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N Perico

Publications and source records attributed to N Perico.

At least 127 records · Page 7Linked to original sources
PubMed1989

Abnormalities in arachidonic acid metabolites in nephrotoxic glomerular injury.

Arachidonic acid metabolites are suspected of contributing in various ways to major pathophysiological events that occur in toxic and immune glomerular injury. This paper focuses on the role of arachidonate metabolites in the experimental models of adriamycin nephrosis and cyclosporin A nephrotoxicity in rats as examples, respectively, of a toxic nephropathy characterized by increased glomerular permeability to proteins and a toxic nephropathy with macrophage accumulation and progressively deteriorating renal function. The important pathogenic contribution of thromboxane A2 to the impairment of renal function in these experimental models is discussed.

Animals↗
PubMed1989

Blunted excretory response to atrial natriuretic peptide in experimental nephrosis.

Adriamycin (ADR) nephrosis and a model of unilateral ADR-induced proteinuria were produced in Sprague-Dawley (S.D.) rats to investigate the mechanism of sodium retention by the nephrotic kidney. Plasma volume, as measured by the dilution principle using radioiodinated serum albumin, was significantly higher in nephrotic animals than in control ones (NS: 69.61 +/- 15.02: control: 47.05 +/- 5.32 ml/kg: P less than 0.01). Similarly plasma levels of immunoreactive ANP (iANP) were significantly higher in nephrotic animals compared to controls (NS 104.22 +/- 36.41: control 59.94 +/- 20.88 pg/ml; P less than 0.05). Using the unilateral model we found a markedly reduced diuretic and natriuretic response to the infusion of synthetic rat atrial natriuretic peptide (ANP 1-28) in proteinuric kidney but not in contralateral kidney, despite a comparable increase in glomerular filtration rate. To explain the blunted diuresis and natriuresis in the presence of normal glomerular response to ANP, we investigated the possibility of an abnormality at post-glomerular level by studying ANP receptor density and affinity of the inner stripe of outer medulla and the inner medulla in ADR-and vehicle-treated rats. The inner stripe of outer medulla and the inner medulla receptor density and affinity were not significantly different in ADR rats as compared to animals given the vehicle alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of tertatolol on renal function in the isolated perfused rat kidney.

Tertatolol, a new beta-adrenergic blocker, increases glomerular filtration rate (GFR) and renal plasma flow (RPF), and enhances diuresis and natriuresis in experimental animals and humans. The mechanism underlying the renal effects of tertatolol has not been established. In the present study we addressed the possibility that tertatolol influences renal function by a direct intrarenal mechanism. For this purpose we used a preparation of isolated rat kidney perfused with an artificial cell-free medium. Tertatolol when given as a bolus injection into the renal artery at the dose of 25 and 50 micrograms/kg, but not of 12.5 micrograms/kg, significantly enhanced the glomerular filtration rate (GFR) and perfusate flow rate (PFR). In contrast, the intrarenal bolus injection of different doses of propranolol (100, 250, or 500 micrograms/kg) was unable to change GFR and PFR to a significant extent. While no change in urine flow rate was found when the lowest dose of tertatolol was used, the compound at the dose of 25 and 50 micrograms/kg progressively increased urine flow during the time of perfusion. A similar effect of tertatolol was observed for urinary sodium and potassium excretion. In contrast, different doses of propranolol did not significantly change the urine flow rate or sodium and potassium excretion rates. We conclude that tertatolol, but not propranolol, increases GFR and PFR, and enhances urine output and sodium excretion in the isolated perfused rat kidney. These findings indicate that tertatolol preserves renal function by a mechanism independent of systemic changes.

Adrenergic beta-Antagonists↗
PubMed1989

Atrial natriuretic factor in hypertensive and normotensive insulin-dependent diabetics.

