Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy

Podocyte injury is believed to contribute to glomerulosclerosis in membranous nephropathy. To identify the factors involved, we investigated the effects of basic fibroblast growth factor (bFGF), a cytokine produced by podocytes, on rats with membranous nephropathy (passive Heymann nephritis [PHN]). All rats received a daily i.v. bolus of 10 microg bFGF or vehicle from days 3-8 after PHN induction. In proteinuric PHN rats on day 8, bFGF injections further increased proteinuria. Podocytes of bFGF-injected PHN rats showed dramatic increases in mitoses, pseudocyst formation, foot process retraction, focal detachment from the glomerular basement membrane, and desmin expression. bFGF injections in PHN rats did not alter antibody or complement deposition or glomerular leukocyte influx. bFGF-injected PHN rats developed increased glomerulosclerosis when compared with control PHN rats. Also, bFGF induced proteinuria and podocyte damage in rats injected with 10% of the regular PHN-serum dose. None of these changes occurred in bFGF-injected normal rats, complement-depleted PHN rats or rats injected with 5% of the regular PHN serum dose. These divergent bFGF effects were explained in part by upregulated glomerular bFGF receptor expression, induced by PHN serum. Thus, bFGF can augment podocyte damage, resulting in increased glomerular protein permeability and accelerated glomerulosclerosis. This bFGF action is confined to previously injured podocytes. Release of bFGF from glomerular sources (including podocytes themselves) during injury may represent an important mechanism by which podocyte damage is enhanced or becomes self sustained.     

Cationic dextran induces mesangioproliferative nephritis in rats independent of glomerular IgA deposition

BACKGROUND: Dextran-induced mesangioproliferative glomerulonephritis in mice and, as recently reported, in rats is used as a model of IgA nephropathy. The pathogenetic role of the glomerular IgA deposits in this model, however, is unclear since IgG is often deposited in parallel. METHODS: Lewis rats were immunized with cationic DEAE-dextran. Following this, rats received 5 x/week i.v. injections of 3 mg DEAE-dextran each, from days 20 to 80 and were then followed until day 120. RESULTS: Rats developed transient proteinuria (range 63-152 mg/24 h) and haematuria on day 80. Renal biopsies obtained at days 60, 80, 100 and 120 showed mild to severe mesangioproliferative changes at days 80 and 100 which did not persist at day 120. Electron-microscopy revealed mesangial immune deposits, signs of endothelial activation and vacuoles in mesangial cells and podocytes. Compared to normal, age-matched controls, in the nephritic rats significant (P < 0.05) increases were noted for glomerular total cellularity, alpha-smooth-muscle actin expression (a marker of activated mesangial cells), monocyte/macrophage counts, and matrix proteins. Using three different antibodies, no evidence of glomerular IgA deposition was detected at any time point. In contrast, glomerular IgG, IgM, C3, and occasional small C5b-9 deposits were present in nephritic rats. Circulating IgG but not IgA anti-dextran antibodies could be demonstrated in nephritic rats. CONCLUSIONS: The data confirm that mesangioproliferative glomerulonephritis can be induced in rats by immunization and chronic challenge with cationic dextran. Our data also show that in rats glomerular IgG deposition rather than IgA, appears to play an important pathogenetic role in this mesangioproliferative glomerulonephritis model.     

Zinc therapy in acrodermatitis enteropathica

Albino Holtzman, albino Wistar and hooded HS rats were injected fortnightly for 14 weeks with human glomerular basement membrane (GBM) emulsified in Freund's complete adjuvant. Half of the rats were pretreated with Freund's complete adjuvant and some were unilaterally nephrectomized. Anti-GBM antibody glomerulonephritis, characterized by proteinuria (greater than 100 mg/16 h) and a diffuse linear deposition of host immunoglobulin along the glomerular basement membrane, was first detected in Holtzman rats 4 weeks after treatment with GBM had begun, and had developed in 69% of these rats by 15 weeks. In contrast, none of the similarly treated Wistar or HS rats became proteinuric at any time, although a few showed weak glomerular fluorescence at the end of the experiment. Thus Holtzman rats are susceptible, and HS and Wistar rats are resistant to experimental anti-GBM antibody glomerulonephritis. Pretreatment with Freund's complete adjuvant apparently shortened the induction period of the experimental disease in the Holtzman rats whereas unilateral nephrectomy appeared to decrease their susceptibility to it.     

