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Biomedical subjects

R E Bulger

Publications and source records attributed to R E Bulger.

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

A comparison in rodents of renal and intestinal toxicity of cisplatin and a new water-soluble antitumor platinum complex: N-methyl-iminodiacetato-diaminocyclohexane platinum (II).

A new third-generation water-soluble platinum complex, N-methyliminodiacetato-1,2-diaminocyclohexane platinum (II) (MIDP) has been reported to have remarkable antitumor activity against several murine tumor model systems. In the present study, the renal and intestinal toxicity of MIDP was compared directly with that of cis-diamminedichloroplatinum (cisplatin). Measurement of renal physiologic parameters in Fischer 344 rats 3 and 5 days after receiving equitherapeutic doses of either cisplatin or MIDP (6.0 and 25 mg/kg, respectively) revealed that, whereas cisplatin significantly reduced glomerular filtration rates (GFR) and increased blood urea nitrogen (BUN) and serum creatinine values, MIDP produced no alteration in either GFR or BUN levels and only a slight rise (Day 5) in serum creatinine value. Histopathologic analyses by light and electron microscopy showed severe renal proximal tubular necrosis in cisplatin-treated rats yet no detectable lesions were produced by MIDP. Determination of elemental platinum content revealed that less platinum was retained in the kidneys of MIDP-treated rats than in cisplatin-treated animals. The degree of drug-mediated intestinal injury was determined for each drug by measurement of jejunal crypt cell regeneration in mice. Cisplatin reduced crypt survival by 1 log whereas no killing of crypt cells was seen even at MIDP doses exceeding the median lethal dose. Our data demonstrate that far less renal and intestinal toxicity results from administration of MIDP than from administration of cisplatin.

Animals↗
PubMed1986

Rat renal papilla: comparison of two techniques for x-ray analysis.

Major differences in elemental and water content in cells of rat papillae have been reported by investigators using the frozen hydrated/frozen dried method versus that using external standards for x-ray microanalysis. These differences could not be ascribed to either cryosectioning at warmer temperatures or to the analytical algorithm used by either group. In this study, six paired left and right renal papillae were subjected to x-ray analysis. The frozen hydrated/frozen dried method was used on undipped papilla, while both methods were applied simultaneously to contralateral papillae dipped in albumin standard. No significant differences were seen between the physiologic state of the left and right kidneys prior to freezing. Our results demonstrated two major problems with application of an albumin peripheral standard: 1) albumin dipping significantly changed elemental and water content in papillary collecting duct cells, epithelial cells and interstitium, but interstitial cells were not affected; 2) the peripheral albumin standard itself also changed water and elemental content in a direction consistent with movement of Na and Cl from tissue to standard, and water from standard to tissue.

Albumins↗
PubMed1986

Simultaneous comparison of techniques for x-ray analysis of proximal tubule cells.

Major differences in elemental and water content in cells of rat papillae in antidiuresis have been reported using x-ray microanalysis. The reason for these reported differences in unknown. In order to determine if the differing microprobe techniques used in these reports could account for the differences measured, we analyzed elemental concentrations in rat proximal tubule cells using both methods simultaneously on the same cells. Both methods provided comparable results. Furthermore, no differences in element or water content of proximal tubule cells cryosectioned with albumin at -53 degrees C and those cells cryosectioned at -80 degrees C were seen. Therefore, the differing values previously reported for elemental analysis of rat kidney cannot be ascribed to either cryosectioning at a warmer temperature or to the analytical algorithm used by either group.

Albumins↗
PubMed1986

Kidney morphology: update 1985.

Many new observations have been made correlating changes in renal morphology with changes in renal function. These changes have led to a better definition of the various segments which make up the renal tubule. These morphological patterns vary in different species as is documented by morphologic studies and by differences in the patterns of enzymes in various nephron segments. The subdivision of cells located in the mesangial region of the glomerulus into several types may provide new areas to study with respect to disease processes.

Animals↗
PubMed1986

Renal damage caused by heavy metals.