Since insulin increases renal sodium reabsorption, hyperinsulinaemia in insulin-treated insulin-dependent diabetes mellitus might lead to sodium retention and, in turn, increase atrial natriuretic factor (ANF) values. We investigated ANF levels in insulin-dependent diabetes mellitus with and without hypertension. We infused saline (2 mmol/kg per 90 min) in nine normotensive controls, eight normotensive diabetics, seven hypertensive controls and six hypertensive diabetics during the imposition of a euglycaemic glucose clamp with an artificial pancreas. Baseline ANF values were higher in the normotensive and hypertensive diabetics than in the normotensive and hypertensive controls. During a sodium load the sodium excretion rate increased significantly in controls but not in the diabetic groups. The ANF pattern was similar, values being significantly increased in controls and unchanged in diabetic patients. We conclude that euglycaemic, slightly hyperinsulinaemic, insulin-dependent diabetes mellitus patients with and without hypertension are characterized by higher baseline ANF values and an impaired response to an acute saline load as shown by the sodium excretion rate and the plasma ANF concentration.

Atrial Natriuretic Factor↗
PubMed1989

Renal metabolism and urinary excretion of thromboxane B2 in the rat.

We wanted to evaluate whether the kidney tissue can metabolize thromboxane (Tx) B2 and, specifically, whether the 2,3-dinor metabolite might be formed in the kidney and excreted in the urine. For this purpose, we used an isolated perfused kidney preparation exposed to vehicle or TxB2 at different infusion rates. Approximately 96% of the total TxB2 infused was recovered in the venous effluent, whereas approximately 1% was found in urine. Isolated perfused kidneys exposed to [3H]TxB2 eliminated in the urine 1.2% of the [3H]TxB2 infused, measured by thin-layer chromatographic analysis, and actively metabolized [3H]TxB2 to 2,3-dinor-TxB2, 11-dehydro-TxB2, and possibly 2,3,4,5-tetranor-TxB1. No metabolites of TxB2 were recovered in the venous effluent. As a marker of renal TxB2 metabolic activity, urinary 2,3-dinor-TxB2 was quantified by high-resolution gas chromatography-negative-ion chemical ionization mass spectrometry. The 2,3-dinor-TxB2 was detected both before and during TxB2 infusion in urinary samples but not in the venous effluent. The ratio of 2,3-dinor-TxB2-TxB2 increased during the infusion reaching a peak value immediately after stopping the TxB2 infusion. These results indicate that, in the rat, the kidney tissue metabolizes TxB2 to 2,3-dinor-TxB2, and both TxB2 and 2,3-dinor-TxB2 are excreted in the urine.

Animals↗
PubMed1989

Renal handling of aspirin in the rat.

Aspirin (ASA), in addition to blocking platelet cyclooxygenase, thus preventing thromboxane A2 formation, can also block renal cyclooxygenase thus inhibiting the renal synthesis of vasodilatory prostaglandins (PGs) which can induce renal function deterioration. The purpose of the present study was to clarify the pharmacological basis of the inhibitory effect of ASA on renal cell cyclooxygenase in the rat. ASA was given to rats either i.v. or p.o. at doses ranging from 10 to 200 mg/kg. After both i.v. and p.o. administration ASA was rapidly detected in plasma as intact molecule. The kinetics were of a dose-dependent type with a disproportionate increase in plasma level increasing the dose. Plasma salicylic acid (SA) concentrations peaked after ASA with a precursor product relationship. ASA levels in kidney homogenates were also determined after i.v. and p.o. ASA. Whereas after i.v. administration ASA was detected in the kidney as intact molecule, no ASA was detected in the kidney after p.o. administration. SA was measurable in the kidney after both i.v. and p.o. ASA with a time course which paralleled the plasma concentrations. Results of isolated kidneys perfused with a medium containing ASA and of kidney homogenates exposed to ASA "in vitro" indicate that ASA is rapidly converted to SA by kidney tissue enzymes. After ASA hydrolysis SA accumulates in the kidney and may protect renal cyclooxygenase from the inhibitor effect of ASA.

Animals↗
PubMed1989

Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials.

