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Biomedical subjects

J Cambar

Publications and source records attributed to J Cambar.

At least 37 records · Page 2Linked to original sources
PubMed1996

Circadian rhythms in renal function in hypertensive TGR(mRen-2)27 rats and their normotensive controls.

Patients with secondary hypertension frequently display abnormal circadian blood pressure profiles, characterized by a failure to decrease blood pressure at night. The transgenic TGR(mRen-2)27 rat strain, developing fulminant hypertension after the mouse salivary Ren-2 renin gene has been integrated into its genome, provides a fundamental model of genetic hypertension. Because of an inverse circadian blood pressure profile and an unchanged rhythmic pattern of heart rate compared with the normotensive Sprague-Dawley (SPR) strain, it was proposed to serve as an animal model of genetic hypertension. It was the aim of the present study to investigate the circadian rhythmicity in renal function of the transgenic rat to determine whether hypertension and disturbed circadian blood pressure profile would affect kidney function. Urinary water, electrolyte, and protein excretion, as well as glomerular filtration rate and renal plasma flow, were determined in unrestrained freely moving transgenic hypertensive (TGR) and SPR normotensive control rats by collecting urine and arterial blood every 4 h. Significant and similar circadian rhythms were found in renal excretion and hemodynamics in both normotensive and hypertensive strains. Peaks occurred in the active dark period, whereas troughs were found in daytime for all parameters. However, it has to be pointed out that, although the circadian profiles were not grossly perturbed in hypertensive animals, some small differences between SPR and TGR strains did exist in renal function. These discrepancies were precisely related to acrophase, showing a slight phase delay, and also to relative amplitude in TGR. This study demonstrates that the inverted circadian blood pressure profile affected only slightly the circadian rhythms in kidney function in TGR compared with SPR. These findings support the notion that time-dependent changes in systemic blood flow may be of greater importance for circadian regulation of kidney function than systemic blood pressure.

Animals↗
PubMed1996

Relationship between circadian changes in renal hemodynamics and circadian changes in urinary glycosaminoglycan excretion in normal rats.

Circadian changes in renal hemodynamics and urinary glycosaminoglycan (GAG) excretion were studied in normal Sprague-Dawley rats to further investigate rhythms in kidney function. Urinary water, protein, and GAG excretion, as well as glomerular filtration rate (GFR) and renal plasma flow (RPF), were determined every 4h over the 24h cycle in an attempt to characterize any temporal changes. Urinary flow rate and proteinuria peaked during the dark activity period of the animals, consistently at the same hour, whereas the lowest values were detected during the resting phase. GAG are mucopolysaccharides entering the constitution of the glomerular basement membrane (GBM), which is the key component in the process of glomerular filtration. Similarly, the urinary excretion rate of GAG showed a circadian rhythmicity in phase with urinary water and protein excretion, with markedly increased values observed during the nocturnal phase of the animals. Moreover, GFR and RPF were demonstrated to exhibit large circadian variations in phase with renal excretory rhythmicity, showing nighttime values significantly greater compared to daytime ones. Strong correlations were found between GFR and RPF rhythms, as well as between GAG and GFR, and GAG and RPF rhythms, although the latter were not statistically significant. This pattern suggests that the circadian rhythmicity in urinary excretion rate of GAG in physiological conditions could presumably be secondary to the temporal changes in renal hemodynamics. In this respect, knowledge of renal chronobiology helpfully contributes to increase our understanding of renal physiology.

Animals↗
PubMed1996

Pharmacologic profile of iobitridol, a nonionic iodinated contrast medium.

The present article combines and summarizes the preclinic studies carried out in vitro and in vivo to determine the pharmacologic and biochemical profile of iobitridol, a new nonionic iodinated low-osmolality contrast medium (CM). The effects of this product on the main hemodynamic, bronchopulmonary, neurologic, renal, blood chemistry and electrophysiologic parameters and RBC morphology were studied in detail in comparison with CM in the same chemical category or with reference substances of the same osmolality. The in vivo studies were performed under conditions resembling clinical use. Iobitridol showed an excellent pharmacologic and biochemical profile, which was identical or superior to that of other products in its category.

Animals↗
PubMed1996

[Circadian changes in physiological urinary excretion of glycosaminoglycans in healthy rats].

