Characterization of biological properties of synthetic and biological leukotriene B3

The effect of micropuncture of the renal papilla through an intact ureter on urinary concetrating ability of rats was examined. Micropuncture of the renal papilla caused a fall in urine osmolality in the punctured kidney from 1718 ± 106 to 1035 ± 79 mosmol/kg·H₂O. In order to investigate the role of renal prostaglandins in this process, PGE₂ excretion was measured and found to increase from 63.4 ± 14.0 to 205.5 ± 57.1 pg/min. Urine osmolality and PGE₂ excretion from the contralateral kidney were not significantly altered. In animals given meclofenamate (2 mg/kg·hr), renal PGE₂ excretion was reduced to 22.3 ± 5.1 pg/min prior to micropuncture and it remained low at 8.9 ± 1.8pg/min after papillary micropuncture. Meclofenamate also blocked the fall in urine osmolality caused by micropuncture of the renal papilla, with urine osmolality averaging 1940 ± 122 before and 1782 ± 96 mosmol/kg·H₂O after the micropuncture. These results indicated that papillary micropuncture through an intact ureter increased renal PGE₂ excretion and that a rise in renal production of PGE₂ or some other prostanoid is associated with a fall in urine concentrating ability.     

Role of renal prostaglandins in the fall in urine osmolality after papillary micropuncture

The effect of micropuncture of the renal papilla through an intact ureter on urinary concetrating ability of rats was examined. Micropuncture of the renal papilla caused a fall in urine osmolality in the punctured kidney from 1718 ± 106 to 1035 ± 79 mosmol/kg·H₂O. In order to investigate the role of renal prostaglandins in this process, PGE₂ excretion was measured and found to increase from 63.4 ± 14.0 to 205.5 ± 57.1 pg/min. Urine osmolality and PGE₂ excretion from the contralateral kidney were not significantly altered. In animals given meclofenamate (2 mg/kg·hr), renal PGE₂ excretion was reduced to 22.3 ± 5.1 pg/min prior to micropuncture and it remained low at 8.9 ± 1.8pg/min after papillary micropuncture. Meclofenamate also blocked the fall in urine osmolality caused by micropuncture of the renal papilla, with urine osmolality averaging 1940 ± 122 before and 1782 ± 96 mosmol/kg·H₂O after the micropuncture. These results indicated that papillary micropuncture through an intact ureter increased renal PGE₂ excretion and that a rise in renal production of PGE₂ or some other prostanoid is associated with a fall in urine concentrating ability.     

Amelioration with vessel dilator of acute tubular necrosis and renal failure established for 2 days

Seventeen Sprague-Dawley rats had ischemic nonoliguric acute renal failure (ARF) induced by vascular clamping resulting in their preischemic blood urea nitrogen (BUN) and creatinine levels of 16 +/- 1 and 0.56 +/- 0.05 mg/dl to increase to 162 +/- 4 and 8.17 +/- 0.5 mg/dl, P < 0.001, respectively, at day 4 of postischemia. Vessel dilator, a 37-amino-acid cardiac peptide hormone (0.3 microg x kg(-1) x min(-1) ip), decreased the BUN and creatinine levels to 53 +/- 17 mg/dl and 0.98 +/- 0.12 mg/dl (P < 0.001) in another seven animals where ARF had been established for 2 days. Water excretion doubled with ARF and was further augmented by vessel dilator. Transthoracic echocardiography revealed left ventricular dilation as a probable cause of the increase in vessel dilator in the circulation with ARF, and vessel dilator infusion reversed this dilation. At day 6 of ARF, mortality decreased to 14% with vessel dilator from 88% without vessel dilator. Acute tubular necrosis was <5% in the vessel dilator-treated rats compared with 25% to >75% in the placebo-treated ARF animals. We conclude that vessel dilator improves acute tubular necrosis and renal function in established ARF.     