Previous studies have shown that platelet-activating factor (PAF) receptor blocking has a protective effect on rabbit nephrotoxic nephritis (NTN). We examined whether arachidonic acid (AA) metabolism is altered in NTN and whether a PAF receptor antagonist has any influence on such changes. Rabbits injected with anti-glomerular basement membrane antiserum in the heterologous phase had a markedly increased glomerular thromboxane B2 (TxB2) production level, whereas no changes have been detected in glomerular 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2). During the autologous phase of the disease, the glomerular TxB2 level was even higher than in the heterologous phase. The level of 6-keto-PGF1 alpha was significantly lower than normal, and the level of PGE2 was unchanged in respect to the basal values. The use of L-652,731 (a specific PAF receptor antagonist) reversed the abnormal generation of AA metabolites at glomerular level both in the heterologous and autologous phase of the disease. The effect of L-652,731 on AA metabolism is likely to be an indirect result of the PAF receptor blocking, because L-652,731 given to normal rabbits had no direct effect on glomerular AA metabolism. To assess whether the beneficial effect of L-652,731 in NTN is at least in part mediated by its capability of suppressing the excessive intrarenal synthesis of thromboxane A2 (TxA2), we compared the effect of L-652,731 with that of a selective TxA2-synthase inhibitor (FCE-22178). FCE-22178 ameliorated the morphologic expression of rabbit NTN and reduced function deterioration. The protective effect of L-652,731 on proteinuria in the autologous phase and on glomerular filtration rate in both phases was superior to that of FCE-22178. We conclude that an excessive intraglomerular synthesis of TxA2 occurs in rabbit NTN that can play a role in renal function deterioration. Both a specific PAF receptor antagonist and a TxA2-synthase inhibitor reduced the exaggerated TxA2 synthesis and favorably influenced the evolution of the disease.

Animals↗
PubMed1989

Tumor necrosis factor induces glomerular damage in the rabbit.

Tumor necrosis factor (TNF) is a polypeptide hormone produced by activated macrophages detectable in the circulation of experimental animals given endotoxin. Recent evidence strongly suggests that many of the deleterious effects of endotoxin in experimental animals are mediated by TNF. Because endotoxemia in experimental animals and humans is associated with glomerular damage the present investigation was designed to establish whether TNF directly induces glomerular functional and structural changes. Twenty-three rabbits were given human recombinant TNF at the doses of 0.08, 0.8, and 8.0 micrograms/kg/h as a continuous 5-hour intravenous infusion. Animals were killed at the end of the infusion. All rabbits given 0.8 and 8.0 micrograms/kg/h TNF developed anemia (Ht value decrease at 5 hours: 0.8 microgram/kg/h, 15%; 8.0 micrograms/kg/h, 16%); leukopenia (leukocyte count decrease at 5 hours: 0.8 micrograms/kg/h, 47%; 8.0 micrograms/kg/h, 59%); thrombocytopenia (platelet count decrease at 5 hours; 0.8 micrograms/kg/h, 45%; 8.0 micrograms/kg/h, 57%). Rabbits given 8.0 micrograms/kg/h also had renal failure (serum creatinine from 1.02 +/- 0.15 to 1.64 +/- 0.34 mg/dl). By light microscopy only occasional polymorphonuclear leukocytes in the glomerular capillaries were detectable in rabbits infused with 0.08 micrograms/kg/h TNF, whereas with 0.8 micrograms/kg/h TNF the presence of inflammatory cells in the glomerular capillaries was the prominent finding. With 8.0 micrograms/kg/h TNF beside leukocyte accumulation, fibrin was detected in the glomerular capillary lumens of two of eight animals. Electron microscopy found dose-dependent glomerular endothelial cell damage in animals given TNF with fibrinlike material in the capillary lumens. Glomerular changes induced by TNF were remarkably similar to those previously found in animals given endotoxin. Thus, TNF is likely to be the mediator of endotoxin-induced glomerular damage and can be regarded as a new mediator of macrophage-dependent damage in glomerulonephritis.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Increased urinary excretion of thromboxane B2 and 2,3-dinor-TxB2 in cyclosporin A nephrotoxicity.