Studies of tubular injury and necrosis caused by heavy metals have indicated involvement by various parts of the proximal tubule. This paper describes the patterns of injury seen after administration of mercuric chloride, uranyl nitrate, and cisplatin to animal models. Studies describing a possible role of the mesangium of the renal corpuscle in proximal tubular injury are included.

Acute Kidney Injury↗
PubMed1986

Protective effects of O-(beta-hydroxyethyl)-rutoside on cis-platinum-induced acute renal failure in the rat.

Cis-platinum (CP) is an important antineoplastic chemotherapeutic agent which causes significant renal toxicity in humans and experimental animals. This present study was designed to determine whether the free radical scavenger, O-(beta-hydroxyethyl)-rutoside (HR), exerts beneficial effects on the kidneys of rats receiving an intravenous injection of 6 mg/kg body weight of CP. Renal functional and structural changes were evaluated and quantitated in three groups of Fischer 344 female rats. Group HR/S control rats received HR treatment and a sham injection of sterile saline (S). Group S/CP rats were treated with S and intravenous CP while rats in group HR/CP received both HR and CP. The experimental group S/CP and HR/CP rats had markedly elevated blood urea nitrogen and creatinine concentrations, increased fractional excretion of sodium chloride, and decreased glomerular filtration rate when compared to group HR/S controls. Group HR/CP rats, however, had significantly lower blood urea nitrogen and creatinine values when compared to the group S/CP rats, 69 +/- 14 mg/dl versus 267 +/- 41, and 1.5 +/- 0.4 versus 5.9 +/- 0.9, respectively (p less than 0.001 for both). Renal function was also better preserved in group HR/CP rats when compared to those in group S/CP. The glomerular filtration rate in group HR/CP rats, 329 +/- 67 microliter/min/gm of kidney weight and urinary osmolality, 586 +/- 42 mOsmoles/kg H2O, was significantly greater than in group S/CP rats, 46 +/- 19 microliter/min/gm of kidney weight, and 374 +/- 28 mOsmoles/kg H2O, respectively (p less than 0.005 for both). The fractional sodium excretion was also less in group HR/CP rats, 2.7% +/- 0.6, when compared to group S/CP rats, 10.2% +/- 0.8 (p less than 0.001). There were no apparent pathological changes in group HR/S rats. In contrast, renal tubular injury and necrosis were observed in both group S/CP and HR/CP rats which were both treated with CP. The injury was confined to the S3 segment of the proximal tubule located in the outer stripe region of the outer medulla. While the injury was readily apparent in both experimental groups, group HR/CP rats had significantly less proximal tubule injury than group S/CP rats when the Wilcoxon nonparametric rank sum test was applied to the morphological data. We conclude that the free radical scavenger, O-(beta-hydroxyethyl)-rutoside, provides partial protection against the structural and functional alterations which are induced in the kidney after the intravenous administration of cis-platinum.

Acute Kidney Injury↗
PubMed1984

Protective effect of intrarenal calcium membrane blockers before or after renal ischemia. Functional, morphological, and mitochondrial studies.

