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Biomedical subjects

A Chaudhari

Publications and source records attributed to A Chaudhari.

At least 37 records · Page 2Linked to original sources
PubMed1986

Effect of experimental diabetes on glomerular filtration rate and glomerular prostanoid production in the rat.

Glomerular hyperfiltration is an early functional renal lesion seen both in experimental and human diabetes mellitus. This increase in the glomerular filtration rate has been thought to be mediated, in part, by changes in vasoregulatory hormones such as the prostanoids. The present study was designed to measure glomerular prostanoid production in rats with experimental diabetes to determine whether the biochemical changes in prostanoid production could be consistent with the hemodynamic alterations noted. Sprague-Dawley rats were studied either 7 or 28 days after intravenous streptozotocin administration (60 mg/kg). Measurements of the glomerular filtration rate were performed in two groups of diabetic animals 28 days after streptozotocin administration: one group with intact prostanoid production, the other having received a cyclooxygenase inhibitor for the 4-week period. Similar studies were performed in nondiabetic control rats. Measurements of glomerular prostanoid production were performed in control and diabetic animals 7 days after streptozotocin administration. The results of these studies indicate that experimental diabetes mellitus is associated with an increase in the glomerular filtration rate and that this increase can be blocked by the administration of a cyclooxygenase inhibitor. In addition, the determination of levels of various glomerular prostanoids indicated an increased production of prostacyclin and a decreased production of thromboxane during this period of hyperfiltration. Thus, these data support the premise that altered prostanoid biosynthesis may be one of the biochemical mediators of the hyperfiltration seen in early experimental diabetes mellitus.

Animals↗
PubMed1985

Specific prostaglandin E2 binding sites in isolated rat glomeruli: evidence for glomerular PGE receptors.

Stimulation of adenylate cyclase by prostanoids in isolated glomerulus has been demonstrated previously suggesting the interaction of these lipids with specific receptors. In the present study, the presence and characteristics of these purported specific PGE receptors has been evaluated. Binding studies were performed with both [3H]PGE1 and [3H]PGE2 in isolated rat glomeruli obtained by standard sieving methods. Radioligand binding was demonstrated to be both reversible and saturable. The equilibrium dissociation constant (Kd) value for PGE2 was 14.3 nM and maximum number of receptor sites (Bmax) was 81.4 fmol/mg protein. Similar values were obtained for PGE1. Competitive binding studies performed with [3H]PGE1 in the presence of various prostanoids revealed a common binding site for PGE1, PGE2 and 16,16-dimethyl PGE2. The relative potency for displacement of [3H]PGE1 binding of various prostanoids was PGE1 = 16,16-dimethyl PGE2 = PGE2 much greater than T X B2 = PGD2 much greater than PGF 2 alpha greater than 6-keto-PGF 1 alpha. Hill plot analysis of both [3H]PGE1 and [3H]PGE2 binding studies showed a simple non-cooperative bimolecular interaction between PGE and a single receptor population. Finally, a dose-dependent stimulation of adenylate cyclase was noted with various concentrations of PGE1 in a membrane preparation derived from a similar glomeruli preparation. Thus the results of these studies provide evidence for the presence of specific PGE receptors in the rat glomerulus.

Alprostadil↗
PubMed1984

Altered glomerular eicosanoid biosynthesis in uranyl nitrate-induced acute renal failure.

The present studies were designed (1) to examine the pattern of changes in eicosanoid biosynthesis in isolated rat glomeruli, and (2) to correlate these changes with the previously observed alterations in renal perfusion and glomerular filtration rate which occur after uranyl nitrate administration, a model of toxin-induced acute renal failure. In the first part of this study, the in vitro and the in vivo effects of two cyclooxygenase inhibitors were examined for their ability to inhibit rat glomerular eicosanoid biosynthesis. Inhibition of prostaglandin E2 and prostaglandin F2 alpha generation by 1 mM aspirin in vitro was 76 and 82%, respectively. Similar inhibitions of 85 and 72% of biosynthesis of the above-mentioned lipids by 0.1 mM indomethacin were also noted. Intraperitoneal administration of aspirin (150 mg/kg) resulted in a significant inhibition of 88% or greater of prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F2 alpha, and thromboxane B2 biosynthesis. These results indicated that the expected alterations produced under in vivo conditions were detectable by in vitro techniques used in this study. 24 h after the administration of uranyl nitrate (25 mg/kg), significant increases in the biosynthesis of prostaglandin E2 (124%) and prostaglandin F2 alpha (88%) were observed when compared to the control values. No significant changes in prostacyclin or thromboxane formation were noted at this time. A further increase in the biosynthesis of prostaglandin E2 (248%), prostaglandin F2 alpha (262%), and a significant increase in prostacyclin (120%), measured as 6-keto-prostaglandin F1 alpha, were noted at 48 h. No changes in thromboxane B2 biosynthesis were noted. It is concluded that these data are consistent with the hypothesis that the increased glomerular biosynthesis of vasodilator eicosanoids (i.e., prostaglandin E2 and prostacyclin) may play a significant role in the homeostatic regulation of renal perfusion and glomerular filtration after acute toxic injury to the kidney.