Cyclosporin A (CsA) administration to rats is associated with a selective increase in urinary excretion of immunoreactive thromboxane B2 (i-TxB2), the stable breakdown product of TxA2. The exaggerated synthesis of TxA2 may play a role in the reduction of glomerular filtration rate (GFR) observed both in animals and humans undergoing CsA treatment. The present study was designed to get further insight into the origin of the abnormal i-TxB2 urinary excretion. Rats given orally CsA (50 mg/kg/day) for 30 days had a significant increase in the urinary excretion of both 2,3-dinor-TxB2 and TxB2 measured by technique of capillary column gas chromatography-negative ion chemical ionization mass spectrometry (HRGC-NICIMS). Urinary TxB2 is more likely to reflect the renal synthesis of the parent compound, whereas 2,3-dinor-TxB2 is considered to reflect the amount of TxB2 formed in the circulation. Experiments in isolated perfused kidney (IPK) taken from animals given CsA for 30 days showed a lower percentage increase in urinary TxB2 over vehicle treated animals. Moreover in IPK the ratio 2,3-dinor-TxB2/TxB2 was lower than in vivo. The amount of i-TxB2 detectable in serum of animals given CsA was not different from that of control animals. In contrast, isolated glomeruli taken from rats given CsA had an increase in their TxA2 synthesis measured as i-TxB2 in the supernatants. Ultrastructural studies on kidney specimens from animals given CsA showed a focal glomerular endothelial damage together with a marked infiltration of blood borne cells of monocyte-macrophage type in the glomerular tuft. In contrast, kidney specimens taken from IPK preparations were devoid of inflammatory cells. In vitro CsA did not interfere with platelet arachidonic acid (AA) metabolism as shown by a normal i-TxB2 generation in vitro by rat platelet-rich plasma (PRP) exposed to CsA and then challenged with AA or ADP. Similarly isolated glomeruli and isolated proximal tubules from normal rats when challenged with CsA in vitro converted AA into TxA2 normally. It is suggested that the cause of the increased urinary excretion of 2,3-dinor-TxB2 is the consequence of intrarenal platelet and macrophage activation, probably triggered by the endothelial damage. The parallel increase in the urinary excretion of unmetabolized TxB2 is likely to reflect a concomitant activation of resident renal cell AA metabolism induced by CsA.

Animals↗
PubMed1988

Tertatolol ameliorates renal function in rats with chronic renal failure.

Tertatolol is a new beta-blocking agent which induces renal vasodilation in experimental animals and humans and increases glomerular filtration rate (GFR), diuresis and natriuresis. The mechanisms underlying renal effects of tertatolol are not known. Our aims were to establish whether tertatolol influences renal function by a systemic or by an intrarenal effect and to assess whether tertatolol could maintain GFR in chronic renal failure. Tertatolol but not propranolol when given as i.v. bolus injection at the dose of 25 and 50 micrograms/kg. b.w. induces a significant increase in GFR and perfusate flow rate (PFR) in an isolated perfused kidney model [GFR: tertatolol, 25 micrograms/kg; preinjection: 0.477 +/- 0.077 ml/min/g of kidney; 30 min postinjection: 0.996 +/- 0.114 ml/min/g of kidney. Tertatolol (50 micrograms/kg) preinjection: 0.517 +/- 0.040 ml/min/g of kidney; 30 min postinjection: 0.879 +/- 0.035 ml/min/g of kidney. Propranolol (500 micrograms/kg) preinjection: 0.574 +/- 0.045 ml/min/g of kidney; 30 min postinjection: 0.538 +/- 0.029 ml/min/g of kidney. PFR: tertatolol, 25 micrograms/kg, preinjection: 30.00 +/- 0.79 ml/min; 30 min postinjection: 36.20 +/- 2.58 ml/min. Tertatolol (50 micrograms/kg) preinjection: 29.30 +/- 1.44 ml/min; 30 min postinjection: 38.01 +/- 1.87 ml/min. Propranolol (500 micrograms/kg) preinjection: 28.70 +/- 1.04 ml/min; 30 min postinjection: 28.30 +/- 0.91 ml/min]. In the same preparation tertatolol significantly increases urine flow rate and Na+ excretion [urine flow rate: tertatolol (25 micrograms/kg) preinjection: 28.28 +/- 4.10 microliter/min; 60 min postinjection: 38.23 +/- 6.74 microliter/min. Tertatolol (50 micrograms/kg) preinjection: 24.02 +/- 0.63 microliter/min; 60 min postinjection: 33.18 +/- 2.07 microliter/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1988

Effect of platelet-activating factor and its specific receptor antagonist on glomerular permeability to proteins in isolated perfused rat kidney.

