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Biomedical subjects

B B Davis

Publications and source records attributed to B B Davis.

At least 127 records · Page 7Linked to original sources
PubMed1981

6-Ketoprostaglandin E1 stimulation of rat and rabbit renal adenylate cyclase-cyclic AMP systems.

6-Ketoprostaglandin E1 effects on rat and rabbit renal adenylate cyclase-cyclic AMP systems were examined. Adenylate cyclase activity was assessed in the 1000 X g fractions prepared from different areas of kidney. 6-Ketoprostaglandin E1 caused a dose-dependent increase in rat cortical and medullary adenylate cyclase activity with 8 x 10(-6) M being the lowest effective concentration. Combinations of maximal stimulatory concentrations of 6-ketoprostaglandin E1 and prostaglandin I2 caused stimulation similar to that seen with either agent alone. In contrast, the combination of either prostaglandin with parathyroid hormone (cortex) or antidiuretic hormone (medulla) resulted in enzyme activity significantly greater than with either agent alone. Similar results were observed in the rabbit. In addition, rabbit cortical and medullary slice cyclic AMP content was increased by 6-ketoprostaglandin E1. Maximal stimulatory effects of 6-ketoprostaglandin E1 on adenylate cyclase activity and cyclic AMP content were similar to prostaglandin I2. Therefore, the similarity in physiologic actions of 6-ketoprostaglandin E1 and prostaglandin I2 may be due to the stimulation of adenylate cyclase by both agents. These prostaglandins and the polypeptide hormones appear to activate different renal adenylate cyclase-cyclic AMP systems.

Adenylyl Cyclases↗
PubMed1981

Mass spectrometry of 2-substituted 5-nitro-2-furyl thiazoles. Identification of microsomal nitroreduction products by electron impact mass spectrometry.

The electron impact mass spectral fragmentation of nitro heterocyclic carcinogens N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, 2-amino-4-(5-nitro-2-furyl)thiazole, 2-methyl-4-(5-nitro-2-furyl)thiazole and 2-methylamino-4-(5-nitro-2-furyl)thiazole were studied. The molecular ions undergo two modes of cleavage: one giving [M-84]+ ions which include the 2-substituted thiazole ring, while the other gives rise to the fragment [M-74]+ ions. The products of anaerobic microsomal nitroreduction of 2-methyl-4-(5-nitro-2-furyl)thiazole were isolated and purified by high-pressure liquid chromatography. The metabolites undergo different fragmentation patterns compared to the parent nitro analogs. Metabolites from anaerobic enzymatic reduction showed identical gas chromatographic, high-pressure liquid chromatographic and thin-layer chromatographic properties to the chemically synthesized material. The metabolites were identified as 1-(2-methyl-4-thiazolyl)-3-cyano-1-propenone and 1-(2-methyl-4-thiazolyl)-3-cyano-1-propane by mass spectral fragmentation pattern.

Animals↗
PubMed1981

Localization of exaggerated prostaglandin synthesis associated with renal damage.

Regional localization of the exaggerated prostaglandin E2 (PGE2) synthesis caused by hydronephrosis was studied in unilateral ureteral ligated rabbits. The renal distribution of PGE2 production was compared in the hydronephrotic and contralateral kidneys. Basal and bradykinin-stimulated PGE2 synthesis were increased in cortical and medullary slices of the hydronephrotic kidneys. Contralateral (control) cortical slices produced very low levels of PGE2 and were insensitive to stimulation by bradykinin (BK). The hydronephrotic cortex produced 10 times more PGE2 than the contralateral cortex and responded to BK stimulation with increased PGE2 synthesis. Cortical slices from the hydronephrotic kidney exhibited a time-dependent increase in PGE2 release, presumably as a result of new protein synthesis. The division of the hydronephrotic cortex into outer and inner regions revealed that the inner cortex produced more PGE2 than the outer cortex. A similar division of the hydronephrotic medulla showed that the inner medulla produced slightly greater amounts of PGE2 than the outer medulla. The present study demonstrates that hydronephrosis causes increases in prostaglandin synthesis throughout the kidney. We suggest from these results and other studies that a possible explanation for this finding is the involvement of the collecting duct system in this response. The gradient of PGE2 production detected in the cortex may have a very significant role in the control of renal hemodynamics and could provide an explanation for the large decrease in blood flow to the inner cortex caused by indomethacin treatment.