Acute Kidney Injury↗
PubMed1983

Mechanism of increased renal prostaglandin E2 in uranyl nitrate-induced acute renal failure.

We have previously demonstrated that decreased cortical prostaglandin metabolism can contribute significantly to an increase in renal tissue levels and activity of prostaglandin E2 in bilateral ureteral obstruction, a model of acute renal failure. In the present study, we have further investigated whether alterations in prostaglandin metabolism can occur in a nephrotoxic model of acute renal failure. Prostaglandin synthesis, prostaglandin E2 metabolism (measured as both prostaglandin E2-9-ketoreductase and prostaglandin E2-15-hydroxydehydrogenase activity), and tissue concentration of prostaglandin E2 were determined in rabbit kidneys following an intravenous administration of uranyl nitrate (5 mg/kg). No changes in the rates of cortical microsomal prostaglandin E2 and prostaglandin F2 alpha synthesis were noted at the end of 1 and 3 days, while medullary synthesis of prostaglandin E2 fell by 47% after 1 day and 43% after 3 days. Cortical cytosolic prostaglandin E2-9-ketoreductase activity was found to be decreased by 36% and 76% after 1 and 3 days respectively. No significant changes were noted in cortical cytosolic prostaglandin E2-15-hydroxydehydrogenase activity after 3 days. Cortical tissue levels of prostaglandin E2 increased by 500% at the end of 3 days. These data demonstrate that in nephrotoxic acute renal failure, decreased prostaglandin metabolism (i.e., prostaglandin E2-9-ketoreductase activity) can result in increased tissue levels of prostaglandin E2 in the absence of increased prostaglandin synthesis and suggest that alterations in prostaglandin metabolism may be an important regulator of prostaglandin activity in acute renal failure.

Acute Kidney Injury↗
PubMed1982

Decreased renal prostaglandin metabolism in ureteral obstruction.

Studies were performed in rabbits to assess whether alterations in renal prostaglandin metabolism occur with ureteral obstruction. After 3 days, the cortical metabolism of prostaglandin E2 (as measured by prostaglandin E2-9-ketoreductase activity) decreased by almost 40% in unilateral and 50% in bilateral ureteral obstruction when compared to appropriate control levels. Medullary prostaglandin E2 metabolism decreased by 70% after unilateral ureteral obstruction but was unchanged in response to bilateral ureteral obstruction. Enzyme kinetics data from bilateral ureteral obstructed and sham-operated kidneys revealed non-competitive inhibition. In contrast to metabolism, cortical prostaglandin E2 biosynthesis increased by 122% over the control levels in unilateral, and 205% in bilateral ureteral obstruction. However, medullary prostaglandin E2 synthesis fell by almost 40% after bilateral obstruction. These data suggest that decreased renal prostaglandin metabolism, together with increased biosynthesis, could have significant effects on local prostaglandin tissue concentrations and thus explain the enhanced activity of these lipids previously noted in this model.

Animals↗
PubMed1982

Alterations in tissue glutathione and angiotensin converting enzyme due to inhalation of diesel engine exhaust.

Quantitative changes in reduced glutathione (GSH) and angiotensin converting enzyme (ACE) of lung and extrapulmonary tissues were determined following exposure of laboratory animals to diesel engine exhaust (DEE). Exposure of male rats and guinea pigs to DEE containing 750 micrograms particulates per cubic meter for 12 wk did not cause any changes in GSH levels of lung, liver, and heart compared to control values. Rats were then exposed for various time periods to 6 mg/m3 DEE. Two weeks of exposure produced statistically significant increases of 21 and 7% in GSH levels of lung and liver, respectively, but not change in the heart. Following 4 wk of exposure, lung showed a 14% increase and heart an 11% increase in GSH level. Furthermore, rats exposed for 4 wk to DEE did not show any particular susceptibility toward the GSH-depleting effect of acetaminophen as compared to controls. A significant depletion (15%) of hepatic GSH was observed after 8 wk of exposure, while lung was still showing an increase of 18% in GSH and heart was unaffected. Time-dependent increases of 18 and 33% in serum ACE activity were noted after 4 and 8 wk of exposure. Pulmonary ACE activity did not decrease until after 8 wk, and then to a small extent (7%). The observed increases in GSH may have been related to the presence of NO2 in the DEE. On the other hand, the depletion of hepatic GSH suggests production of electrophilic compounds due to an induction of metabolic activity of liver. The change in serum ACE activity may be due to time-requiring perturbations in the pulmonary endothelial cells.