Platelet-activating factor (PAF) is a lipid mediator of inflammation believed to play a role in glomerulonephritis by favoring immune complex formation and modulating the subsequent inflammatory reaction. Some evidence indicates that PAF may also be one of the mediators of proteinuria. Previous work suggested that PAF can increase glomerular permeability to proteins, activating platelets and inflammatory cells to release cationic proteins. In the present study, we addressed the possibility that PAF might directly increase glomerular permeability to proteins independently of platelets and inflammatory cells. We used a preparation of isolated rat kidney perfused with an artificial cell-free medium. After stabilization and two 10-minute control clearance periods, kidneys perfused in a closed circuit were exposed to PAF (2 nM or 10 nM final concentration) or 2-lyso-PAF (10 nM final concentration) or vehicle for 40 minutes. Glomerular filtration rate, measured as creatinine clearance, and renal vascular resistance did not significantly change when either PAF (2 nM or 10 nM) or 2-lyso-PAF, or vehicle were added to the perfusion fluid. Unlike vehicle or 2-lyso-PAF, addition of PAF at the final concentration of 2 and 10 nM to the perfusate produced a dose-dependent progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by L-652,731, a specific PAF receptor antagonist, suggesting that PAF's effect on glomerular permeability to proteins is likely to be related to its biologic activity. Several pharmacologic manipulations addressed to the potential mediators of PAF effect on glomerular permeability to proteins would exclude that the effect of PAF on isolated perfused kidney is mediated by cyclooxygenase or lipoxygenase products, or is the result of oxygen-free radical generation. The possibility that PAF enhances glomerular permeability to proteins by changing the glomerular barrier electrostatic properties was explored using polyethylene-imine. Electron microscopy examination revealed no difference in the distribution of electron-dense deposits along the glomerular basement membrane in kidneys exposed to 10 nM PAF or vehicle.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Renal response to atrial peptides is reduced in experimental nephrosis.

The aim of this study was to evaluate the renal response to atrial extracts (AE) and synthetic atrial natriuretic factor (ANF) in control rats and in rats with experimental nephrotic syndrome (NS). NS was obtained by a single intravenous injection of adriamycin (7.5 mg/kg). Bolus injection of AE from normal or NS rats resulted in marked increase of diuresis and natriuresis in bioassay control rats (AE from normal rats, urine flow rate, 14.87 +/- 2.94 to 186.18 +/- 55.86 microliters/min; Na excretion, 0.68 +/- 0.26 to 21.80 +/- 5.45 mu eq/min; AE from NS, urine flow rate, 13.49 +/- 4.30 to 167.14 +/- 51.44 microliters/min; Na excretion, 0.98 +/- 0.57 to 20.71 +/- 9.76 mu eq/min). In contrast, blunted diuretic (from 11.26 +/- 3.05 to 65.20 +/- 27.30 microliters/min) and natriuretic (from 0.58 +/- 0.15 to 4.52 +/- 1.59 mu eq/min) effect was observed when AE were injected in rats with NS. Injection of the vehicle in which AE were dissolved or ventricular extracts did not increase urinary flow rate or Na excretion in both control and NS animals. Bolus injection of synthetic ANF (Arg-101-Tyr-126) induced marked diuretic and natriuretic response in control but not in NS rats. Similar results were obtained when AE were infused by constant infusion in control or in NS bioassay rats. AE given by constant infusion induced comparable increase in glomerular filtration rate (GFR) over basal values both in control and NS animals (controls, 39%; NS rats, 40%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Renal injury induced by long-term administration of cyclosporin A to rats.