The present study examined whether a pre- or postischemic infusion of verapamil (V) or a postischemic infusion of nifedipine (N), drugs which block calcium (Ca++) influx across plasma membranes, provides protection against ischemic acute renal failure (ARF) in dogs. Renal hemodynamics and excretory function were examined 1 h (initiation phase) and 24 h (maintenance phase) after a 40-min intrarenal infusion of norepinephrine (NE). In each case, the uninfused contralateral kidney served as control. Four groups were studied: (a) dogs receiving NE alone; (b) dogs receiving an intrarenal infusion of V for 30 min before NE (V + NE); (c) dogs in which intrarenal V was infused for 2 h, beginning immediately after completion of NE infusion (NE + V); and (d) dogs in which intrarenal N was infused for 2 h, beginning immediately after completion of NE infusion (NE + N). Glomerular filtration rate (GFR) in the NE kidneys, as assessed by inulin clearance, at 1 and 24 h averaged 2.4 +/- 1.1 and 5.0 +/- 2.0 ml/min, respectively, as compared with control kidney GFRs of 28.0 +/- 3.5 and 43.8 +/- 5.0 ml/min, respectively (both at least P less than 0.01). In the V + NE group, GFR at 1 and 24 h averaged 15.0 +/- 5.5 and 31.0 +/- 4.5 ml/min, respectively, both at least P less than 0.05 as compared with values from NE kidneys. GFRs in the NE + V group averaged 15.0 +/- 2.4 and 16.3 +/- 3.6 ml/min at 1 and 24 h, both at least P less than 0.02 as compared with values from NE kidneys. GFR in the NE + N group averaged 18.6 +/- 6.0 ml/min at 24 h (P less than 0.05 as compared with GFRs in the NE kidneys). In addition, function of cortical mitochondria (Mito) was examined at the end of the 40-min NE infusion and after 1 and 24 h of reperfusion in the NE alone and NE + V groups. Mito respiration, assessed by acceptor control ratios, was reduced at each period in the NE alone kidneys. After 24 h, these Mito had accumulated Ca++ and exhibited reduced Ca++ uptake and increased Ca++ release rates. Mito from NE + V kidneys respired normally, did not accumulate Ca++, and exhibited no alterations in Ca++ uptake or release. Light and electron microscopy also demonstrated morphological protection of V against tubular necrosis and cell injury. Mito from the NE + N kidneys also respired normally and did not accumulate significant amounts of Ca++. The results of the present studies therefore demonstrated that chemically dissimilar calcium entry blockers exert substantial functional, cellular, and morphological protection against experimental ischemic ARF. These findings are compatible with the hypothesis that increased cytosolic Ca++ is critically important in the maintenance of renal vasoconstriction and the development of cellular necrosis with subsequent tubular obstruction in NE-induced ischemic ARF. V or N may provide protection against renal injury by retarding any increase in cytosolic Ca++ in renal vasculature and epithelium.

Acute Kidney Injury↗
PubMed1984

Partial protection by chlorpromazine in mercuric chloride-induced acute renal failure in rats.

Previous studies have demonstrated that the anesthetic amine, chlorpromazine hydrochloride (CPZ), prevents cell necrosis in experimentally induced ischemic liver and heart disease and decreases the extent of galactosamine-induced cell death in the liver. The present model was designed to determine whether CPZ exerts a similar beneficial effect in kidney in a nephrotoxic model of acute renal failure in rats induced by the administration of mercuric chloride (2 mg/kg of body weight). The functional and structural changes in the kidney were evaluated and quantitated in animals pretreated with CPZ (40 mg/kg of body weight) or saline and then subjected to nephrotoxic injury. Compared to controls, the glomerular filtration rate was significantly lower (p less than 0.001) in saline- and CPZ-pretreated rats receiving mercuric chloride. Twenty-four hours after mercuric chloride administration the glomerular filtration rate was 446 +/- 38 microl/minute/gm of kidney weight, the fractional sodium excretion was 0.4 +/- 0.2%, and the urinary osmolality was 1440 +/- 193 mOsmoles/kg of H2O in the CPZ-treated animals compared to 26 +/- 18 microl/minute/gm of kidney weight (p less than 0.001), 10.1 +/- 9.8% (p less than 0.025), and 353 +/- 28 mOsmoles/kg of H2O (p less than 0.005), respectively, in the animals receiving mercuric chloride alone. The percentage of proximal tubule cell necrosis was 26.5 +/- 8.9% in the CPZ-pretreated group compared to 88.1 +/- 3.6% in the untreated group (p less than 0.001). Metabolic cage studies were performed to follow the time course of this model for 48, 72, and 96 hours after mercury injection. The serum creatinine values and fractional sodium excretions were significantly less in animals receiving CPZ compared to the untreated group at all time intervals examined. The serum urea nitrogen concentration and glomerular filtration rate were similar for the two groups after 48 hours, but the serum urea nitrogen level was significantly lower and the glomerular filtration rate higher after 72 and 96 hours in the animals pretreated with CPZ. In agreement with these findings were observations that animals pretreated with CPZ had significantly fewer necrotic cells 48 and 72 hours after mercury administration, and tubular regeneration appeared to be markedly accelerated. These results suggest that pretreatment with CPZ markedly lessens the degree of structural and functional impairment seen in mercuric chloride-induced acute renal failure in rats and increases the rate of recovery.

