Dietary sodium restriction and the development of two-kidney, one-clip hypertension in young versus adult rats.

To determine the effects of moderate versus severe dietary sodium restriction on the development of 2-kidney, 1-clip (2K,1C) hypertension, young male Wistar rats were placed on diets containing 9, 26, or 101 (control) mumol sodium/g food. Three days later, a solid silver clip (i.d. 0.20 mm) was placed on the left renal artery and diets were continued up to 6 weeks. Adult rats received a 0.25-mm clip. In young clipped rats receiving the 101 mumol/g diet, blood pressure (BP), plasma renin activity (PRA), and BP response to captopril were increased as early as 1 week after clipping and increased further over time. Moderate sodium restriction (26 mumol sodium/g) led to only a slight delay in the development of hypertension; the levels of BP and PRA, the BP response to captopril, and the extent of cardiac hypertrophy achieved by 6 weeks were not different between the 2K, 1C rats receiving 26 or 101 mumol sodium/g. Sodium restriction to 9 mumol/g decreased rate of growth and completely prevented the rise in BP and in left ventricular weight. At 3 and 6 weeks the severely sodium-restricted rats had significantly higher PRA levels than the 2K, 1C control group. However, the BP response to captopril was attenuated relative to the other hypertensive groups. In adult rats, this level of sodium restriction had a small, but significant effect on body weight, but still prevented the increase in BP and in left ventricular weight. In conclusion, dietary sodium restriction can prevent the development of 2K,1C hypertension in both young and adult rats, but only if the restriction is severe. This effect may relate to a marked reduction in the pressor effectiveness of the renin-angiotensin system by low sodium intake per se or by associated metabolic or other changes.     

Sodium homeostasis in transplanted rats with a spontaneously hypertensive rat kidney

Recipients of a kidney from spontaneously hypertensive rats (SHR) but not from normotensive Wistar-Kyoto rats (WKY) develop posttransplantation hypertension. To investigate whether renal sodium retention precedes the development of posttransplantation hypertension in recipients of an SHR kidney on a standard sodium diet (0.6% NaCl), we transplanted SHR and WKY kidneys to SHR x WKY F1 hybrids, measured daily sodium balances during the first 12 days after removal of both native kidneys, and recorded mean arterial pressure (MAP) after 8 wk. Recipients of an SHR kidney (n = 12) retained more sodium than recipients of a WKY kidney (n = 12) (7.3 +/- 10 vs. 4.0 +/- 0.7 mmol, P < 0.05). MAP was 144 +/- 6 mmHg in recipients of an SHR kidney and 106 +/- 5 mmHg in recipients of a WKY kidney (P < 0.01). Modest sodium restriction (0.2% NaCl) in a further group of recipients of an SHR kidney (n = 10) did not prevent posttransplantation hypertension (MAP, 142 +/- 4 mmHg). Urinary endothelin and urodilatin excretion rates were similar in recipients of an SHR and a WKY kidney. Transient excess sodium retention after renal transplantation may contribute to posttransplantation hypertension in recipients of an SHR kidney.     

Sexual Dimorphism in Urinary Angiotensinogen Excretion During Chronic Angiotensin II−Salt Hypertension

BackgroundThe intrarenal renin−angiotensin system contributes to hypertension by regulating sodium and water reabsorption throughout the nephron. Sex differences in the intrarenal components of the renin−angiotensin system have been involved in the greater incidence of high blood pressure and progression to kidney damage in males than females.ObjectiveThis study investigated whether there is a sex difference in the intrarenal gene expression and urinary excretion of angiotensinogen (AGT) during angiotensin II (Ang II)−dependent hypertension and high-salt (HS) diet.MethodsMale and female Sprague-Dawley rats were divided into 5 groups for each sex: Normal-salt control, HS diet (8% NaCl), Ang II−infused (80 ng/min), Ang II−infused plus HS diet, and Ang II−infused plus HS diet and treatment with the Ang II receptor blocker, candesartan (25 mg/L in the drinking water). Rats were evaluated for systolic blood pressure (SBP), kidney AGT mRNA expression, urinary AGT excretion, and proteinuria at different time points during a 14-day protocol.ResultsBoth male and female rats exhibited similar increases in urinary AGT, with increases in SBP during chronic Ang II infusion. HS diet greatly exacerbated the urinary AGT excretion in Ang II−infused rats; males had a 9-fold increase over Ang II alone and females had a 2.5-fold increase. Male rats displayed salt-sensitive SBP increases during Ang II infusion and HS diet, and female rats did not. In the kidney cortex, males displayed greater AGT gene expression than females during all treatments. During Ang II infusion, both sexes exhibited increases in AGT gene message compared with same-sex controls. In addition, HS diet combined with Ang II infusion exacerbated the proteinuria in both sexes. Concomitant Ang II receptor blocker treatment during Ang II infusion and HS diet decreased SBP and urinary AGT similarly in both sexes; however, the decrease in proteinuria was greater in the females.ConclusionDuring Ang II−dependent hypertension and HS diet, higher intrarenal renin-angiotensin system activation in males, as reflected by higher AGT gene expression and urinary excretion, indicates a mechanism for greater progression of high blood pressure and might explain the sex disparity in development of salt-sensitive hypertension.     