Animals↗
PubMed1981

Renal metabolism of drugs and xenobiotics.

The renal cortex, outer medulla and inner medulla exhibit different profiles of drug metabolism. Mixed-function oxidase activity was present in cortex but not inner medulla. Cooxidation by prostaglandin endoperoxide synthetase was detected in inner medulla but not cortex. Both mixed-function oxidase and cooxidation were demonstrable in outer medulla. Urinary bladder carcinogens such as FANFT and benzidine and the renal carcinogen diethylstilbestrol were cooxidized by prostaglandin endoperoxide synthetase. Cooxidation could be a mechanism of activation of urinary bladder carcinogens and of nephrotoxic agents.

Animals↗
PubMed1981

Conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in renal slices from the rat.

Isolated renal cortical slices were used to study the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and 24,25-dihydroxyvitamin D3 [24,25](OH2)D3] by the rat kidney. Production of 1,25-(OH)2D3 and 24,25-(OH)2D3 was linear with time (30-90 min) and tissue weight (40-250 mg). Production of 1,25-(OH)2D3 was greatest (134 +/- 17 pg/mg tissue.h) in animals fed a low calcium, vitamin D-deficient diet. The greatest 24,25-(OH)2D3 production (106 +/- 17 pg/mg tissue.h) was seen in animals fed a high calcium, vitamin D-replete diet, 1,25-(OH)2D3 production was reduced to 23% of maximum by the addition of 1.2% calcium or 0.8% strontium to the vitamin D-deficient, low calcium diet. Production of 1,25-(OH)2D3 and 24,25-(OH)2D3 was greatly reduced in renal cortical slices that had been heated before incubation. Slices of renal medulla produced only small amounts of 1,25-(OH)2D3 compared to slices of renal cortex. These studies provide direct evidence for the production of 1,25-(OH)2D3 and 24,25-(OH)2D3 by the mammalian renal cortex. They also demonstrate that this production may be modulated by dietary calcium, strontium, and vitamin D.

24,25-Dihydroxyvitamin D 3↗
PubMed1981

Solute concentration affects bradykinin-mediated increases in renal prostaglandin E2.

The effects of solute concentration on the bradykinin-mediated increase in inner medullary slice prostaglandin E2 (PGE2) synthesis were investigated. PG content was determined by specific RIA. Bradykinin stimulation was prevented by the addition of the following solutes to Krebs buffer: 1.0 M urea, 0.5 or 1.0 M NaCl, 0.5 or 1.0 M mannitol, 1.0 M urea plus 0.5 M NaCl, or 1.0 M mannitol plus 0.5 M NaCl. By contrast, basal PGE2 synthesis was increased by 1.0 M mannitol or by 1.0 M mannitol plus 0.5 M NaCl, but decreased by 1.0 M urea. Urea elicited a concentration-dependent, reversible inhibition of bradykinin stimulation, with 0.01 M urea being the lowest effective concentration. By contrast, basal PGE2 synthesis was only reduced at a urea concentration greater than 0.6 M. Arachidonic acid-mediated increases in both PGE2 and PGF2 alpha synthesis were not prevented by 1.0 M urea. The latter suggests that neither PG endoperoxide synthetase nor PG endoperoxide E isomerase are inhibited by urea. The data indicate that different hypertonic solutions have different effects on basal PG production, but all inhibit bradykinin stimulation.

