading (242+/-6 mmHg) was significantly higher than that in the control group (223+/-9 mmHg; p<0.05). The survival duration was significantly shorter in the low-protein group (113+/-4 days) than in the control group (135+/-22 days; p<0.05). These results suggest that maternal protein malnutrition in SHRSP exerted a high salt sensitivity and a malignant influence on stroke incidence on offspring.     

Feeding blueberry diets inhibits angiotensin II-converting enzyme (ACE) activity in spontaneously hypertensive stroke-prone rats

Feeding flavonoid-rich blueberries to spontaneously hypertensive stroke-prone rats (SHRSP) lowers blood pressure. To determine whether this is due to inhibition of angiotensin-converting enzyme (ACE) activity, as seen with other flavanoid-rich foods, we fed blueberries to SHRSP and normotensive rats and analyzed ACE activity in blood and tissues. After 2 weeks on a control diet, the hypertensive rats showed 56% higher levels of ACE activity in blood as compared with the normotensive rats (p < 0.05). Feeding a 3% blueberry diet for 2 weeks lowered ACE activity in the SHRSP (p < 0.05) but not the normotensive rats. ACE activity in plasma of SHRSP was no longer elevated at weeks 4 and 6, but blueberry feeding inhibited ACE in SHRSP after 6 weeks. Blueberry diets had no effect on ACE activity in lung, testis, kidney, or aorta. Our results suggest that dietary blueberries may be effective in managing early stages of hypertension, partially due to an inhibition of soluble ACE activity.     

Vitamin C lowers blood pressure and alters vascular responsiveness in salt-induced hypertension

The present study was undertaken to investigate the effect of vitamin C treatment on blood pressure and vascular reactivity in salt-induced hypertension. Male Sprague-Dawley rats were fed a normal rat diet, a high-sodium (8% NaCl) diet, a normal rat diet plus vitamin C treament (100 mg x kg(-1) x day(-1)), or a high-sodium diet plus vitamin C treatment for 6 weeks. Salt loading significantly increased blood pressure, which was attenuated by vitamin C treatment. Aortic rings from the different groups were suspended for isometric-tension recording. The contractile response to noradrenaline was significantly increased in the salt-loaded rats. Vitamin C reduced the sensitivity of aortic rings to noradrenaline in rats on normal and high-sodium diets. In noradrenaline-precontracted rings, the relaxation response to acetylcholine, which was attenuated in the salt-loaded rats, was restored by vitamin C treatment. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the enhanced response to acetylcholine caused by vitamin C. The results suggest that the antihypertensive effect of vitamin C is associated with a reduction in vascular sensitivity to noradrenaline and enhancement of endothelium-dependent relaxation due to increased nitric oxide bioavailability.     

Hypertension aggravates glomerular dysfunction with oxidative stress in a rat model of diabetic nephropathy

Oxidative stress may contribute to the pathogenesis of diabetic nephropathy (DN), although the detailed mechanism of reactive oxygen species (ROS) regulation is still unclear. This study examined the effect of high-salt diet on ROS production and expression of antioxidant enzymes in control and experimentally diabetic rats. Wistar fatty rats (WFR) as a type 2 diabetes mellitus model and Wistar lean rats (WLR) as a control were fed a normal-salt diet (NS) and high-salt diet (HS) from the age of 6 to 14 weeks. We then examined the blood pressure, urinary albumin excretion (UAE), and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. The expression of antioxidant enzymes including α-catalase (CAT), Cu-Zn superoxide dismutase (SOD), Mn SOD, and glutathione peroxidase (GPx) were analyzed in the glomeruli of the rats using Western blotting. The expression of NAD(P)H oxidase p47^phox and NFκB p65 was evaluated using immunohistochemical staining. By 14 weeks of age, the WFR-HS group exhibited hypertension and markedly increased UAE. The level of 8-OHdG, a marker of oxidative damage, in the WFR-HS group was also higher than that in the WLR groups or WFR-NS group. The expression of α-CAT and Mn SOD proteins was significantly decreased in isolated glomeruli in the WFR-HS group. GPx and Cu-Zn SOD expression did not differ between the WFR and WLR groups. High expression of ROS and decreases in antioxidants were seen in the glomeruli of diabetic rats with hypertension, suggesting that oxidative stress may be involved in the development of DN.     