Role of the renin-angiotensin system in the adaptation to high salt intake in immature rats

The response of the renin-angiotensin system, extracellular fluid volume, plasma volume, plasma sodium and mean arterial blood pressure to an increase in salt intake (8% NaCl in the diet for 10 days) was compared in immature (20 days) and adult (80 days) rats which were either sham-operated or uninephrectomised. Salt feeding induced a significant increase in plasma sodium in immature animals, and a greater suppression of the renin-angiotensin system in immature than in adult rats, although extracellular fluid volume, plasma volume and blood pressure remained unchanged. Following uninephrectomy, however, the renin-angiotensin system was maximally suppressed in both age groups and in younger animals extracellular fluid volume, plasma volume and blood pressure were significantly increased. It is concluded that (i) the renin-angiotensin system in immature rats is more responsive to a chronically increased salt intake, (ii) this greater responsiveness partly compensates for the lower natriuretic efficiency of the kidneys of immature rats, which becomes evident after reduction of renal mass, and (iii) these events bear a relation to the higher susceptibility of prepubertal rats to the hypertensive effect of a chronically increased salt intake.     

Renal effects of administered atrial natriuretic peptide in the conscious, aging rat

Studies were performed in conscious, chronically catheterized male Sprague-Dawley rats to investigate the effect of administered atrial natriuretic peptide (ANP) on blood pressure, renal hemodynamics and urinary electrolyte excretion. Studies were performed on young adult (3-4 month old) rats and on aging rats (18-24 months of age). Low dose ANP (80 ng/kg/min for 60 min) had no effects on renal hemodynamics in either young or old rats and produced only a slight blood pressure reduction in young animals. No effect on urinary electrolyte excretion was evident in young rats whereas in the old animals, low dose ANP produced large rises in the rate of sodium excretion, fractional excretion of sodium and urine flow rate. A four fold higher dose of ANP evoked a moderate natriuretic and a marked antihypertensive response in young rats. Time control studies indicated that time alone had no influence on urinary sodium excretion rate, the fractional excretion of sodium or urine flow rate. These studies indicate a much enhanced sensitivity to the natriuretic effects of administered ANP by the kidneys of old rats.     

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.     

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.     

正常大鼠植入高血压大鼠肾脏后动脉血压的变化

本实验对12周龄的自发性高血压大鼠(spontaneouslyhypertensiverat,SHR)及其对照组WistarKyoto(WKY)大鼠进行了肾脏移植的研究,并观察受肾移植大鼠动脉血压的变化以及免疫抑制剂对动脉血压的影响。用尾套法对接受同窝另一同胞WKY大鼠肾脏移植且存活5周的6只WKY大鼠(A组)及接受SHR肾脏移植且存活5周的6只WKY大鼠(B组)的尾动脉收缩压进行检测,移植前A、B两组受肾移植大鼠的尾动脉收缩压分别为180±093和183±068kPa,无统计学显著差异(P>005);移植后3、4、5周时,B组大鼠的尾动脉收缩压显著高于A组大鼠,移植后5周时,A,B两组大鼠的收缩压分别为190±071和230±069kPa(P<0001);所用剂量的免疫抑制剂CsA对双侧肾脏完整以及右侧肾脏切除的SHR、WKY大鼠的动脉血压无显著影响。以上结果表明,SHR的肾脏在高血压的形成中可能起重要作用     