Interaction between prostaglandin E2 and leukotriene D4 on the excretion of electrolytes by the dog kidney in vivo

Recent experiments indicate that prostaglandin E₂ potentiates the vasodilatory properties of leukotrienes in the skin microcirculation. The present experiments were undertaken to study the effect of leukotriene D₄ and prostaglandin E₂ on renal hemodynamics and urinary electrolytes in the dog. Experiments were performed in three groups of anesthetized Mongrel dogs: the first group was studied under hydropenia, whereas the two remaining groups were studied during water diuresis with (Group 3) or without indomethacin (Group 2). LTD₄ (100ng/min) and PGE₂ (3ug/min) were infused in the left renal artery to minimize systemic effects of these compounds. LTD₄ alone failed to influence urinary sodium excretion in all 3 groups. In Group 1, urinary sodium increased from 77 ± 6 to 393 ± 74uEq/min during PGE₂, and further increased to 511 ± 52uEq/min during LTD₄ + PGE₂. No change occured in the contralateral right kidney. In this group, glomerular filtration as well as renal plasma flow were not statistically influenced. In Group 2, the same phenomenon was observed for urinary sodium. The combined infusion of LTD₄ + PGE₂ increased urinary sodium without significant changes in glomerular filtration and renal plasma flow. Finally, in Group 3, indomethacin was shown to reduce the natriuretic effects of LTD₄ and PGE₂: during PGE₂ alone, urinary sodium increased from 90 ± 14 to 260 ± 66uEq/min, and only rose from 80 ± 10 to 175 ± 19uEq/min during the combined infusion of LTD₄ and PGE₂. In groups 2 and 3, free water clearance was utilized as an index of sodium chloride reabsorption in the thick ascending limb: this parameter increased from 2.35 ± 0.25 to 4.70 ± 0.30ml/min, while urinary volume was increasing from 3.55 ± 0.25 to 10.05 ± 0.65ml/min, during LTD₄ + PGE₂. Indomethacin, administered in Group 3, (3mg/kg/hr) again abolished the effect of combined PGE₂ + LTD₄. These results indicate a potentiating effect of leukotriene D₄ on the PGE₂-induced natriuresis in the anesthetized dog. These phenomena occured in the absence of significant changes in renal hemodynamics, therefore suggesting a direct tubular effect of these arachidonic acid metabolites. Finally, the water diuresis experiments suggest a proximal site of action of PGE₂ and LTD₄.     

High urine flow rate increases prostaglandin E excretion in the conscious dog

Although previous studies from this and other laboratories have shown that urinary prostaglandin E excretion (U_PGEV) can vary independent of urine flow rate, recent studies during water diuresis in the conscious dog have suggested that high urine flow rate per se may increase U_PGEV. To examine the effect of urine flow rate on U_PGEV we administered either mannitol, chlorothiazide or Ringer's solution to mongrel dogs and measured U_PGEV. During anesthesia neither mannitol or chlorothiazide increased U_PGEV. There was, however, a consistent increase with all three agents in awake animals. This increase in U_PGEV was independent of alterations in glomerular filtration rate. There was a consistent increase in urinary sodium excretion and decrease in urinary osmolality with all three agents. The changes in PGE, however, were similar to those found during water diuresis when no increase in sodium excretion was found. It is not presently clear whether these findings reflect a true increase in renal PGE synthesis due to some change in flow or pressure within the renal medulla or rather represent unchanged PGE synthesis by renal tubular cells, the high tubule fluid flow rate causing increased entry into the tubular lumen in contrast to the renal interstitium.     

Early changes in renal function following chemically induced nephropathy

The functional changes in the rat kidney 24 h after administration of 2-bromoethanamine hydrobromide (BEA) have been extensively described. There is, however, little information regarding earlier alterations. The present study was designed to measure early changes in renal function in order to clarify further pathomechanisms of the BEA-induced lesion. Experiments were performed in two groups of Wistar rats with different infusion rates during the first 3 h following injection of 100 mg/kg BW BEA compared to sham-injected rats. Analysis included measuring urine flow, osmolality, urea, sodium and potassium as well as inulin and para-aminohippuric acid clearance. Our studies show a tubular as well as a glomerular involvement in BEA-induced nephropathy. A significantly higher urine flow occurred already in the first 30 min following injection of BEA. Urine osmolality began to decrease after 90 min, Na excretion was elevated at 3 h, K excretion was not significantly different from the control group, urea excretion was increased after 30 min. Contrary to other studies we found a continuously decreasing glomerular filtration rate and PAH clearance during the first 3 h. Our results suggest an early effect of BEA on tubular function (increasing sodium excretion), papillary concentration capacity (increasing urine flow combined with decreasing osmolality) and glomerular function (decreasing glomerular filtration rate).     