Animals↗
PubMed1981

Inhibition of bradykinin stimulation of renal medullary prostaglandin E2 synthesis by phosphodiesterase inhibitors.

Effects of phosphodiesterase inhibitors DL-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20) and 1-methyl-3-isobutylxanthine (MIX) on prostaglandin E2 (PGE2) synthesis were examined using rabbit renal inner medullary slices incubated in Krebs' buffer with or without 1 mM RO-20 or 2 mM MIX. Basal and bradykinin-mediated PGE2 synthesis were inhibited in a dose-dependent, reversible manner by both RO-20 and MIX. Arachidonic acid-mediated increases in PGE2 synthesis were not inhibited. By contrast, 1 mM aspirin completely inhibited PGE2 synthesis. Phosphodiesterase inhibitors increased slice cyclic AMP content more than 6-fold. However, this elevation in tissue cyclic AMP content did not appear to be the cause of decreased PGE2 synthesis. Exogenous 3 mM cyclic AMP and 3 mM dibutyryl cyclic AMP did not alter PGE2 synthesis. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, prevented RO-20 and MIX-mediated increases in cyclic AMP but had no effect on PGE2 synthesis. Exogenous 3 mM cyclic GMP and dibutyryl cyclic GMP did not alter PGE2 synthesis. Neither RO-20 nor MIX had a direct effect on PG endoperoxide synthetase. These results indicate MIX and RO-20 inhibit renal medullary PGE2 production by limiting the availability of arachidonic acid. These effects of MIX and RO-20 on PGE2 synthesis are not secondary to their effects on cyclic nucleotide phosphodiesterase.

1-Methyl-3-isobutylxanthine↗
PubMed1981

Transport of the renal carcinogen 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)allydidene]amino) hydantoin by renal cortex and cooxidative metabolism by prostaglandin endoperoxide synthetase.

Transport of the renal carcinogen 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)-allydidene]amino) hydantoin (HMN) by the renal cortex and metabolism by the kidney was evaluated. Organic acid and base transport by renal cortical slices was determined using [131I]Hippuran and [14C]tetraethylammonium, respectively. HMN caused a dose-dependent reversible inhibition of [131]Hippuran accumulation but did not alter [14C]tetraethylammonium uptake. By contrast, benzidine inhibited organic base but not acid transport. The decrease in absorbance at 405 nm was used as an index of microsomal metabolism of HMN. Reduced nicotinamide adenine dinucleotide phosphate-dependent metabolism of HMN was not observed with either cortical or medullary microsomes. However, there was prostaglandin endoperoxide synthetase-mediated metabolism of HMN. Specific substrate, cofactor, and inhibitor studies suggest that metabolism occurs by the prostaglandin hydroperoxidase activity of prostaglandin endoperoxide synthetase. At least one product of HMN metabolism was characterized and shown to be different from HMN by its high-pressure liquid chromatographic and ultraviolet spectral properties. The renal mixed-function oxidases system, lipid peroxidation, nitroreduction, and lipoxygenase did not seem to be involved in HMN metabolism. These results are consistent with the hypothesis that the kidney is a site for cooxidative metabolism of chemicals which elicit carcinogenic and nephrotoxic effects in the kidney. Facilitated transport of HMN into renal tissue by the organic acid transport system may explain the greater potential for HMN to elicit renal carcinogenesis compared to other tissues.

Animals↗
PubMed1981

Aspirin inhibition of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced lesions of the urinary bladder correlated with inhibition of metabolism by bladder prostaglandin endoperoxide synthetase.