Acute Kidney Injury↗
PubMed1984

Proliferative lesions found in rat kidneys after a single dose of cisplatin.

Proliferative lesions in inbred F344 rat kidneys were studied at 6 and 15 months after a single injection of 6 mg cisplatin [CAS: 15663-27-1; cis-diamminedichloroplatinum (ll)]/kg body weight. Solid or cystic lesions developed from altered proximal tubular epithelial cells. The lesions affecting the renal proximal tubules had both granular (organelle-rich) and clear (organelle-poor) variants. These altered cells retained microvilli and contained numerous lysosomes, mitochondria, and abundant rough-surfaced endoplasmic reticulum and free ribosomes. In addition, papillary hyperplasia was seen at 15 months and involved the epithelium lining the renal papilla. The hyperplastic changes of the papillary epithelium were morphologically similar to those produced by other drugs.

Animals↗
PubMed1983

The aging male rat: structure and function of the kidney.

The progression of anatomic and functional changes that occur with aging in normal male Sprague-Dawley rats was investigated. Renal function studies were followed by vascular perfusion fixation of the kidneys. The kidneys were examined with light microscopy and scanning and transmission electron microscopy. The glomerular filtration rate of 12-month-old rats (0.30 +/- 0.06 ml/min/100 gm body weight) was significantly lower (P less than .05) than the rates of the 3-month-old (0.91 +/- 0.08 ml/min/100 gm body weight) and 5-month-old (0.99 +/- 0.16 ml/min/100 gm body weight) rats. Urine protein levels were moderately elevated in 12-month-old rats. Structural changes mainly involved the renal corpuscle and proximal tubule. The parietal layer of Bowman's capsule was transformed from a squamous to a columnar epithelium resembling that of the proximal tubule in 48% of the capsules surveyed in 12-month-old rats. This value was significantly higher (P less than .05) than that of the 5- (14%) or 3- (6%) month-old rats. Thin sheets of cytoplasm extended from podocytic cell bodies over the layer of pedicels. The proximal tubule displayed focal areas of cell injury and necrosis. Basement membranes associated with the renal corpuscle, glomerulus, and proximal tubule were considerably thickened in the oldest group of rats. Some cellular infiltration occurred in the interstitium. Therefore, kidneys of aging Sprague-Dawley rats exhibited capsular metaplasia, death, and injury of proximal tubular epithelial cells, and other structural changes not seen in younger animals. Some of these changes may underlie the functional deterioration of their kidneys.

Aging↗
PubMed1983

Endothelial characteristics of glomerular capillaries in normal, mercuric chloride-induced, and gentamicin-induced acute renal failure in the rat.