Animals↗
PubMed1981

Effect of exposure to diesel exhaust on pulmonary prostaglandin dehydrogenase (PGDH) activity.

There has been evidence that an acute exposure of laboratory animals to nitrogen dioxide (NO2) for a short period of time can cause marked inhibition of pulmonary PGDH activity. Since diesel exhaust contains NO2, this investigation was undertaken to determine the effect of long-term exposure of guinea pigs and rats to diesel exhaust. The study involves measurement of PGDH activity in the lung tissue as obtained from these animals following exposure to 250 and 1500 micrograms m-3 of diesel particles for various time periods in relation to the appropriate time-matched controls. In guinea pigs, exposure for 6 weeks to 250 micrograms m-3 of diesel exhaust seems to stimulate the PGDH activity about two-fold in comparison to the time-matched controls while, paradoxically, the exposure to 1500 micrograms m-3 of diesel exhaust did not show any particular effect. The exposures to diesel exhaust for 12 weeks, as well as 24 weeks, seem to show concentration dependent lowering of PGDH activity as compared to the time-matched controls. This study also documents the well-known species difference in PGDH activity in that the rat shows much lower activity of this enzyme than the guinea pig. Because of undetectable enzyme activity in many samples, it has not been possible to draw any meaningful conclusion as to the effect of diesel exposure on the enzyme in rat.

Aerosols↗
PubMed1981

Possible formation of nitrosamine in guinea pigs following exposure to nitrogen dioxide and dimethylamine.

The possibility of formation of nitrosamine was investigated in animals exposed to a combination of dimethylamine (DMA) and NO2. First, the distribution and covalent binding of DMA and dimethylnitrosamine (DMN) in rats and guinea pigs were determined. The apparent volume of distribution and biological half-life for [14C]-DMA or [14C]DMN did not reveal any species difference. In general, there were no marked differences in accumulation of radioactivity in tissues of guinea pigs and rats 4 h after the administration of DMA, while the guinea pig tissues showed higher accumulation after DMN administration. Nucleic acid fractions prepared from liver and lungs of both species following administration of DMN or DMA in vivo showed much higher covalent binding with DMN than with DMA. Furthermore, the covalent binding of DMN was found to be due to bioactivation, whereas the DMA binding was nonspecific. Since guinea pig liver showed a higher degree of covalent binding than rat liver, this species was used to investigate the possible increase in covalent binding in the presence of NO2 and DMA as a reflection of DMN formation. There was no evidence of enhancement of covalent binding when animals pretreated with [14C]-DMA were exposed for various lengths of time to different concentrations of NO2.

Animals↗
PubMed1980

Correlation between monoamine oxidase inhibitors and anticonvulsants.

Monoamine oxidase inhibitory and anticonvulsant properties of 2-substituted styryl-6-bromo-3-(4-ethylbenzoate/4 benzhydrazide)-4-quinazoles are studied. All styryl quinazolone esters except compound number 9 exhibited monoamine oxidase inhibitory properties during oxidative deamination of kynuramine. Corresponding hydrazides were found to have relatively higher activity. All these quinazolones were able to protect against pentylenetetrazol induced seizures. These observations in general do not prove that monoamine oxidase inhibitory properties represent the biochemical basis for the anticonvulsant activity of these compounds.

Animals↗
PubMed1979

Inhibition of pulmonary prostaglandin metabolism by exposure of animals to oxygen or nitrogen dioxide.

The effects of exposure of animals to 100% O2 and NO2 on the rate of prostaglandin metabolism by lung and kidney were studied in vitro. Exposure of guinea pigs to 100% O2 for 48 h inhibited the metabolism of prostaglandin F2 alpha by both NAD+- and NADP+-dependent prostaglandin dehydrogenase in lung, but had no effect on the metabolism in kidney. Succinate dehydrogenase, but not glucose 6-phosphate dehydrogenase, in guinea-pig lung was inhibited by exposure to 100% O2. Exposure to 46 p.p.m. but not 16 or 29 p.p.m. NO2 for 6 h inhibited guinea-pig lung prostaglandin dehydrogenase in vitro. The inhibition of pulmonary prostaglandin dehydrogenase by exposure to 100% O2 or to 49 p.p.m. NO2 was dependent on the duration of exposure, but returned to control values within 7 days after cessation of the exposure. The pulmonary transport system responsible for removing circulating prostaglandins from the blood was not affected by exposure to 100% O2 as measured by using the isolated perfused lung. Kinetic analysis of the inhibition of pulmonary prostaglandin dehydrogenase activity in guinea pig exposed to 100% O2 showed non-competitive inhibition with respect to both prostaglandin F2 alpha and NAD+, which suggests destruction or inactivation of the enzyme. Pulmonary prostaglandin dehydrogenase appears to be inhibited by exposure to oxidant gases, which may lead to elevated prostaglandin concentrations in the lungs or in the systemic circulation.