Plasma immunadsorption treatment in patients with primary focal and segmental glomerulosclerosis

BACKGROUND: In primary focal and segmental glomerulosclerosis (FSGS) renal prognosis is poor if no remission of proteinuria can be obtained by treatment. In some patients a permeability factor, responsible for damaging the glomerular epithelial cell and detectable by an in vitro test (GVV-test), seems to be present in the serum. METHOD: We determined the effects of an immunadsorption treatment (IAT) on proteinuria and glomerular permselectivity (using a neutral dextran and dextransulfate-sieving technique to assess glomerular size and charge selectivity) in five patients with FSGS in the native kidneys and three patients with recurrence of FSGS after kidney transplantation. Furthermore, we performed the GVV-test using sera obtained from the patients before and after therapy. RESULTS: IAT reduced proteinuria by more than 50% in four patients, all of whom had an improvement in glomerular-size selectivity. Charge selectivity was better preserved after therapy in three out of these four subjects. The GVV-test prior to IAT was positive in two patients who also responded clinically to therapy. After IAT the GVV-test was negative in all patients, indicating an elimination of the proteinuric factor in the two previously positive patients. CONCLUSION: We conclude that a positive GVV-test before treatment makes a favourable response of IAT on proteinuria likely in patients with FSGS. If a reduction of proteinuria can be obtained by IAT this is due to an improvement in glomerular size and/or charge selectivity.     

Patterns of gene expression during teleost embryogenesis: lactate dehydrogenase isozyme ontogeny in the medaka (Oryzias latipes)

Ultrastructural changes in the visceral epithelium and proximal tubules of rats were studied by scanning and transmission electron microscopy during the onset and progression of puromycin aminonucleoside nephrosis (PAN)-induced proteinuria. These changes were compared with those that occur during a similar degree of proteinuria induced by intraperitoneal injections of albumin. With the onset of proteinuria and oliguria, PAN rats exhibit loss of podocyte pedicels and podocyte major processes, an increase in pinocytotic activity, and an accumulation of cytoplasmic vacuoles and granules of variable size, shape, and electron density. Loss of podocyte pedicels involves a gradual decrease in pedicel height beginning at the pedicel tip and progressing down the pedicel arm, formation of nublike protrusions and interpedicel microbridges (35 to 45 nm. in width and 40 to 60 nm. in length) along the pedicel's base, the merging of microbridges to form more extensive regions of interpedicel contact, and a gradual broadening and retraction of pedicels. In response to hyperalbuminemia-induced proteinuria, kidney podocytes exhibit reactions during PAN, however, the podocyte pedicels, slit pores, and major processes of rats with hyperalbuminemia-induced proteinuria remain discrete. The loss of pedicels and major processes during PAN, therefore, apparently results from the effects of puromycin aminonucleoside per se rather than from the proteinuria associated with this disease. The proximal tubules of rats with hyperalbuminemia-induced proteinurea exhibit the same characteristic changes as PAN rat proximal tubules (i.e., loss of brush border, dilated lumina, abnormally thin walls, and accumulation of periodic acid-Schiff positive electron-dense luminal casts and cytoplasmic protein absorption droplets). The significance of these ultrastructural findings during PAN and hyperalbuminemia-induced proteinurea are discussed in terms of the etiology of PAN.     