Particular chemical structure and original molecular arrangement make the glomerular basement membrane (GBM) to play a key role in the glomerular filtration, by restraining selectively the transglomerular pathway of high molecular weight charged macromolecules. The present study gives evidence, for the first time in the literature, of circadian changes in physiological urinary glycosaminoglycans (GAGs) excretion, main components of the GBM, in normal rats. Urine was collected every 4 hours during 6 consecutive spans in 45 Sprague-Dawley rats, housed in individual metabolism cages (8.00-12.00, 12.00-16.00, 16.00-20.00, 20.00-00.00, 00.00-04.00 and 04.00-08.00). GAGs, water, protein and electrolyte excretion were quantified in each sample. The analysis of these solute temporal changes was done by the cosinor method and shows that a circadian rhythm can be detected. These rhythms exhibit a significant increase between 20.00 and 8.00, with a peak between 00.00 and 04.00 and a minimum between 12.00 and 20.00. A precise estimation of the rhythmic characteristics permitted to detect the acrophase of each parameter nearly at the same time, respectively at 23.25 for diuresis, 23.33 for GAGs, 23.32 for proteins, 23.32 for sodium and 23.44 for potassium excretion. Such chronophysiological data suggest a tight correlation between urinary GAGs excretion and urinary water and electrolyte excretion in physiological conditions, in normal rats. Because of the great complexicity of the factors involved in the kidney the renal excretion regulation, the different origins of these temporal changes are largely discussed.

Animals↗
PubMed1996

[Chronotoxicology, a relatively unknown approach in toxicology].

Biorhythmicity of living organisms is well-known for many decades by numerous studies in cell biology, in physiology and more recently in pharmacology. Reality of temporal changes in structures and functions of biological systems is clear whatever their complexity level. Such temporal variations can explain that the same xenobiotics, whatever its origin (pathogenous, medicamentous or toxic) does not induce the same efficacity or side effects in a living organisms, if it is given at different hours in the day or at different seasons in the year. This review considers the classical and recent data of the temporal dimension of the toxicology, so called chronotoxicology, describing as well experimental aspects as clinical ones showing the influence of time administration of drugs largely used in clinic with a poor unfair therapeutic index on their efficacity, tolerance and toxicity. Toxicological studies using lethal or sublethal doses with specific organ targets as liver, ear, digestive tractus or kidney will be described. Conclusions of this review evidence the necessity to precise for such chronotoxicological experiments the time of the day and the month of the year where they are performed.

Animals↗
PubMed1994

Image analyser as a tool for the study of in vitro glomerular vasoreactivity.

Many drugs used in clinics can dramatically reduce renal hemodynamics. For some years there have been developed in our laboratory two in vitro glomerular models, isolated glomeruli and mesangial cell cultures, to quantitate, by video image analyzer, the direct glomerular effect of vasoreactive agents. The present study shows the vasoconstrictive effects of angiotensin II and cyclosporin in both models and compares their glomerular vasoconstriction with or without vasodilating agents such as verapamil. This drug-induced glomerular vasoreactivity is time- and dose-dependent; moreover, it can be reversible after perfusion in control conditions. The interest of these in vitro glomerular models is validated by fair correlations between in vivo and in vitro data and between the responses of both. These models can be considered as tools for assessing glomerular vasoreactivity of nephrotoxic agents.

Angiotensin II↗
PubMed1994

Characterization of C-type natriuretic peptide receptors in human mesangial cells.

Our aim was to examine whether the human glomerulus was a target for C-type natriuretic peptide (CNP) and how A, B and C receptors of natriuretic peptides (ANPR-A, ANPR-B, ANPR-C) were distributed in glomerular mesangial and epithelial cells. CNP stimulated cyclic GMP production in cultured human mesangial and epithelial cells with similar threshold concentrations (1 nM) and maximum effects (basal value x 30 at 1 microM). In contrast, atrial natriuretic peptide (ANP) was only stimulatory in epithelial cells. [125I] CNP bound specifically to mesangial cells with a Kd of 0.47 nM and Bmax of 42 fmol/mg. Equilibrium of binding was obtained after four to five hours at +4 degrees C and nonspecific binding represented 10 to 20% of total binding. HS142-1 (100 micrograms/ml), a specific inhibitor of ANPR-A and ANPR-B, suppressed 90% of CNP-dependent cyclic GMP production whereas it had little effect on [125I]-CNP binding, suggesting that C receptors were largely predominant in mesangial cells. No biological effect of CNP on mesangial cells, including change in basal or angiotensin II-induced contractility and inhibition of basal or serum-dependent proliferation, could be demonstrated. Similar results were obtained with 8-bromo-cyclic GMP and sodium nitroprusside. Intraglomerular localization of ANPR-A, ANPR-B and ANPR-C mRNA was studied using reverse transcriptase-polymerase chain reaction with amplification of their corresponding cDNA by different primers. Amplification products were identified on gel electrophoresis by their predicted sizes and sequencing. ANPR-A, ANPR-B and ANPR-C mRNA were present in epithelial cells whereas only ANPR-B and ANPR-C mRNA were detected in mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗
PubMed1994

Dosing time-dependent nephrotoxicity of cyclosporin A during 21-day administration to Wistar rats.