15-Oxoprostaglandin 13-Reductase↗
PubMed1979

Studies on the covalent binding of an intermediate(s) in prostaglandin biosynthesis to tissue macromolecules.

We investigated the covalent binding of intermediates in prostaglandin biosynthesis to tissue macromolecules. Following incubation of [1-14C]arachidonic acid with the microsomal fraction from guinea pig lung, ram or bovine seminal vesicle, human platelets, rabbit kidney, or rat stomach fundus, the amount of covalent binding of arachidonic acid metabolites expressed as percentage of total arachidonic acid metabolized varied from tissue to tissue ranging from 3% in human platelets to 18.2% in ram seminal vesicles. In general, the thromboxane synthesizing tissues had less covalently bound metabolites than the other tissues. The amount of covalently bound metabolites was increased in the guinea pig lung microsomes when the thromboxane synthetase inhibitor, N-0164, was added to the incubation mixture. The covalent binding of arachidonic acid metabolite(s) was greatly reduced by the addition of glutathione to the incubation mixture. In addition to the covalently bound metabolites, water-soluble metabolites derived from arachidonic acid metabolism were also observed. The amount of water-soluble metabolites was small in each tissue except for the rat stomach fundus. In the rat stomach fundus the water-soluble metabolites accounted for over 50% of the total metabolites. Conditions which would tend to increase or decrease the levels of free prostaglandin endoperoxides during the incubation of arachidonic acid with the microsomes gave increased or decreased levels of covalent binding. Our data suggest that the prostaglandin endoperoxides are responsible for the covalent binding observed during prostaglandin biosynthesis. This covalent binding to tissue macromolecules may be of physiological and pathological significance.

Animals↗
PubMed1978

Conjugation of 15-keto-prostaglandins by glutathione S-transferases.

Incubation of 15-keto[3H]prostaglandin F2alpha with glutathione (GSH) produced a metabolite of 15-keto-prostaglandin F2alpha which was not extractable from aqueous solution and thus termed 'water-soluble metabolite'. The addition of cytosol of guinea pig liver to the incubation mixture increased the formation of water soluble metabolite of 15-keto-prostaglandin F2alpha 3-fold. The conversion of 15-keto-prostaglandin F2alpha to water soluble metabolite in both the presence and absence of enzyme was linear during 10 min of incubation and required 2.5 mM GSH for maximal activity. Liver and kidney cytosol possess about 70 and 25 times, respectively, as much activity as compared to lung cytosol. Chromatographic analysis of the water soluble metabolite obtained from incubation of either 15-keto[3H]prostaglandin F2alpha and GSH or [3H]GSH and 15-keto-prostaglandin F2alpha showed that the water-soluble metabolite was an adduct of 15-keto-prostaglandin F2alpha and GSH. The addition of prostaglandin A1, a substrate of GSH S-transferases, to the incubation mixture competitively inhibited the formation of the water-soluble metabolite of 15-keto[3H]prostaglandin F2alpha. Presumably, 15-keto-prostaglandin F2alpha and other 15-keto-prostaglandins are converted to GSH conjugates by GSH S-transferases. This indicates that 15-keto-metabolites produced by prostaglandin dehydrogenase may be further metabolized to GSH conjugates.

Animals↗
PubMed1978

Anticonvulsant and antiproteolytic properties of 3,5-disubstituted oxadiazole-2-thiones and their inhibition of respiration in rat brain homogenates.

Eight 5-(3,4-methylenedioxyphenyl)-3-arylaminomethyl-1,3,4-oxadiazole-2-thiones were synthesized, characterized by their sharp melting points, elemental analyses, and IR spectra, and evaluated for anticonvulsant activity. All substituted oxadiazole-2-thiones possessed anticonvulsant activity, which was reflected by their ability to provide 10--70% protection against pentylenetetrazol-induced convulsions in mice at 100 mg/kg ip. These compounds inhibited in vitro nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, alpha-ketoglutarate, and NADH by rat brain homogenates as well as NAD-independent oxidation of succinate by rat brain homogenates. Antiproteolytic activity of these substituted oxadiazole-2-thiones was reflected by their ability to inhibit trypsin hydrolysis of bovine serum albumin. These results indicated that the inhibition of cellular respiration and antiproteolytic activity of these substituted oxadiazole-2-thiones is not the biochemical basis for their anticonvulsant activity.

Animals↗