Renal endothelin in chronic angiotensin II hypertension

To determine the influence of chronic ANG II infusion on urinary, plasma, and renal tissue levels of immunoreactive endothelin (ET), ANG II (65 ng/min) or saline vehicle was delivered via osmotic minipump in male Sprague-Dawley rats given either a high-salt diet (10% NaCl) or normal-salt diet (0.8% NaCl). High-salt diet alone caused a slight but not statistically significant increase (7 +/- 1%) in mean arterial pressure (MAP). MAP was significantly increased in ANG II-infused rats (41 +/- 10%), and the increase in MAP was significantly greater in ANG II rats given a high-salt diet (59 +/- 1%) compared with the increase observed in rats given a high-salt diet alone or ANG II infusion and normal-salt diet. After a 2-wk treatment, urinary excretion of immunoreactive ET was significantly increased by approximately 50% in ANG II-infused animals and by over 250% in rats on high-salt diet, with or without ANG II infusion. ANG II infusion combined with high-salt diet significantly increased immunoreactive ET content in the cortex and outer medulla, but this effect was not observed in other groups. In contrast, high-salt diet, with or without ANG II infusion, significantly decreased immunoreactive ET content within the inner medulla. These data indicate that chronic elevations in ANG II levels and sodium intake differentially affect ET levels within the kidney and provide further support for the hypothesis that the hypertensive effects of ANG II may be due to interaction with the renal ET system.     

Role of the renin-angiotensin-aldosterone system in the enhancement of salt sensitivity caused by prenatal protein restriction in stroke-prone spontaneously hypertensive rats

We previously demonstrated that maternal protein restriction during pregnancy enhanced salt sensitivity and shortened life span in stroke-prone spontaneously hypertensive rats (SHRSP). The present study was conducted to investigate the participation of the renin-angiotensin-aldosterone system in the development of salt sensitivity in the offspring of dams fed a low-protein diet during pregnancy. We used SHRSP offspring from dams fed a 20% casein diet (CN) or a 9% casein diet (LP) during pregnancy. The CN and LP SHRSP offspring were further subdivided into tap-water-drinking and 1%-saline-drinking groups from the postnatal 10th week. A remarkable elevation in blood pressure in response to salt loading was observed in the LP SHRSP offspring. The protein levels of CYP11B2, an enzyme for aldosterone synthesis, were markedly elevated in response to salt loading in the kidneys of LP offspring. Treatment of the LP offspring with an aldosterone receptor antagonist prevented the blood pressure from elevating and lengthened the average life span in LP offspring in response to the drinking of 1% saline. No difference in the activity of angiotensin-converting enzyme or in the protein level of the angiotensin type 1 receptor was found between the CN and LP offspring in either the tap-water-drinking or saline-drinking conditions. In conclusion, the increment of aldosterone production in response to high-salt loading may contribute to the elevated salt sensitivity of the offspring of protein-restricted dams.     

Primary dysfunction in aggregation and secretion of SHRSP platelets: not secondary to the circulation of "exhausted" platelets

The thrombin-induced secretion of [14C]-serotonin and adenine nucleotides from stroke-prone spontaneously hypertensive rats (SHRSP) platelets was markedly reduced with the development of hypertension accompanying hypo-aggregability compared with that from age-matched Wistar Kyoto rats (WKY) platelets. Calcium Ionophore A23187-induced secretion and aggregation were also attenuated in SHRSP platelets. Additionally, an enhancement of platelet secretion as well as aggregation by extracellular Ca2+ was less in SHRSP platelets than in WKY platelets. The platelet contents of adenine nucleotides and serotonin were not different between SHRSP and WKY at 5-16 weeks of age whereas they became significantly lower in SHRSP beginning at 22 weeks. The serotonin content in SHRSP platelets at 36 weeks of age was only 55% of that in WKY platelets. It is suggested that the reduced platelet aggregation and secretion observed in SHRSP platelets at ages lower than approximately 20 weeks are not secondary phenomena to the circulation of degranulated platelets, but the primary defect of SHRSP platelets appears to be an impaired function of Ca2+.     

Muscarinic cholinoceptors and choline acetyltransferase activity in the hypothalamus of spontaneously hypertensive rats

To study the role of central cholinergic mechanisms in hypertension, we have determined muscarinic receptors using [³H](-)quinuclidinyl benzilate (QNB) and choline acetyltransferase (ChAT) activity in the brain regions of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and renal hypertensive rats. The number of muscarinic receptors was significantly (33–38%) elevated in the hypothalamus of SHR and SHRSP at the ages of 16 and 24 weeks compared to that of Wistar-Kyoto rats (WKY). An increased density of muscarinic receptors was consistently observed in the prehypertensive (5 weeks) and developmental (10 weeks) stages of hypertension. In contrast, in the hypothalamus of rats with renal hypertension there was no muscarinic receptor alteration. The receptor alteration in the SHRSP hypothalamus was not abolished by a chronic hypotensive treatment which prevented the development of hypertension, suggesting that an enhancement of the muscarinic receptors in spontaneous hypertension does not occur secondarily to the elevation of blood pressure. The hypothalamus of SHR and SHRSP at the ages of 5 and 24 weeks showed significantly less activity of ChAT. These data demonstrate that there is a specific increase in muscarinic receptors and a decrease in cholinergic activity in the hypothalamus of SHR and SHRSP. Thus, the present study suggests an important role for hypothalamic cholinergic receptors in the pathogenesis of spontaneous hypertension.     