Anti-vitronectin antibodies enhance anti-Thy-1-induced proteinuria in PVG/c, but not in Wistar rats

Injection of rats with mouse monoclonal IgG2a anti-Thy1.1 antibodies (ER4G) results in rapid development of proteinuria in Wistar rats, reaching average values of 160 mg/24 h on day 3 after antibody administration. In contrast, no overt proteinuria was observed in PVG/c+ rats (maximum, 40 mg/24 h on day 3). This study investigates whether differences in the inactivation of C5b-9 complexes in the glomerulus by complement inhibitors are responsible for the differences in proteinuria between the two rat strains. Regardless of the presence of proteinuria, an increased expression of Crry by mesangial cells (MC) was observed within 24 h after injection of ER4G in both Wistar and PVG/c+ rats. Double-label immunofluorescence using goat anti-mouse Ig antibodies demonstrated an expression of Crry exclusively on MC. Furthermore, Crry colocalized with C5b-9 complexes on MC, as detected by a monoclonal antibody against the rat C5b-9 neo-antigen. In PVG/c+ rats, C5b-9 complexes persisted in the mesangial area for at least 7 d and colocalized immediately (within 1 h) and homogeneously with vitronectin. However, in proteinuric Wistar rats, C5b-9 complexes disappeared from the glomerular mesangium within 6 d. In these rats, mesangial colocalization of C5b-9 with vitronectin could only occasionally be detected. Pretreatment of PVG/c+ rats with antibodies against vitronectin, followed by administration of ER4G, resulted in the immediate development of proteinuria (maximum, 119 mg/24 h on day 3; P < 0.05), whereas Wistar rats did not become more proteinuric. This study provides evidence that differences in susceptibility of PVG/c+ and Wistar rats to complement-mediated damage of the glomerulus may be related to the degree of inactivation of C5b-9 complexes by complement regulatory factors.     

The transducing pathway of Ca2+ influx during progesterone-initiated acrosome reaction of guinea pig sperm

Although idiopathic membranous nephropathy (IMN) is thought to represent a diffuse glomerulopathy, it was found that three of 31 children histologically diagnosed as IMN showed focal and segmental deposition of immunoglobulin G (IgG) and C3 on the glomerular capillary walls. The present study attempted to comparatively investigate clinical and pathological features of the diffuse group and the focal segmental group in 31 IMN children. Immunofluorescence study revealed that 28 of 31 IMN exhibited diffuse granular deposition of IgG along glomerular capillary walls. In contrast, focal and segmental deposition of IgG and C3 was noted in three children with IMN. In addition, focal and segmental electron-dense deposits were identified in these cases. In two children of the focal segmental group, immunofluorescent patterns of IgG deposition were unchanged even at the second biopsy. The focal segmental form of IMN tended to occur in younger children than diffuse IMN. However, other clinical parameters such as the range of proteinuria, hematuria, serum albumin and prognosis did not show any significant differences between both groups. Electrophoretic profiles of urinary proteins on sodium dodecylsulfate-polyacrylamide gel electrophoresis were not different between both groups. It is proposed that the focal segmental form of IMN may have a distinctive glomerulopathy from the typical form of IMN.     

Cyclosporine protects glomeruli from FSGS factor via an increase in glomerular cAMP