Chronic administration of cyclosporin A (CyA) to animals and humans results in renal damage characterized by tubulointerstitial lesions and renal insufficiency. This nephrotoxicity limits the use of CyA in the management of graft rejection. Despite recent investigations in this area, relatively few studies correlate structural and functional abnormalities in animals undergoing long-term CyA treatment. The authors therefore treated 30 rats with CyA at the dose of 40 mg/kg/48 hr for up to 5 months. An additional group of 30 rats was given the vehicle alone and was considered as a control group. Renal morphology and function were studied. For evaluation of the effect of drug withdrawal, a third group of 25 animals received CyA for 3 months and was followed for another 2 additional months after drug withdrawal. The results show that the chronic administration of CyA to rats induced complex renal morphologic changes, associated with renal insufficiency, polyuria, and enhanced sodium excretion. Withdrawal of the drug resulted in almost complete normalization of morphologic and functional parameters. The early morphologic expression of CyA nephrotoxicity was isometric vacuolization and loss of brush border involving the proximal tubular cells, followed by a peculiar lesion in distal tubular cells due to glycogen accumulation. Glomerular and interstitial damage was mild and appeared only after 3 months of CyA administration. No vascular abnormalities were found in rats treated with CyA for 5 months. A CyA-induced decrease in the glomerular filtration rate (GFR) correlates with brush border loss but not with isometric vacuolization. The distal tubular glycogen accumulation was associated with the development of polyuria and enhanced sodium excretion. Given the high blood sugar level and severe glycosuria in animals treated chronically with CyA, it is also concluded that CyA possesses a diabetogenic effect which is likely to be responsible for glycogen accumulation at the tubular level.

Animals↗
PubMed1986

Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A.

Animals and humans undergoing a chronic treatment with cyclosporin A (CyA) show a reduction in glomerular filtration rate (GFR). The cause of this abnormality has not been established. Since CyA interferes with arachidonic acid (AA) metabolism in various cells, we wished to determine whether alterations in renal AA metabolites contribute to deteriorating renal function in rats on CyA. We show that chronic CyA treatment induces a progressive increase in the renal synthesis of thromboxane (TX) A2. This is a selective abnormality in that CyA does not influence the renal synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). A significant negative correlation has been found between TXB2 urinary excretion rate and inulin clearance. No correlation has been observed between TXB2 excretion and p-aminohippuric acid clearance. The withdrawal of CyA is followed by a normalization of both TXB2 urinary excretion rate and GFR. The administration of a selective TXA2 inhibitor, UK-38,485, resulted in a significant reduction in urinary excretion of TXB2 accompanied by a significant increase in GFR. We conclude that chronic treatment with CyA in rats is associated with a selective increase in renal TXA2 synthesis and suggest that this abnormality may play a role in the reduction of GFR.

Animals↗
PubMed1986

Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins?

Cyclosporine A (CsA) is a recently introduced immunosuppressive agent that represents a significant advance in the clinical control of graft rejection. However despite the remarkable effectiveness, one of the limiting factors to a more extensive use of CsA appears to be its nephrotoxicity. CsA is reported to induce a tubular epithelial damage whereas histological examination of glomeruli does not reveal abnormalities unless particularly high doses of the drug are used. On the other hand a decrease in glomerular filtration rate (GFR) has been reported in association with acute administration of CsA. Relatively few studies are available to compare structural and functional abnormalities in the same animals after an acute administration of CsA. Here we evaluated morphological abnormalities and renal function in the same animals treated for 20 days with CsA. Moreover in the attempt to find a link between tubular damage and decrease in GFR we studied the effect of CsA on the renin-angiotensin system as well as on glomerular synthesis of prostacyclin (PGI2) and prostaglandin E2 (PGE2). Our results confirmed that CsA induces a focal damage of tubular epithelial cells with isometric vacuolization of cytoplasm. No glomerular or vascular changes have been detected at histological examination. Serum creatinine was significantly elevated after 20 days of treatment, whereas creatinine clearance showed a progressive tendency to decrease without reaching a statistical significance. Plasma renin activity was found to progressively increase during CsA administration, whereas the synthesis of PGI2 and PGE2 by isolated glomeruli was not modified in CsA-treated animals in respect to animals receiving the solvent alone.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