The effects of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) -induced urinary bladder lesions, endogenous bladder prostaglandin E2 synthesis, and the metabolism of FANFT by bladder epithelial microsomes were examined. Rats were fed 0.5% aspirin and/or a diet containing 0.1% or 0.2% FANFT. Bladder lesions were observed with light and scanning electron microscopy, and the prostaglandin E2 content of rat bladder was measured by radioimmunoassay. Metabolism of FANFT was measured by decreased absorbance at 400 nm. Aspirin inhibited the appearance of hyperplastic lesions induced by feeding 0.1% or 0.2% FANFT for 6 or 12 weeks. Aspirin reduced bladder prostaglandin E2 content at 1, 2, 6, and 13 weeks compared to corresponding control values. Rat and rabbit microsomal metabolism of FANFT were dependent upon specific fatty acid substrate and prevented by specific inhibitors (including aspirin) of prostaglandin endoperoxide synthetase. Other inhibitor and substrate specificity studies suggest that FANFT was not metabolized by xanthine oxidase, lipoxygenase, lipid peroxidation, or mixed-function oxidases. These results suggest that the metabolism of FANFT by prostaglandin endoperoxide synthetase may be involved in the metabolic activation of FANFT necessary for the induction of bladder cancer in rats.

Animals↗
PubMed1981

Prostaglandin hydroperoxidase-mediated 2-amino-4-(5-nitro-2-furyl) [14C]thiazole metabolism and nucleic acid binding.

Prostaglandin hydroperoxide-mediated metabolism and binding of 2-amino-4-(5-nitro-2-furyl) [14C]thiazole ([14C]ANFT) metabolite to nucleic acids and proteins were investigated with rabbit bladder transitional epithelial and solubilized ram seminal vesicle microsomes. Metabolism was assessed by spectrophotometric and radiochemical techniques. Substrate and inhibitor studies are consistent with both metabolism and binding of [14C]ANFT occurring by the prostaglandin hydroperoxidase activity of prostaglandin endoperoxide synthetase. The ratio of the rates of [14C]ANFT product formation is approximately 3:7:10 (organic soluble:non-trichloroacetic acid precipitable: trichloroacetic acid precipitable) over a wide range of arachidonic acid concentrations. Approximately 2 and 1% of the total [14C]ANFT metabolized binds to transfer RNA and DNA, respectively. The metabolite isolated from the organic phase had a chromatographic profile and ultraviolet spectra different from authentic ANFT. If transfer RNA or DNA is added at the end of a 5-min incubation, no binding to nucleic acids was observed. The demonstration of prostaglandin hydroperoxidase-mediated covalent binding to nucleic acids is consistent with the involvement of this enzyme in 5-nitrofuran-induced bladder carcinogenesis.

Animals↗
PubMed1981

Microsomal nitroreductase activity of rabbit kidney and bladder: implications in 5-nitrofuran-induced toxicity.

Reductive metabolism of the aromatic nitro group of 5-nitrofurans is thought to be an important step in the mechanism of their toxicity. Microsomal nitroreductase activity with p-nitrobenzoic acid and N-[4-(5-nitro-2-furyl)-2-thiazolyl[formamide (FANFT) as substrates was assessed in the renal cortex, outer medulla, inner medulla, bladder transitional epithelial and non-epithelial bladder tissue. Cortex and transitional epithelial tissue contained the most p-nitrobenzoic acid reductase activity. However, FANFT reductase activity was similar in all areas tested except nonepithelial bladder tissue, which was 10% of the others. FANFT reduction was inhibited by oxygen, but not by carbon monoxide, allopurinol or aspirin and required NADPH. These results are consistent with NADPH-cytochrome c reductase catalyzed FANFT reduction. In medullary microsomes, the apparent Km and Vmax were 0.125 mM and 0.84 nmol/mg of protein per min, respectively. Transitional epithelial microsomes incorporated approximately 1 and 10% of the total [2-14C]FANFT metabolized into t-RNA and trichloroacetic acid-precipitable material, respectively. Two products of FANFT reduction were demonstrated by high-pressure liquid chromatography. One product was reversibly oxidized to FANFT and the other was tentatively identified by mass spectral analysis as an open chain nitrile. In view of the relatively low oxygen tension in the renal inner medulla and bladder mucosa, these results suggest that medullary and transitional epithelial nitro-reductases may be involved in the pathogenesis of 5-nitrofuran toxicity.