葛根素对甘油致急性肾功能衰竭兔血液流变学和肾血流量的影响

目的 肌注甘油复制急性肾功能衰竭(ARF)兔模型,观察葛根素(Pue)对ARF兔血液流变学和肾血流量的影响.方法 健康雄性日本大耳白兔30只,随机分为正常组、ARF模型组、Pue 1组(20 mg/kg)、Pue 2组(40mg/kg)、Pue 3组(80 mg/kg).各组于不同时间点测量其肾血流量、血液流变学指标和肾功能指标(Cr、BUN),并观察肾组织形态学改变.结果 与模型组比较,Pue 2组和Pue 3组治疗后各时间点Cr、BUN降低(P＜0.05),血液流变学指标降低明显(P＜0.05),肾血流量增加差异具有统计学意义(P＜0.05).Pue 2组和Pue 3组肾小管上皮细胞肿胀减轻,管型少见.结论 葛根素可明显改善急性肾功能衰竭兔血液流变性,增加肾血流量,进而达到改善、减轻肾小管损害的作用.     

Molsidomine, a nitric oxide donor and L-arginine protects against rhabdomyolysis-induced myoglobinuric acute renal failure

Rhabdomyolysis-induced myoglobinuric acute renal failure accounts for about 10-40% of all cases of acute renal failure (ARF). Nitric oxide and reactive oxygen intermediates play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). This study was designed to investigate the effect of molsidomine and L-arginine in glycerol induced ARF in rats. Six groups of rats were employed in this study, group I served as control, group II was given 50% glycerol (8 ml/kg, intramuscularly), groups III and IV were given glycerol plus molsidomine (5 mg/kg, and 10 mg/kg p.o. route respectively) 60 min prior to the glycerol injection, group V animals were given glycerol plus L-arginine (125 mg/kg, p.o.) 60 min prior to the glycerol injection, and group VI received L-NAME (10 mg/kg, i.p.) along with glycerol 30 min prior to glycerol administration. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, reduced glutathione and superoxide dismutase. Tissue and urine nitrite levels were measured as an index of total nitric oxide levels. Glycerol treatment resulted in a marked decrease in tissue and urine nitric oxide levels, renal oxidative stress and significantly deranged the renal functions along with deterioration of renal morphology. Pre-treatment of animals with molsidomine (10 mg/kg) and L-arginine 60 min prior to glycerol injection markedly attenuated fall in nitric oxide levels, renal dysfunction, morphological alterations, reduced elevated TBARS and restored the depleted renal antioxidant enzymes. The animals treated with L-NAME along with glycerol further worsened the renal damage observed with glycerol. As a result, our results indicate that molsidomine and L-arginine may have beneficial effects in myoglobinuric ARF.     

Urinary excretion of prostaglandin E2 and prostaglandin F2α in potassium-deficient rats

Potassium-deficiency was induced in rats by dietary deprivation of potassium. The animals became polyuric and urine osmolality decreased more then three-fold compared to controls. Urinary excretion of prostaglandin E₂ (PGE₂) and prostaglandin F_2α (PGF_2α) did not increase during 2 weeks of potassium depletion. Partial inhibition of renal prostaglandin synthesis by meclofenamate did not increase the urine osmolality after water deprivation. These results make unlikely the hypothesis that the polyuria of potassium-deficiency, is the result of enhanced renal synthesis of prostaglandins with subsequent antagonism of the hydro-osmotic effect of vasopressin. Male animals consistently excreted less PGE₂ than female animals.     