Cyclosporine (CsA) administration to patients with recurrent focal segmental glomerulosclerosis (FSGS) after transplantation results in remission of proteinuria. We have shown that sera from patients with recurrent FSGS can increase the glomerular albumin permeability (Palbumin) and that increase in glomerular cAMP levels can alter the permeability characteristics of glomeruli in vitro. The purpose of this study was to determine if the increased glomerular levels of cAMP were related to the protective effects of CsA on an increase in Palbumin by FSGS sera. Glomeruli from Sprague-Dawley rats following intraperitoneal administration of CsA (25 mg/kg/day), cremophore (25 mg/kg/day), or saline for 5 days were incubated with 1:50 dilution of serum from three FSGS patients or with pooled normal human serum prior to calculation of Palbumin. Glomerular cAMP was measured by radioimmunoassay. Glomerular ultrastructural changes were assessed by transmission electron microscopy (TEM). Serum from three FSGS patients markedly increased Palbumin of glomeruli from saline or cremophore treated rats (saline, 0.68+/-0.08; 0.72+/-0.07; 0.70+/-0.07; and cremophore, 0.79+/-0.05; 0.81+/-0.02; 0.79+/-0.01; n=25 glomeruli in each group). In contrast Palbumin of glomeruli from CsA treated rats was not increased by any of the three FSGS sera tested (0.03+/-0.02; 0.04+/-0.05; 0.02+/-0.07, n=25 glomeruli in each group). Glomerular cAMP (pmol/mg of protein) increased 5 fold in CsA treated rats (328+/-26; 5 rats) compared with cremophore or saline treated rats (87+/-24 and 65+/-23, P<0.01; 5 rats in each group). The glomerular basement membrane appeared to be thickened and the lamina densa had an irregular appearance after treatment with CsA. No ultrastructural changes of glomerular epithelial or endothelial cells were evident. We conclude that CsA may have a direct protective effect on the glomerular filtration barrier in FSGS. We postulate that increased levels of glomerular cAMP by CsA may play an important role in protecting the glomerular Palbumin effect of the FSGS factor and may contribute to remission of proteinuria in FSGS patients.     

Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme inhibition in rats with established adriamycin nephrosis

1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate. Inhibition of proteinuria might play a role. If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal structural damage. This hypothesis has not been tested in models where treatment is started after the renal disease is well established, i.e. models that mimic the clinical situation. 2. We therefore investigated this hypothesis in 96 male Wistar rats with established adriamycin nephrosis. Reduction of proteinuria was achieved by lisinopril (0, 2, 5 and 10 mg day-1 kg-1) on two different sodium diets (0.3% and 0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and was continued for 6 weeks. 3. Lisinopril reduced blood pressure by 32 +/- 4% and proteinuria by an average of 72 +/- 7%, with stabilization after 2 weeks. Considerable interindividual differences in antiproteinuric response was found. Glomerulosclerosis score was reduced by 15 +/- 5%. All the effects of angiotensin-converting enzyme inhibitors were enhanced by sodium depletion, but sodium depletion in itself did not affect blood pressure (124 +/- 4 mmHg), proteinuria (664 +/- 68 mg/day) or glomerulosclerosis score (30 +/- 5%). Interestingly, the more proteinuria was reduced initially in an individual rat, the less sclerosis was found in the long term in that rat. 4. In conclusion, angiotensin-converting enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in established adriamycin nephrosis. These effects are enhanced by sodium depletion. The individual short-term antiproteinuric effect predicts the protection against ultimate glomerular damage. This is consistent with the hypothesis that reduction of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors exert renoprotection.     

A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome

To investigate the time course of the hepatic glucose metabolism in non-insulin-dependent diabetes (NIDDM), we measured hepatic glucose production (HGP) and first-pass uptake of portal glucose infusion by the liver (HGU) using dual-tracer methods in a NIDDM model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, and in normal controls, Long-Evans Tokushima Otsuka (LETO) rats, at 8, 14, and 28 weeks of age (n = 5, respectively). The fasting plasma glucose level in OLETF rats was significantly higher than in LETO rats at 28 weeks of age (8.9 +/- 1.7 v 6.3 +/- 0.4 mmol/L, P < .01), while there was no significant difference at 8 and 14 weeks. Hyperinsulinemia in OLETF rats appeared at > or = 8 weeks of age. Basal HGP was significantly higher in OLETF than in LETO rats at 8 and 28 weeks (8 weeks, 12.7 +/- 1.7 v 9.4 +/- 1.8 mg x kg(-1) x min(-1), P < .05; 28 weeks, 10.9 +/- 1.6 v 7.1 +/- 1.3 mg x kg(-1) x min(-1), P < .01). At 14 weeks, basal HGP was not significantly different between OLETF and LETO rats. However, at all study points, HGU during a portal glucose infusion was significantly lower in OLETF than in LETO rats (8 weeks, 0.9 +/- 0.2 v 2.3 +/- 0.5, P < .01; 14 weeks, 0.8 +/- 0.3 v 1.4 +/- 0.3, P < .05; 28 weeks, 0.7 +/- 0.2 v 1.4 +/- 0.3 mg x kg(-1) x min(-1), P < .01). Fasting plasma free fatty acid (FFA) levels were not significantly different between OLETF and LETO, except at 8 weeks. Suppression of plasma FFA levels by endogenous insulin during a portal glucose infusion was impaired in OLETF rats compared with LETO rats. In summary, this study demonstrates that derangement of hepatic glucose handling, such as increased basal HGP and decreased HGU, is observed in obese NIDDM model OLETF rats at the prediabetic phase when hyperglycemia is still not apparent. Furthermore, these derangements may be accompanied by impaired lipid metabolism.     