正常大鼠植入高血压大鼠肾脏后 动脉血压的变化

本实验对12周龄的自发性高血压大鼠(spontaneously hypertensive rat,SHR)及其对照组Wistar Kyoto (WKY)大鼠进行了肾脏移植的研究, 并观察受肾移植大鼠动脉血压的变化以及免疫抑制剂对动脉血压的影响。 用尾套法对接受同窝另一同胞WKY大鼠肾脏移植且存活5周的6只WKY大鼠(A组)及接受SHR肾脏移植且存活5周的6只WKY大鼠(B组)的尾动脉收缩压进行检测, 移植前A、 B两组受肾移植大鼠的尾动脉收缩压分别为18.0±0.93 和18.3±0.68 kPa,无统计学显著差异(P>0.05); 移植后3、 4、 5周时, B组大鼠的尾动脉收缩压显著高于A组大鼠, 移植后5周时, A, B两组大鼠的收缩压分别为19.0±0.71 和23.0±0.69 kPa (P<0.001); 所用剂量的免疫抑制剂CsA对双侧肾脏完整以及右侧肾脏切除的SHR、 WKY大鼠的动脉血压无显著影响。 以上结果表明, SHR的肾脏在高血压的形成中可能起重要作用。     

Characteristics of the development of interphase death of hematopoietic tissue in dogs in response to gamma irradiation

In experiments with 2-3 week dogs it was shown that whole-body gamma-irradiation with a dose of 3 Gy causes an insignificant absolute rise in the amount of degrading chromatin of the haemopoietic organs during the first 24 h following irradiation. After 48 h, this cell death parameter is normalized. A considerably lower radiosensitivity of lymphoid cells of dogs compared to small laboratory animals is indicated by a stable DNA content per 1 g of thymus, intactness of its structure after irradiation, and the absence of an increase in thymidine content of blood of young and adult dogs under the effect of 3-3.7 Gy radiation.     

Transient Exposure of Enalapril Normalizes Prenatal Programming of Hypertension and Urinary Angiotensinogen Excretion

Maternal low protein diet programs offspring to develop hypertension as adults. Transient exposure to angiotensin converting enzyme inhibitors or angiotensin II receptor blockers can result in improvement in hypertension. Male rats whose mothers received a low protein diet during the last half of pregnancy were given either vehicle, continuous enalapril (CE) in their drinking water or were given transient enalapril exposure (TE) after weaning at 21 days of age. The TE group had enalapril in their drinking water for 21 days starting from day 21 of life. All rats were studied at 6 months of age. Vehicle treated rats whose mothers were fed a low protein diet were hypertensive, had albuminuria, and demonstrated upregulation of the intrarenal renin-angiotensin system as evidenced by higher urinary angiotensinogen and urinary angiotensin II levels. In low protein rats both continuous and transient exposure to enalapril normalized blood pressure, urinary angiotensinogen and urinary angiotensin II levels at 6 months of age, but only continuous administration of enalapril decreased urinary albumin excretion. These data support the importance of the intrarenal renin-angiotensin system in mediating hypertension in programmed rats and transient exposure to enalapril can reprogram the hypertension and dysregulation of the intrarenal renin-angiotensin system.     

实验性X综合征大鼠模型的建立

目的　建立一种典型的X综合症动物模型。方法　雄性SD大鼠施行两肾一夹术后普通饲料喂养 4周 ,诱发肾性高血压 ,继以高果糖饲料喂养 4周 ,诱导建立X综合症模型。结果　术后 4周 ,大鼠仅出现收缩压升高 ,血糖、血脂未见明显改变。高果糖饲料喂养 4周后 ,大鼠出现高血糖、高胰岛素血症、胰岛素抵抗、高血压和高脂血症。结论　肾性高血压形成后高果糖饮食 1个月 ,可诱导SD大鼠出现典型的X综合症 ,为研究胰岛素抵抗及其伴随的心血管疾病提供了一种理想的动物模型。     