The Effects of Combined Treatment with Niacin and Chromium on the Renal Tissues of Hyperlipidemic Rats

In this study, 12 months old female Swiss albino rats were used. They were randomly divided into four groups. The animals of group I were fed with pellet chow. Group II were fed with pellet chow and treated with 250 μg/kg CrCl₃.6H₂o and 100 mg/kg niacinfor 45 days. Group III were fed a lipogenic diet consisting of 2% cholesterol, 0.5% cholicacidand 2%sun flower oil added to the pellet chow, andgiven 3%alcoholic water for 60 days. Group IV were fed with the same lipogeni cdiet for 60 day sand treated by gavage technique to rats at a dose of 250 mu/kg CrCl_3.6H₂O and 100 mg/kg niacin for 45 days, 15 days after experimental animals were rendered hyperlipidemic. At the 60th day, renal tissue and blood samples were taken from the animals. The sections were examined under light and electron microscopy. The degenerative changes were much more in the hyperlipidemic rats than the control group. The changes in renal tissue were also observed in hyperlipidemic animals given niacin and chromium. In the hyperlipidemic rats, renal glutathione levels decreased and renal lipid peroxidation levels, and serum urea and creatinine levels were increased. But, renal glutathione levels increased and lipid peroxidation levels and serum urea and creatinine levels decreased in hyperlipidemic rats given niacin and chromium. The purpose of this study was to investigate whether a protective effect of a combination of niacin and chromium is present on the renal tissue of hyperlipidemic rats or not. In conclusion, we can say that niacin and chromium do not have a protective effect on the morphology of the renal tissue of hyperlipidemic rats, except a protective effect on their biochemical parameters.     

Losartan Improved Antioxidant Defense,Renal Function and Structure of Postischemic Hypertensive Kidney

Ischemic acute renal failure (ARF) is a highly complex disorder involving renal vasoconstriction, filtration failure, tubular obstruction, tubular backleak and generation of reactive oxygen species. Due to this complexity, the aim of our study was to explore effects of Angiotensin II type 1 receptor (AT1R) blockade on kidney structure and function, as well as oxidative stress in spontaneously hypertensive rats (SHR) after renal ischemia reperfusion injury. Experiments were performed on anaesthetized adult male SHR in the model of ARF with 40 minutes clamping the left renal artery. The right kidney was removed and 40 minutes renal ischemia was performed. Experimental groups received AT1R antagonist (Losartan) or vehicle (saline) in the femoral vein 5 minutes before, during and 175 minutes after the period of ischemia. Biochemical parameters were measured and kidney specimens were collected 24h after reperfusion. ARF significantly decreased creatinine and urea clearance, increased LDL and lipid peroxidation in plasma. Treatment with losartan induced a significant increase of creatinine and urea clearance, as well as HDL. Lipid peroxidation in plasma was decreased and catalase enzyme activity in erythrocytes was increased after losartan treatment. Losartan reduced cortico-medullary necrosis and tubular dilatation in the kidney. High expression of pro-apoptotic Bax protein in the injured kidney was downregulated after losartan treatment. Our results reveal that angiotensin II (via AT1R) mediates the most postischemic injuries in hypertensive kidney through oxidative stress enhancement. Therefore, blockade of AT1R may have beneficial effects in hypertensive patients who have developed ARF.     

The effects of reducing dietary nitrogen and of increasing sodium chloride intake on urea excretion and reabsorption and on urine osmolality in sheep.

Renal responses to reducing dietary nitrogen were studied in four ewes during intravenous infusion of arginine vasopressin. The fall in urea excretion and in plasma urea concentration was accompanied by significant reduction in GFR and in urine osmolality. The fraction of filtered urea reabsorbed increased despite reduction in the urea U/P concentration ratio and this increase was sustained when the urea U/P ratio was further reduced at higher urine flows observed when the drinking water was replaced with saline. This procedure also sustained the RPF which in the absence of additional salt was significantly reduced on the low protein diet. It is suggested that the fall in GFR and the increase in the fraction of filtered urea reabsorbsed may contribute to nitrogen economy and that the increase in fractional reabsorption and the reduction in urine osmolality on the low protein diet provided evidence of active reabsorption of urea by renal tubules.     