Upregulation of osteopontin expression in renal cortex of streptozotocin-induced diabetic rats is mediated by bradykinin

The model of streptozotocin (STZ)-induced diabetes in Wistar rats was used to study the expression of osteopontin during development of diabetic nephropathy. Diabetes was confirmed by serum glucose levels exceeding 16 mmol/l during the experimental period of 12 weeks. During this period of time, diabetic nephropathy developed, as characterized by a reduced glomerular filtration rate (2.7 +/- 0.3 ml/min in controls vs. 1.7 +/- 0.1 ml/min in diabetic rats) and proteinuria (8.3 +/- 1.7 mg/24 h in controls vs. 22.0 +/- 4 mg/24 h in diabetic rats). Northern blot analysis revealed a time-dependent upregulation of renal cortical osteopontin expression reaching 138 +/- 6% of control levels after 2 weeks and 290 +/- 30% (mean +/- SE, n = 6-9) after 12 weeks. By immunostaining, the increased osteopontin expression could be located to the tubular epithelium of the renal cortex. Chronic treatment of animals with ramipril (3 mg/kg) during the 12-week experimental period led to a further increase in osteopontin mRNA expression in diabetic animals, amounting to 570 +/- 73% (mean +/- SE, n = 6) of controls. Increased levels of osteopontin were not associated with accumulation of monocyte/macrophages that were identified by the cell type specific monoclonal antibody ED-1. The increased osteopontin expression in ramipril-pretreated rats was abolished by application of the bradykinin B2-receptor antagonist, icatibant (0.5 mg/kg). In addition, increased osteopontin expression in diabetic rats, which did not receive any treatment after STZ injection, could as well be reduced by icatibant given for the final 2 weeks of the experimental period. These data suggest that a strong bradykinin B2-receptor-mediated upregulation of osteopontin occurs during the pathogenesis of experimental diabetic nephropathy in rats.     

Group II phospholipase A2 as an autocrine growth factor mediating interleukin-1 action on mesangial cells

The effects of intravenous (3 mg/kg i.v.) and intraplantar (50 micrograms/50 microliters i.pl.) morphine were investigated on spinal c-Fos expression induced 2 h after intraplantar carrageenin (6 mg/150 microliters of saline) and on carrageenin (2 mg/150 microliters of saline) induced mechanical hyperalgesia, at day 4, in both naive and chronic morphine treated (80 mg/kg/day s.c. on days 1, 2 and 3) rats. In naive rats, i.v. and i.pl. morphine significantly decreased spinal c-Fos expression (64 +/- 4% and 44 +/- 4% reduction of control carrageenin c-Fos expression, P < 0.0001 for both, respectively) and mechanical hyperalgesia (maximal increase: 326 +/- 29%, P < 0.0001 and 87 +/- 5%, P < 0.005 of control carrageenin paw pressure vocalisation threshold (VTPP), respectively), which only developed in the carrageenin injected paw. Both treatments were ineffective in chronic morphine treated rats (92 +/- 9% and 106 +/- 6% of control carrageenin c-Fos expression; 33 +/- 17% and 30 +/- 15% increase of control carrageenin VTPP, respectively). Furthermore, only i.v. morphine increased the VTPP in the contralateral paw, in naive rats (maximal increase: 90 +/- 8%, P < 0.0001 of control carrageenin VTPP), its effects being significantly less pronounced than for the inflamed paw (P < 0.0001). These studies based on spinal c-Fos expression as an indirect marker of spinal nociceptive processes and on behavioural experiments clearly revealed that chronic treatment with systemic morphine induced tolerance to both its systemic and peripheral effects.     