Identification of Stim1 as a Candidate Gene for Exaggerated Sympathetic Response to Stress in the Stroke-Prone Spontaneously Hypertensive Rat

The stroke-prone spontaneously hypertensive rat (SHRSP) is known to have exaggerated sympathetic nerve activity to various types of stress, which might contribute to the pathogenesis of severe hypertension and stroke observed in this strain. Previously, by using a congenic strain (called SPwch1.72) constructed between SHRSP and the normotensive Wistar-Kyoto rat (WKY), we showed that a 1.8-Mbp fragment on chromosome 1 (Chr1) of SHRSP harbored the responsible gene(s) for the exaggerated sympathetic response to stress. To further narrow down the candidate region, in this study, another congenic strain (SPwch1.71) harboring a smaller fragment on Chr1 including two functional candidate genes, Phox2a and Ship2, was generated. Sympathetic response to cold and restraint stress was compared among SHRSP, SPwch1.71, SPwch1.72 and WKY by three different methods (urinary norepinephrine excretion, blood pressure measurement by the telemetry system and the power spectral analysis on heart rate variability). The results indicated that the response in SPwch1.71 did not significantly differ from that in SHRSP, excluding Phox2a and Ship2 from the candidate genes. As the stress response in SPwch1.72 was significantly less than that in SHRSP, it was concluded that the 1.2-Mbp congenic region covered by SPwch1.72 (and not by SPwch1.71) was responsible for the sympathetic stress response. The sequence analysis of 12 potential candidate genes in this region in WKY/Izm and SHRSP/Izm identified a nonsense mutation in the stromal interaction molecule 1 (Stim1) gene of SHRSP/Izm which was shared among 4 substrains of SHRSP. A western blot analysis confirmed a truncated form of STIM1 in SHRSP/Izm. In addition, the analysis revealed that the protein level of STIM1 in the brainstem of SHRSP/Izm was significantly lower when compared with WKY/Izm. Our results suggested that Stim1 is a strong candidate gene responsible for the exaggerated sympathetic response to stress in SHRSP.     

Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats

Excessive salt intake is known to preferentially increase blood pressure (BP) and promote kidney damage in young, salt-sensitive hypertensive human and animal models. We have suggested that mineralocorticoid receptor (MR) activation plays a major role in kidney injury in young rats. BP and urinary protein were compared in young (3-wk-old) and adult (10-wk-old) uninephrectomized (UNx) Sprague-Dawley rats fed a high (8.0%)-salt diet for 4 wk. The effects of the MR blocker eplerenone on BP and renal injury were examined in the high-salt diet-fed young UNx rats. Renal expression of renin-angiotensin-aldosterone (RAA) system components and of inflammatory and oxidative stress markers was also measured. The effects of the angiotensin receptor blocker olmesartan with or without low-dose aldosterone infusion, the aldosterone synthase inhibitor FAD286, and the antioxidant tempol were also studied. Excessive salt intake induced greater hypertension and proteinuria in young rats than in adult rats. The kidneys of young salt-loaded rats showed marked histological injury, overexpression of RAA system components, and an increase in inflammatory and oxidative stress markers. These changes were markedly ameliorated by eplerenone treatment. Olmesartan also ameliorated salt-induced renal injury but failed to do so when combined with low-dose aldosterone infusion. FAD286 and tempol also markedly reduced urinary protein. UNx rats exposed to excessive salt at a young age showed severe hypertension and renal injury, likely primarily due to MR activation and secondarily due to angiotensin receptor activation, which may be mediated by inflammation and oxidative stress.     

The Diabetic Nephropathy and the Development of Hypertension in Rats

The present study was designed to examine the development of hypertension in diabetic rats treated with streptozotocin (STZ, 1mg/g bw). The rats were studied at 3, 6, 9, 12 and 15 weeks. From the third week the rats were divided in diabetic rats according their glycemias and controls, along 15 weeks. After the third week a group, of rats showed increased urinary protein excretion (93, 134, 155 and 191%) compared to controls. In this group of rats the urinary kallikrein excretion was lower than control and the systolic blood pressure became significantly elevated between 3 and 6 weeks and persisted up to 15 weeks. On the other hand a group of diabetic rats were normotensive with urinary protein excretion similar to controls and urinary kallikrein lower compared to control but significantly higher compared diabetic hypertensive rats. These data suggest that the association of progressive diabetic nephropathy with abnormal endothelium-dependent vasodilation may produce a high prevalence of hypertensive diabetes.