Ischemic conditioning by short periods of reperfusion attenuates renal ischemia/reperfusion induced apoptosis and autophagy in the rat

Prolonged ischemia amplified iscehemia/reperfusion (IR) induced renal apoptosis and autophagy. We hypothesize that ischemic conditioning (IC) by a briefly intermittent reperfusion during a prolonged ischemic phase may ameliorate IR induced renal dysfunction. We evaluated the antioxidant/oxidant mechanism, autophagy and apoptosis in the uninephrectomized Wistar rats subjected to sham control, 4 stages of 15-min IC (I15 × 4), 2 stages of 30-min IC (I30 × 2), and total 60-min ischema (I60) in the kidney followed by 4 or 24 hours of reperfusion. By use of ATP assay, monitoring O₂ ^-. amounts, autophagy and apoptosis analysis of rat kidneys, I60 followed by 4 hours of reperfusion decreased renal ATP and enhanced reactive oxygen species (ROS) level and proapoptotic and autophagic mechanisms, including enhanced Bax/Bcl-2 ratio, cytochrome C release, active caspase 3, poly-(ADP-ribose)-polymerase (PARP) degradation fragments, microtubule-associated protein light chain 3 (LC3) and Beclin-1 expression and subsequently tubular apoptosis and autophagy associated with elevated blood urea nitrogen and creatinine level. I30 × 2, not I15 × 4 decreased ROS production and cytochrome C release, increased Manganese superoxide dismutase (MnSOD), Copper-Zn superoxide dismutase (CuZnSOD) and catalase expression and provided a more efficient protection than I60 against IR induced tubular apoptosis and autophagy and blood urea nitrogen and creatinine level. We conclude that 60-min renal ischemia enhanced renal tubular oxidative stress, proapoptosis and autophagy in the rat kidneys. Two stages of 30-min ischemia with 3-min reperfusion significantly preserved renal ATP content, increased antioxidant defense mechanisms and decreased ischemia/reperfusion enhanced renal tubular oxidative stress, cytosolic cytochrome C release, proapoptosis and autophagy in rat kidneys.     

A high cholesterol diet ameliorates renal tubular lesions in diabetic rats

These studies examine the effect of cholesterol feeding in normal rats and in rats with streptozotocin-induced diabetes mellitus. Four groups were studied: normal rats fed either a standard rat chow or a standard rat chow supplemented with cholesterol and diabetic rats fed standard chow or standard chow plus cholesterol. Diabetic rats fed a standard diet excreted more creatinine and urea in the urine, had higher levels of blood urea nitrogen, and lower serum albumin levels than rats fed standard diet plus cholesterol. Blood glucose levels were similar in the two groups; however, diabetic rats given cholesterol had a greater body weight at the end of the study than diabetic rats eating standard chow. Urine volumes and sodium and potassium excretion in the urine were greater in diabetic rats fed a standard diet than in those fed a high cholesterol diet. Diabetic rats fed a standard diet had distinctive renal lesions characterized by swelling of tubular epithelial cells with clearing of cytoplasm. The nephron segments involved by this striking vacuolar change were the distal convoluted tubule and the thick limbs of Henle's loop. These lesions were identical to those described by Armanni-Ebstein in severely glycosuric patients. These lesions were not observed in any of the animals of the other three groups (including diabetic rats fed a high cholesterol diet). Glomeruli were normal in animals of all groups. Thus, cholesterol administration prevents the development of the Armanni-Ebstein lesions in diabetic rats despite persistent hyperglycemia. The mechanism by which cholesterol administration prevents the accumulation of glycogen in distal tubule cells has not been elucidated. It is suggested that glycogen accumulation in distal tubular segments may explain the greater urine volumes, natriuresis, kaliuresis, and proteinuria observed in diabetic animals fed a standard diet when compared with rats fed the same diet plus cholesterol.     

Fetal Kidney Cells Can Ameliorate Ischemic Acute Renal Failure in Rats through Their Anti-Inflammatory,Anti-Apoptotic and Anti-Oxidative Effects