The effect of angiotensin-converting enzyme inhibitors on proteinuria in chronic glomerulonephritis

The effect of two angiotensin-converting enzyme (ACE) inhibitors, lisinopril and captopril, on proteinuria and renal haemodynamics was investigated in 11 hypertensives (9 men, 2 women; mean age 46 +/- 16 years) with proteinuria (> 1.5 g/24 h) due to chronic glomerulonephritis and impaired renal function (glomerular filtration rate < 75 ml/min). In a randomized and double-blind cross-over trial the patients received, each time for six weeks, either lisinopril (5 mg/d, sometimes increased to 10 mg/d after 3 weeks) or captopril (twice daily 12.5 mg, sometimes increased to twice 25 mg after 3 weeks). Initially and between the individual treatment phases they were on a placebo phase for 4 weeks. The following were measured: protein excretion, including fractional clearance of albumin and IgG, plasma-renin activity and renal haemodynamics. Protein excretion was not significantly reduced by either drug (placebo: 7.1 +/- 4.0 g/d; lisinopril: 5.1 +/- 2.8 g/d; captopril: 5.4 +/- 3.0 g/d). Albumin excretion and fractional albumin clearance were significantly decreased only by lisinopril (P < 0.05), not by captopril. Plasma-renin activity was increased more by lisinopril than captopril (Placebo: 1.0 +/- 0.9 ng/ml.h; lisinopril: 5.2 +/- 2.8 ng/ml.h [P < 0.05]; captopril: 1.8 +/- 1.3 ng/ml.h [P < 0.05]). The renal haemodynamics was only slightly influenced by either drug, but captopril significantly decreased the filtration fraction in the presence of chronic glomerulonephritis and renal failure. - Resulting from their influence on the renin-angiotensin-aldosterone system, ACE inhibitors have, in addition to their known action on renal haemodynamics, an independent effect on the loading barrier of the basal membrane of the kidney.     

Lack of nephrotoxicity of oral ammine/amine platinum (IV) dicarboxylate complexes in rodents

The comparative nephrotoxicity of i.v. cisplatin, i.v. carboplatin and six p.o. ammine/amine Pt(IV) dicarboxylates was studied in rodents following single MTD treatments. In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days. In contrast, mice treated with i.v. carboplatin or p.o. ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range. In rats, i.v. cisplatin caused 5-fold elevations in plasma creatinine (188 +/- 33 microM) and urea (30.4 +/- 8.9 mM), a 10-fold fall in creatinine clearance (0.54 +/- 0.31 ml min-1 kg-1), a 25-fold elevation in urine/plasma glucose concentration ratio (3.28 +/- 0.17), a 20% increase in kidney weight (7.9 +/- 0.56 mg gm-1 body weight) and extensive histological damage 4 days after treatment. In contrast, i.v. carboplatin and p.o. JM216 (the lead compound of this series) caused neither abnormalities in renal function nor histological damage in rats. The nephrotoxicity of single MTD treatments of p.o. ammine/amine Pt(IV) dicarboxylate complexes appears less than i.v. cisplatin and comparable to i.v. carboplatin.     