The incidence of cyclosporine A (CsA) nephrotoxicity with reference to the temporal stage of administration was studied during a chronic 21-day treatment in male Wistar rats. Oral administration (20 mg/kg/day) was given at four different times: 1, 7, 13, or 19 hours after light onset (HALO). Plasma creatinine and blood urea nitrogen (BUN) levels were determined at regular intervals over the 24 h: before treatment (day 0); 7, 14, and 21 days after the beginning of treatment (days 7, 14, and 21); and 7 and 14 days after CsA withdrawal (days 28 and 35). At the same times, creatinine clearance and g-glutamyl transferase urinary excretion were determined in the groups of animals treated at 7 and 19 HALO. Residual concentrations of CsA in the renal tissue were measured at the end of the treatment period (day 21) in all groups. Nephrotoxicity of CsA was dependent on the temporal stage of administration. The renal vasoconstriction showed by the increase in plasma creatinine and BUN levels and the decrease in creatinine clearance was maximal when the CsA was given at 7 and 19 HALO and was correlated to the tissue concentrations of CsA. Tubular injury seems to occur earlier and the return to normal function less rapidly in animals treated at 19 HALO compared with animals treated at 7 HALO.

Administration, Oral↗
PubMed1994

Circadian rhythms of renal hemodynamics in unanesthetized, unrestrained rats.

Catheters were placed in the jugular vein and femoral artery of male Sprague-Dawley rats and connected to a specially designed perfusor for continuous constant infusion of 0.9% NaCl and a syringe to perform simultaneous and intermittent blood collections. This permitted continuous 24-h study of renal hemodynamics, estimated by inulin (Cin) and p-amino-hippuric acid (CPAH) clearances; Cin represents glomerular filtration rate and CPAH renal plasma flow. Animals were individually housed in metabolism cages in a controlled environment with light/dark 12:12 h. Urine was collected every 4 h (12:00, 16:00, 20:00, 24:00, 04:00, and 08:00) and blood sampled at the midpoint of urine collection periods. Urine and plasma sodium, potassium, inulin, and PAH were spectrophotometrically assessed. During continuous infusion of isotonic saline, Cin exhibited circadian changes with large decrease between 12:00 and 20:00 h (0.9 +/- 0.2 ml/min) and acrophase at 00:30 h. Rhythmicity in CPAH was similar with the minimum between 16:00 and 20:00 h (2.5 +/- 0.3 ml/min) and peak between 00:00 and 04:00 h (acrophase at 00:25 h). Water and electrolyte excretion were also circadian rhythmic with a similar nighttime enhancement and daytime minimum. Such circadian changes persisted during continuous 0.9% NaCl infusion for several consecutive days. The unanesthetized, unrestrained rat model enables investigations in renal chronopharmacology and chronotoxicology.

Animals↗
PubMed1994

Protective effect of verapamil in cyclosporin-incubated human and murine isolated glomeruli.

Cyclosporin A (CsA)-induced nephrotoxicity is characterized by a decrease in the glomerular filtration rate (GFR) which is associated with a large increase in renal vascular resistance (RVR). Using a video image analyzer, we have demonstrated CsA-induced glomerular vasoconstriction in rat isolated glomeruli as assessed by a significant reduction of glomerular area. This vasoactive response explains in part the renal hemodynamic changes and the development of CsA-induced reversible decline in renal function. To confirm the direct vasoactive effect of CsA on glomeruli and to determine if calcium-blocking agents modified this response, we compared the changes in area of isolated rat and human glomeruli incubated either with CsA alone or with CsA plus verapamil. The area of the isolated glomeruli was quantitatively evaluated by a camera video image analyzer; each glomerulus served as its own control. Area kinetics were studied at 5 min intervals over 30 min. CsA-induced glomerular size reduction is dose dependent (-4.2% for 10(-10) M and -10.2% for 10(-6) M) and time dependent (-2.3% at 5 min, -4.7% at 10 min, and -12.1% at 30 min for 10(-6) M). With verapamil pretreatment, CsA-induced reduction in glomerular size was reduced (-0.6% and -3.6%, respectively, for 10(-6) M and 10(-7) M verapamil). Thus, verapamil can be considered as a protective agent against CsA-induced vasoconstriction in rat and human isolated glomeruli.

Adult↗
PubMed1994

Effect of cyclosporin and the prostacyclin analogue iloprost on human glomerular vasoreactivity.