Fetal kidney cells may contain multiple populations of kidney stem cells and thus appear to be a suitable cellular therapy for the treatment of acute renal failure (ARF) but their biological characteristics and therapeutic potential have not been adequately explored. We have culture expanded fetal kidney cells derived from rat fetal kidneys, characterized them and evaluated their therapeutic effect in an ischemia reperfusion (IR) induced rat model of ARF. The fetal kidney cells grew in culture as adherent spindle shaped/polygonal cells and expressed CD29, CD44, CD73, CD90, CD105, CD24 and CD133 markers. Administration of PKH26 labeled fetal kidney cells in ARF rats resulted in a significant decrease in the levels of blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin and decreased tubular necrosis in the kidney tissues (p<0.05 for all). The injected fetal kidney cells were observed to engraft around injured tubular cells, and there was increased proliferation and decreased apoptosis of tubular cells in the kidneys (p<0.05 for both). In addition, the kidney tissues of ARF rats treated with fetal kidney cells had a higher gene expression of renotropic growth factors (VEGF-A, IGF-1, BMP-7 and bFGF) and anti-inflammatory cytokine (IL10); up regulation of anti-oxidative markers (HO-1 and NQO-1); and a lower Bax/Bcl2 ratio as compared to saline treated rats (p<0.05 for all). Our data shows that culture expanded fetal kidney cells express mesenchymal and renal progenitor markers, and ameliorate ischemic ARF predominantly by their anti-apoptotic, anti-inflammatory and anti-oxidative effects.     

Prevention of systemic and regional haemodynamic alterations, hypercreatininemia, hyperuremia and hyperphosphatemia by losartan in hypertension with acute renal failure

Patients with pre-existing hypertension are at a particular risk of fatal outcome due to acute renal failure (ARF). We investigate the effects of angiotensin II type-1 receptor blocker (ARB) losartan, on haemodynamics and biochemical parameters in adult male spontaneously hypertensive rats (SHR) with ischemia/reperfusion ARF. SHR were randomly selected in three experimental groups: sham-operated group (SHAM), ARF group, and ARF+LOS group (losartan, 10 mg/kg/b.w. given by infusion during the period of three hours after reperfusion). Beside the improvement of systemic haemodynamics 24 h after reperfusion, losartan significantly increased renal blood flow (RBF: 19.33±3.29 ml/min/kg vs. 8.03±1.04 ml/min/kg, p<0.05) and decreased renal vascular resistance (RVR) compared to ARF (8.85±1.21 mmHg × min × kg/ml vs. 19.90±2.35 mmHg × min × kg/ml, p<0.001). Plasma creatinine (Pcr), urea (Pu) and phosphates (Pphos) were significantly reduced in ARF+LOS group compared to ARF group (Pcr: 99.11±14.56 μmol/l vs. 242.71±20.25 μmol/l, p<0.001; Pu: 33.72±4.69 mmol/l vs. 61.90±3.93 mmol/l, p<0.001; 2.7±0.42 mmol/l vs. 5.57±0.61 mmol/l, p<0.01). Our results demonstrate that losartan improves systemic and regional haemodynamic and biochemical parameters in hypertension with ARF.     

Influence of angiotensins (I,II & III) on prostaglandin production by minced rat renal medulla

Minced rat renal medulla was incubated for 30 min at 37 °C in the presence of angiotensin, I, II or III (100 ng/ml) to determine the existence of a direct stimulating effect on prostaglandin (PG) production. PGE₂, PGF_2α, 6-keto PGF_1α and Thromboxane B₂ (TXB₂)_were determined by radioimmunoassay.For analysis of data variance, the results were separated according to whether the net output of PGE₂ was above or below 1.5 ng PGE₂ equivalent/mg tissue/30 min. Under low-output conditions, angiotensin I, II or III stimulated PGE₂ production significantly (p<0.02) and tended to augment PGF_2α production, while under high-output conditions no effect on PGE₂ or PGF_2α production was observed.Under either output condition, angiotensin I, II or III had no effect on 6-keto PGF_1α and TXB₂.     