Animals↗
PubMed1980

Adaptation to dietary calcium and phosphorus restriction changes with age in the rat.

The purpose of this study was to characterize the changes that take place in adaptation to chronic calcium (Ca) or phosphorus (P) restriction with age. Adaptation in male F344 rats aged 1.5, 3, 12, and 18 mo was studied by feeding rats either a low-Ca diet, a low-P diet, or a high-Ca-P diet for 14 days. Plasma Ca remained relatively constant with age, but plasma P markedly decreased between 3 and 12 mo regardless of diet. Intestinal adaptation was determined by measuring the active transport of Ca by the intestine and by measuring the production of vitamin D-dependent calcium-binder protein. There was significant intestinal adaptation to Ca or P restriction at 1.5 mo, but there was none thereafter because Ca transport declined rapidly with age regardless of diet. The kidney adapted to the low-P diet by significantly reducing P excretion at all ages. In rats on a low-P diet, there was an increase in urinary P, which was due to a decrease in the tubular reabsorption of P and a decrease in urinary Ca with age. These changes in adaptation may reflect a decrease in serum 1,25-dihydroxyvitamin D levels and an increase in parathyroid hormone levels with age.

Adaptation, Physiological↗
PubMed1980

Prostaglandin E2 production by rabbit urinary bladder.

Synthesis of prostaglandin E2 (PGE2) by rabbit bladder was examined. PGE2 synthesis was assessed by thin-layer chromatographic analysis after conversion of [14C]-arachidonic acid to [14C]PGE2 or by a specific radioimmunoassay technique. Intact bladder and microsomes prepared from the bladder transitional epithelium (mucosal) layer and the outer vesicular layer demonstrated synthesis of PGE2. PGE2 synthesis was increased by arachidonic acid and blocked by indomethacin. When the inside medium (bathing the transitional epithelium) contained [14C]arachidonic acid, no detectable radioactivity was observed in the outside medium (bathing the outer layer). Conversely, when the outside medium contained [14C]arachidonic acid, no detectable radioactivity was observed in the inside medium. In addition, [14C]arachidonic acid was incorporated only into tissue directly exposed to bathing media containing the label. These results demonstrate that the rabbit bladder can synthesize PGE2 and that the PGE2- synthesizing systems of the transitional epithelium and outer layer of bladder may be distinct.

Animals↗
PubMed1980

Effect of age on the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 by kidney of rat.

The decreased absorption of calcium by the small intestine of the adult may reflect changes in vitamin D metabolism with age. The purpose of this study was to compare the capacity of young (1.5 mo of age) and adult (12 mo of age) vitamin D-deficient rats to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the physiologically active form of vitamin D. Young rats responded to an oral dose of 25-hydroxyvitamin D3 with significantly increased intestinal absorption of calcium and a three-fold increase in the intestinal content of vitamin D-stimulated calcium-binding protein. Adult rats showed no significant increase in these parameters. The conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 was measured in the whole animal by administering a dose of tritiated 25-hydroxyvitamin D3 and determining the appearance of tritiated metabolites in plasma and small intestine. In the adult rat, only 2.1 +/- 0.6% of the plasma radioactivity was in the form of 1,25-dihydroxyvitamin D3 after 24 h compared with 20.8 +/- 3.0% in the young. The conversion of tritiated 25-hydroxyvitamin D3 to its products was also measured directly in isolated slices of renal cortex. 1,25-Dihydroxyvitamin D3 production by adult renal slices was found to be less than one-tenth that of slices from the young. These results indicate that there is a marked decrease in the capacity of the vitamin D-deficient adult rat to convert 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3. This is probably due to the decreased capacity of the adult kidney to 1-hydroxylate 25-hydroxyvitamin D3. These studies also demonstrate the usefulness of renal slices in measuring changes in the renal conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 in the mammal.

Aging↗