Low dose angiotensin converting enzyme inhibition and glomerular permselectivity in renal transplant recipients

In this study, we determined the fractional clearance of neutral polydisperse dextrans (theta D) and monodisperse dextran sulfate (theta DS) to describe glomerular size and charge selectivity in 25 renal transplant recipients with proteinuria. Thirteen were treated with low dose lisinopril for six months (group 1) and 12 patients without ACE inhibitor therapy formed group 2. Mean arterial blood pressure was stable (group 1, 112 +/- 4; group 2, 109 +/- 2 mm Hg at baseline and after 6 months) whereas creatinine clearance, glomerular filtration rate and renal plasma flow decreased nonsignificantly but were comparable at any time. Lisinopril treatment lowered filtration fraction (22 +/- 2 vs. 19 +/- 2%, P = 0.07) whereas no change was seen in group 2 (20 +/- 2%). The fractional protein excretion (mg urinary protein per day/ml creatinine clearance per day) was stable in group 1, but significantly increased in group 2. The same pattern was found for theta D larger than 56 A. theta DS was stable and consistently elevated in both groups at any time. We conclude that low dose ACE inhibitor treatment in proteinuric renal transplant recipients stabilizes glomerular size selectivity independently of its systemic hemodynamic effects.     

Identification of nitric oxide synthases in isolated bovine brain vessels

Initial reports on antiproteinuric effect of pefloxacine in small groups of patients with minimal-change nephropathy (MCN) and focal and segmental glomerulosclerosis (FSGS) have not been confirmed in other papers. To assess its antiproteinuric effect in experimental animals we administered pefloxacine to rats with adriamycin nephropathy showing morphological changes resembling human minimal-change disease or focal segmental glomerulosclerosis, and clinically with full-blown nephrotic syndrome. Pefloxacine treatment was at least partially effective in preventing further increase of proteinuria in rats with adriamycin nephropathy. The mechanism of this effect remains unclear and deserves further studies concentrating on the glomerular cytokine network and glomerular production of reactive oxygen species.     

Role of kinins in the acute antihypertensive effect of enalapril in hypertensive rats

1. We used the kinin antagonist HOE 140 to investigate the role of endogenous kinins in the acute antihypertensive effect of the angiotensin converting enzyme inhibitor enalapril in chronic and acute renal hypertensive rats. 2. In normotensive rats, treatment with HOE 140 (33 micrograms/kg, sc) caused a complete blockade of the depressor effect of bradykinin (100 ng, ia) without affecting the depressor effect of sodium nitroprusside (1 microgram, i.v.) or the basal blood pressure. 3. HOE 140 treatment (33 micrograms/kg, sc, plus 330 ng/min, i.v.) did not affect basal blood pressure of chronic (6-7 weeks) one-kidney, one clip and two-kidney, one clip hypertensive rats and in rats with acute hypertension, elicited by unclamping the renal pedicle that had been occluded for 5 h, but HOE 140 completely blocked the hypotensive response to bradykinin (100 ng, ia) during the 60-min period after enalapril administration (2 mg/kg, i.v.). 4. Acutely hypertensive rats treated or not with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) presented a similar fall in blood pressure after enalapril (165 +/- 5 to 137 +/- 6 mmHg and 166 +/- 5 to 136 +/- 6 mmHg, respectively). 5. Untreated two-kidney, one clip hypertensive rats presented a rapid and sustained fall in blood pressure after enalapril (177 +/- 4 to 148 +/- 4 mmHg) that did not differ from the HOE 140-treated (33 micrograms/kg, sc, plus 330 ng/min, i.v.) group (177 +/- 6 to 154 +/- 4 mmHg). 6. One-kidney, one clip hypertensive rats treated with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) showed a significantly smaller fall in blood pressure after enalapril (204 +/- 7 to 179 +/- 9 mmHg) compared to the untreated rats (197 +/- 7 to 149 +/- 2 mmHg). 7. These results indicate that kinin potentiation plays an important role in the antihypertensive effect of acutely administered angiotensin converting enzyme inhibitor in the one-kidney, one clip model of hypertension.     

Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular morphology in nephrotic heroin addicts

Renal biopsies of 23 heroin addicts who presented with the nephrotic syndrome were examined by light and electron microscopy. The majority of patients (14) showed focal segmental glomerular sclerosis on light microscopy, four patients showed "minimal change", and two were classified as "focal global sclerosis." In one case focal mesangial proliferation was the outstanding feature; one patient had diabetic glomerulosclerosis; and one had mesangiocapillary glomerulonephritis and dysproteinemia. Visceral epithelial swelling and proliferation were present in 14 patients on light on light microscopy. Electron microscopy showed distinct podocyte changes consisting of loss of foot processes, vacuolization, and cytoplasmic degeneration; focal separation of podocytes from basement membranes was found in 11 of 18 cases. In some instances a few electron-dense deposits were present in the mesangium. Membranous nephropathy was not encountered, although it occurs in 30 to 40% of unselected adult nephrotic individuals. Of 15 patients followed for 2 months to 5 years, one died of heroin overdose, eight went into renal failure, two improved, and four continued to have proteinuria. It is concluded that nephrotic syndrome of heroin addicts is most often associated with focal segmental glomerular sclerosis and occasionally with minimal change disease or focal global sclerosis. Conceivably these three conditions represent different phases of one disease process, although different reactions to heroin or its various vehicles and contaminants cannot be excluded. The morphologic resemblance to experimental aminonucleoside and N,N'-diacetylbenzidine-induced nephrosis suggests a possible toxic origin.     

Relationship between auditory intensity discrimination in noise and olivocochlear efferent system activity in humans

The intravenous (i.v.) steroid anesthetic, eltanolone, compares favorably to propofol with respect to its induction characteristics. This double-blind investigation was designed to compare the induction and recovery profile of eltanolone (versus propofol) when it was used for both induction and maintenance of ambulatory anesthesia. Eighty-three consenting ASA physical status I-III outpatients undergoing minor gynecologic or urologic procedures lasting 10-40 min were randomly assigned to one of three anesthetic treatment groups. All patients received midazolam, 2 mg i.v., and fentanyl, 50 micrograms i.v., before induction of anesthesia. The control group (Group 1) was induced with propofol, 2.4 mg/kg i.v. (18-60 yr or ASA physical status I or II) or 1.6 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus doses of 0.6 mg/kg i.v. in combination with N2O 67% for maintenance of anesthesia. In Group 2, anesthesia was induced with eltanolone, 0.75 mg/kg i.v., (18-60 yr and/or ASA physical status I or II) or 0.5 mg/kg i.v. (61-80 yr and/or ASA physical status III), and maintained with intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. Group 3 received eltanolone, 1.0 mg/kg i.v. (18-60 yr and/or ASA physical status I or II), or 0.75 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. In addition to recording the induction and recovery times and side effects, psychomotor testing was performed before and at 30-min intervals after anesthesia. Induction times (57 +/- 23, 67 +/- 26, and 61 +/- 22s, respectively) were similar in all three groups. Although eltanolone produced no pain on injection (versus 52% in the propofol group), 10% of the eltanolone-treated patients (versus none in the propofol group) developed transient cutaneous (rash-like) reactions. The total dose of study medication used during the anesthetic period was 9.2 +/- 3.7 mg.kg-1.h-1 in the propofol group compared with 3.3 +/- 1.4 mg.kg-1.h-1 and 3.3 +/- 1.9 mg.kg-1.h-1 in Groups 2 and 3, respectively. Early recovery times were significantly shorter after propofol anesthesia. However, times to ambulation, micturition, and being judged "fit for discharge," as well as recovery of cognitive function, were similar in all three groups. Although ethanolone seems to be a safe and effective i.v. anesthetic, these data suggest that it is unlikely to replace propofol in the ambulatory setting. Implications: Eltanolone is an investigational steroid anesthetic that causes less pain on injection and less cardiovascular depression than propofol (the most widely used intravenous anesthetic in the outpatient setting). Unfortunately, emergence from anesthesia after ambulatory surgery is slower with eltanolone compared with propofol. Therefore, it is unlikely that eltanolone will replace propofol for outpatient anesthesia.