Radiation-induced renal damage: the effects of hyperfractionation

The response of mouse kidneys to multifraction irradiation was assessed using three nondestructive functional end points. A series of schedules was investigated giving 1, 2, 4, 8, 16, 32, or 64 equal X-ray doses, using doses per fraction in the range of 0.9 to 16 Gy. The overall treatment time was kept constant at 3 weeks. Kidney function was assessed from 19 to 48 weeks after irradiation by measuring changes in isotope clearance, urine output, and hematocrit. The degree of anemia (assessed from the hematocrit measurements) is a newly developed assay which is an early indicator of the extent of renal damage after irradiation. All three assays yielded steep dose-effect curves from which the repair capacity of kidney could be estimated by comparing the isoeffective doses in different schedules. There was a marked influence of fractionation, with increasing dose being required to achieve the same level of damage for increasing fraction number, even between 32 and 64 fractions. The data are well fitted by a linear quadratic dose-response equation, and analysis of the data in this way yields low values (approximately 3.0 Gy) for the ratio alpha/beta. This would suggest that hyperfractionation , using extremely small X-ray doses per fraction, would spare kidneys relative to tumors and acutely responding tissues.     

不同剂量的X-射线全身照射对小鼠健康状况及涎腺的影响

目的:通过直线加速器全身照射昆明小鼠建立辐射损伤模型,探索不同放射剂量对小鼠健康状况及涎腺功能和结构的影响。方法:选取八种不同剂量对昆明小鼠行体外全身照射,于照射后一个月内观察小鼠生长情况、体重变化;照射后一周、一个月检测各组小鼠血象的变化;测定放射半数致死剂量;照射后两个月,测定各组小鼠的唾液流量及唾液淀粉酶含量,并对下颌下腺组织切片行HE染色。结果:13Gy和15Gy照射组小鼠的体重逐渐下降,一周后死亡,其余组小鼠体重最终呈增加趋势。X-射线全身照射的半数致死量为10Gy。照射后一周,照射组小鼠的白细胞数目明显降低,与对照组比较有明显统计学差异(P0.01);在其他血象方面,除了7Gy组外,其他照射组与对照组比较也均有统计学差异(P0.05)。照射一个月后,各照射组小鼠的血象均恢复正常。照射后两个月,9Gy组和11Gy组小鼠的唾液流量及唾液淀粉酶含量均显著低于0Gy组,且11Gy组较9Gy组亦明显降低,差异均有统计学意义(P0.05)。随照射剂量的增加,小鼠的下颌下腺腺泡细胞数目逐步减少,结构排列紊乱,组织损伤逐渐加重。结论:X-射线全身照射引起小鼠健康状况受损,免疫功能减低,损伤程度与放射线强度呈剂量依赖性,小鼠半数致死量为10Gy,该剂量适合建立全身放射损伤模型。     

Role of the renal nerve in glucocorticoid hypertension

The present study was designed to investigate the involvement of the renal nerve in glucocorticoid hypertension and to assess the role of the renin-angiotensin system in dexamethasone-induced hypertension. The elevated blood pressure in dexamethasone treated rats showing a significant increase in plasma renin concentration (PRC) and activity (PRA) was attenuated dose-dependently by the angiotensin I converting enzyme (ACE) inhibition. Bilateral renal denervation caused a partial decrease in the elevated blood pressure, abolished the increased PRC and PRA, and reduced the dose-dependent decrease in blood pressure with ACE inhibition in dexamethasone treated rats. Although the reduction in body weight and increases in urine volume, urinary sodium excretion and hematocrit were clearly seen following dexamethasone administration, dexamethasone-treated renal denervated rats showed the same degree of change in any of the variables as dexamethasone-treated sham-operated rats. Thus, our results indicate that the stimulation of the renin-angiotensin system through the activation of the renal nerve may be partially responsible for the dexamethasone-induced high blood pressure and, therefore, bilateral renal denervation reduces, partially but significantly, the elevated blood pressure, suggesting that the attenuation of oversecretion of renin contributes to the lowering of the blood pressure.     