Cyclosporin is known to cause a decrease in renal blood flow and glomerular filtration rate in both humans and animals. These acute modifications are reversible if the drug is withdrawn, and seem to be caused by a local hormonal imbalance between vasoconstricting and vasodilating substances. We studied human glomeruli incubated with either CsA alone, iloprost alone, or CsA + iloprost. Photomicrographs of glomeruli were taken at t0, t1, t2 and t5 min and glomerular areas were measured with a videoanalyser linked to a computer. Results show a significant vasoconstriction with CsA alone, and no significant modification of glomerular areas with iloprost or CsA + iloprost. We conclude that iloprost prevents CsA-induced vasoconstriction in human glomeruli in vitro.

Cyclosporine↗
PubMed1993

Effects of a low-protein diet on urinary glycosaminoglycan excretion in adriamycin-treated rats.

Adriamycin (ADR) induces glomerular damage in rats with persistent severe proteinuria which reaches a peak 15 days after a single 5 mg/kg intravenous (i.v.) injection. We studied in ADR-treated rats the effects of a low-protein (6%) diet (LPD) supplemented with keto acids on urinary protein and glycosaminoglycan (GAG) excretion and glomerular GAG contents. Animals were divided into three groups: group 1 was used as control, and groups 2 and 3 received a single i.v. injection of ADR; group 2 was fed a standard diet (21% protein) and group 3 an LPD. After ADR, group 2 developed heavy proteinuria and showed a progressive increase in urinary GAG excretion starting a few days after the beginning of proteinuria onset and persisting throughout the experiment. After ADR, group 3 (LPD treatment) did not develop proteinuria, and the level of urinary GAGs was comparable to that of controls. The glomerular GAG level in ADR-treated rats was greatly reduced as compared to controls; this decrease was partly eliminated in rats on an LPD. These results suggest that an LPD has a direct effect on cellular GAG production and turnover in ADR-induced glomerulonephritis.

Animals↗
PubMed1993

Intrinsic properties of the nonpeptide angiotensin II antagonist losartan in glomeruli and mesangial cells at high concentrations.

Intrinsic activities of the nonpeptide angiotensin II antagonist losartan were examined in a number of in vitro assays. Losartan produced contraction of rat isolated glomeruli at 100 mumol/l and of human mesangial cells at 1 to 100 mumol/l. Cell surface reduction was associated with disorganization of the alpha actin microfilament bundles. Losartan also stimulated cytosolic calcium concentration in cultured human mesangial cells at high concentrations (10-100 mumol/l). Losartan-dependent cytosolic free calcium concentration increase was not affected by nicardipine or 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxy-benzoate hydrochloride, whereas it was abolished in a calcium-free medium. There was a marked homologous desensitization response to losartan which was also obtained after pretreatment by EXP 3174 (2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole-5-carboxylic acid), the metabolite of losartan. The search for other agonistic effects of losartan in human mesangial cells including inositoltriphosphate formation, prostaglandin E2 production, [3H]leucine or [3H]thymidine incorporation was negative. Losartan and EXP 3174 were not toxic for human mesangial cells at the concentrations studied as judged by the absence of release of lactate dehydrogenase and the normal uptake of neutral red. These studies demonstrate that losartan exhibits glomerular effects in vitro only at high concentrations. Their relevance to in vivo situations is still questionable.

Angiotensin II↗
PubMed1992

[Protective effect of verapamil and dopamine against cyclosporine-induced vasoconstriction in isolated glomeruli in rats].

Cyclosporin A (CsA)-induced nephrotoxicity is characterized by dramatic changes in glomerular filtration rate and renal plasma flow, largely limiting the clinical use of this drug. The vasoconstrictive response of CsA could explain, in part, these hemodynamic alterations. The present study compares the area changes in rat-isolated glomeruli incubated with CsA alone or after pre-treatment with verapamil and dopamine. In verapamil-pretreated CsA-intoxicated glomeruli, size decrease was reduced (-1.5 percent at T10, -3.1 percent at T20 and -4.8 percent at T30), when compared with CsA alone (-4.7 percent at T10, -10.1 percent at T20 and -12 percent at T30). The results obtained with dopamine were similar. In conclusion, verapamil and dopamine can be regarded as fair protective agents against CsA-induced vasoconstriction in rat-isolated glomeruli.

Animals↗
PubMed1992

2-Amino-2-oxazolines, V: Synthesis of some 5-dialkylaminomethyl-2-amino-2-oxazolines and evaluation of their diuretic activity.

A series of 5-dialkylaminomethyl-2-amino-2-oxazolines was prepared and screened for diuretic activity. These compounds were previously examined for their lipophilic behaviour using a reversed-phase HPLC technique. The capacity factors, expressed as log k'w, were correlated with the partition coefficient log P. A QSAR analysis of the diuretic activity in relation with the lipophilicity was attempted for these structurally related compounds.

Animals↗