Modulation of prostaglandin of the renal vascular action of arginne vasopressin

To determine whether the renal vascular effect of arginine vasopressin (AVP) is modulated by renal prostaglandin E₂ (PGE₂) were determined during the infusion of AVP in dogs during control conditions and after the administration of the inhibitor of prostaglandin synthesis, indomethacin. During control conditions, intrarenal administration for 10 min of a dose of AVP calculated to increase arterial renal plasma AVP concentration by 75 pg/ml produced a slight renal vasodilation (p<0.01) and an increase in renal venous plasma concentration of PGE₂. Renal venous PGE₂ concentration during control and AVP infusion averaged 33 ± 7 and 52 ± 12 pg/ml (p<0.05), respectively. After administration of indomethacin, the same dose of AVP induced renal vasoconstriction (p<0.05) and failed to enhance renal venous PGE₂ concentration (9 ± 1 to 8 ± 1 pg/ml). Intrarenal administration of 20 ng/kg. min of AVP for 10 min induced a marked renal vasoconstriction (p<0.01) and increased renal venous plasma PGE₂. Renal venous PGE₂ during control and AVP infusion averaged 31 ± 10 and 121 ± 31 pg/ml (p<0.01), respectively. Administration of the same dose of AVP following indomethacin produced a significantly greater and longer lasting renal vasoconstriction (p<0.01) and failed to increase renal venous plasma PGE₂ (10 ± 1 to 9 ± 1 pg/ml). These results indicate that a concentration of AVP comparable to that observed in several pathophysiological conditions induces a slight renal vasodilation which is mediated by renal prostaglandins. The results also indicate that higher doses of AVP induce renal vasoconstriction and that prostaglandin synthesis induced by AVP attenautes the renal vasoconstriction produced by this peptide.     

Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.

Acute renal failure (ARF) in response to ischemia-reperfusion is thought to be associated with neutrophil infiltration. Neutrophil recruitment depends on adhesion molecules, including P-selectin. Our study sought to characterize the role of P-selectin in ischemia-reperfusion (I/R) -induced acute renal failure (ARF). In wild-type (wt) and P-selectin-deficient (P-/-) mice (both C57BL/6), ARF was induced by 32 min bilateral renal ischemia, followed by reperfusion (I/R). Wt showed a 12- and 20-fold increase in creatinine at 24 and 48 h after I/R, respectively. Similar changes were seen in blood urea nitrogen (BUN). By contrast, in P-/- creatinine and BUN increased only moderately (fourfold over sham). In wt, renal myeloperoxidase activity, indicating neutrophil infiltration, peaked after 24 h (19-fold over sham). This was significantly attenuated in P-/- (fivefold over sham). Western blot analysis revealed maximum P-selectin expression 12 h after I/R in wt. Immunostaining detected P-selectin in glomerular endothelium and in platelets adherent in glomerular and peritubular vessels. Postischemic injection of P-selectin antibody at 10 min after reperfusion, but not isotype control antibody, protected wt from ARF similar to the protection seen in P-/-. We conclude that blocking P-selectin even after onset of reperfusion protects mice from I/R-induced ARF, suggesting potential therapeutic strategies aimed at blocking P-selectin.     

Enhanced skeletal muscle arteriolar reactivity to ANG II after recovery from ischemic acute renal failure

In addition to the long-term renal complications, previous studies suggested that after acute renal failure (ARF), rats manifest an increased pressor response to an overnight infusion of ANG II. The present study tested whether recovery from ARF results in alterations in sensitivity to the peripheral vasculature. ARF was induced in Sprague-Dawley rats by 45 min of bilateral renal ischemia and reperfusion. Animals were allowed to recover renal structure and function for 5-8 wk, after which the acute pressor responses to ANG II were evaluated either in vivo in in situ skeletal muscle arterioles or in isolated gracilis muscle arteries in vitro. Baseline arterial pressure was not different in ARF rats vs. sham-operated controls, although ARF rats exhibited an enhanced pressor response to bolus ANG II infusion compared with control rats. Steady-state plasma ANG II concentration and plasma renin activity were similar between ARF and control rats. Constrictor reactivity of in situ cremasteric arterioles from ARF rats was enhanced in response to increasing concentrations of ANG II; however, no difference was observed in arteriolar responses to elevated PO2, norepinephrine, acetylcholine, or sodium nitroprusside. Isolated gracilis muscle arteries from ARF rats also showed increased vasoconstriction in response to ANG II but not norepinephrine. In conclusion, recovery from ischemic ARF is not associated with hypertension but is associated with increased arteriolar constrictor reactivity to ANG II. Although the mechanisms of this altered responsiveness are unclear, such changes may relate, in part, to cardiovascular complications in patients with ARF and/or after renal transplant.