Vascular permeability and late radiation fibrosis in mouse lung

It has been suggested that fibrosis which develops after irradiation is caused by increases in vascular permeability. Plasma proteins leak into irradiated tissue where fibrinogen may be converted into fibrin which is gradually replaced by fibrous tissue. Vascular and fibrotic changes in mouse lung were investigated after X irradiation of the right hemithorax. Blood volume and accumulation of extravascular proteins were measured using indium (111In)-labeled red cells, iodinated (131I) albumin, and iodinated (125I) fibrinogen. Tracers were injected 1-47 weeks after irradiation and lungs were excised 24 or 96 hr later to determine radioactivity. The amount of collagen was estimated by measuring the hydroxyproline content. During the first few months after X rays, lung blood volume decreased to a plateau which depended on radiation dose (10-25 Gy). Small increases in extravascular albumin and fibrinogen occurred at 1-12 weeks after 10-25 Gy. Subsequently, protein returned to normal after 10 Gy, remained elevated after 15 Gy, and increased after 20 and 25 Gy. Hydroxyproline per gram of dry irradiated lung was increased at 18 weeks after 15-25 Gy. Subsequently it showed little change although both total hydroxyproline content and dry weight decreased after 20 and 25 Gy. Support for the hypothesis was that hydroxyproline per gram only increased after X-ray doses which caused marked extravasation of protein. There was no evidence, however, for deposition of 125I-fibrin or for a gradual increase in fibrosis corresponding to the prolonged excess of extravascular protein.     

Influence of protein nutrition on dose-survival relationship following rat kidney irradiation

Immediately following unilateral nephrectomy the remaining kidney of juvenile male Sprague-Dawley rats was sham irradiated or irradiated to doses of 14-30 Gy. Following irradiation the animals were placed on isocaloric diets of either 20 or 4% protein. Median life spans for the animals on the low protein diet were significantly increased compared to the median life spans on the 20% protein diet. Serum urea nitrogen (SUN) levels were periodically measured in rats from each of the experimental groups. SUN levels in the irradiated rats fed the 20% protein diet increased significantly over unirradiated controls as a function of time. In contrast animals fed the 4% protein diet showed no significant changes in SUN levels irrespective of the size of radiation dose and time post irradiation. Renal protective factors calculated as the ratio of 80% survival times for animals fed the 20% protein diet compared to animals fed the 4% protein diet can be calculated to be 2.3 at 18 Gy and 2.8 at 22 Gy. Likewise, a SUN protective factor calculated as the ratio of percentage of nonirradiated control SUN values for the two diets (SUN 20% irradiated) (SUN 20% nonirradiated) (SUN 4% irradiated) (SUN 4% nonirradiated) is 2.4 for 18 Gy and 3.9 for 22 Gy.     

Effect of neutron and gamma radiation on physical endurance of rats in the swimming test

Three groups of adult male Wistar rats were exposed to neutrons (a single dose of 2 Gy) and gamma radiation (a continuous dose of 6 Gy delivered within 10.5 days) and a combination of both types of radiation. The physical fitness of irradiated and control rats was measured using a forced swimming test in the course and after the termination of the irradiation. A marked decrease in the physical fitness of all irradiated animals was followed by its normalization 3 weeks after irradiation.     

Kidney and lung injury in irradiated rats protected from acute death by partial-body shielding

Ninety-six CD-1 male rats were exposed to gamma-ray doses (0-25 Gy) in increments of 5 Gy. One femur, the surgically exteriorized GI tract, and the oral cavity were shielded during irradiation to protect against acute mortality from injury to the hematopoietic system, small intestine, and oral cavity. In addition, the thoraxes of half of the animals from each dose group were shielded. At approximately monthly intervals from 2 to 10 months after irradiation the hematocrit, plasma urea nitrogen (PUN), and 51Cr-EDTA clearance were measured. During the study 20 thorax-shielded and 19 thorax-irradiated animals died. All rats whose thoraxes received 25 Gy irradiation and three out of seven rats whose thoraxes received 20 Gy died 1 to 3 months postirradiation with massive pleural fluid accumulation. Shielding the thoraxes prevented this mode of death at these doses. Kidney injury was judged to be the primary cause of death of all thorax-shielded animals and 15- and 20-Gy thorax-irradiated animals. Animals with kidney damage had elevated PUN and reduced 51Cr-EDTA clearance and hematocrits. The relative merits of each of these end points in assessing radiation-induced kidney injury after total-body exposure are discussed.     

Early changes in the ultrastructure of axodendritic synapses in the rat sensorimotor cortex following whole-body irradiation with high-dose fast neutrons

Changes in morphometric parameters have been established in axodendritic synapses of sensorimotor cortex of adult mature rats exposed to neutron irradiation. Neutron irradiation dose and summarized dose rate were 10 Gy and 0.35 Gy, respectively. The changes were observed 0.25, 1, 3, 6 and 24 hours after irradiation. The observations suggest an increase in synaptic activity, with the range of irradiation action and functional characteristics decreasing in subsequent time periods.