A reduction in glomerular capillary endothelial pore size and density has been reported in several models of acute renal failure. It has been suggested that these changes underlie the decrease in glomerular filtration rate and altered glomerular capillary hemodynamics measured in various experimental models of acute renal failure. We have thoroughly quantitated the surface characteristics of glomerular capillaries in control rats and in rats with either mercuric chloride-induced acute renal failure (2 mg/kg body wt) evaluated at 6 and 24 h after administration of the nephrotoxin or with gentamicin (G)1-induced acute renal failure evaluated after 8-9 d of 40 mg/kg body wt twice a day. Despite reductions in glomerular filtration rate in the experimental groups, no significant differences were observed between control (C) and any experimental group with respect to percent areas occupied by fenestrated endothelium (C = 53.6 +/- 2.7%; 6 h HgCl2 = 50.9 +/- 1.9%; 24 h HgCl2 = 53.9 +/- 5.7%; G = 56.7 +/- 2.4%), by cytoplasmic ridges (C = 31.2 +/- 1.5%; 6 h HgCl2 = 29.8 +/- 1.9%; 24 h HgCl2 = 30.6 +/- 3.1%; G = 26.5 +/- 1.5%), nonfenestrated endothelium (C = 15.5 +/- 4.0%; 6 h HgCl2 = 19.3 +/- 2.0%; 24 h HgCl2 = 15.6 +/- 4.3%; G = 16.9 +/- 2.3%), in the individual pore area expressed in square nanometers (C = 1,494 +/- 75; 6 h HgCl2 = 1,326 +/- 48; 24 h HgCl2 = 1,559 +/- 130; G = 1,340 +/- 101), or in the percentage of total pore area within fenestrated areas that were measured (C = 12.8 +/- 0.8%; 6 h HgCl2 = 11.2 +/- 0.7%; 24 h HgCl2 = 10.9 +/- 0.8%; G = 10.9 +/- 0.7%). These results provide quantitative data on the normal glomerular capillary endothelial surface characteristics and suggest that reductions of glomerular filtration rate in acute renal failure are not always associated with alterations in glomerular endothelial capillaries.

Acute Kidney Injury↗
PubMed1983

Protective effect of oral clonidine in the prophylaxis and therapy of mercuric chloride--induced acute renal failure in the rat.

Previous studies have demonstrated that the sympathomimetic agent clonidine, administered intravenously immediately prior to injury, provides partial protection against the acute structural and functional impairments associated with experimental ischemic and nephrotoxic ARF. To determine the effect of clonidine, administered orally, on the prolonged course of HgCl2-induced ARF, two groups of rats were studied for a period of 5 days after injury. For 5 days before HgCl2 administration (2 mg/kg s.c.) and throughout the study group I drank water while group II had clonidine (5 mg/L) added to water. The fatality rate was 77% in group I as compared to 11% in group II (p less than 0.001). Renal function (CCr and FENa) was better preserved and recovered more rapidly in group II rats protected with clonidine. Both groups showed varying degrees of proximal tubular cell injury, but group II had significantly fewer necrotic cells and demonstrated earlier evidence of regeneration. Whereas none of the injured cells in the clonidine-pretreated group revealed evidence of calcification, on the second day half the cells of the pars recta in the outer stripe of the medulla were calcified in group I. In group III animals, oral clonidine was started 2 hr after the injection of HgCl2 and also resulted in a significant reduction in fatality rate from 40% in control group to 0% in the clonidine-treated group. In addition, CCr and FENa were better preserved and recovered more rapidly in this group of clonidine-treated rats. These results indicate that oral clonidine, administered either before or shortly after HgCl2-induced ARF, exerts a salutory effect on the course and mortality of ARF by providing protection of renal function and enhancement of the recovery process.

Acute Kidney Injury↗
PubMed1982

The pelvic epithelium of the rat kidney: a scanning and transmission electron microscopic study.

The renal pelvis of the rat is characterized by extensions called specialized fornices that penetrate into the outer zone of the outer medulla (a type II as classified by Pfeiffer, 1968, 1970). The renal pelvic epithelium, therefore, covers areas of the kidney from the inner medulla, the inner and outer stripe of the outer medulla, and the cortex. The renal pelves of seven rats were studied by transmission and scanning electron microscopy. The transitional epithelium on the nonparenchymal surface of the pelvis was three to four cell layers thick (zone 0-1). This epithelium became thinner where it covered the renal cortex (zone 1-2) or the outer medulla. Although the apical cells of the epithelium retained the asymmetric luminal unit-membrane plaques, the number of cytoplasmic fusiform vesicles decreased as one studied the epithelium progressing over the zones from cortex toward papilla. Scanning electron microscopy demonstrated a small number of surface cells of a different morphology that were characterized by apical microvilli. The number of these microvillous lining cells increased as the epithelium covering the outer (zone 2-3) and inner (zone 3-4) stripe regions of the outer medulla was viewed, until the inner medulla was entirely covered by this cell type. In a reciprocal manner, the cells with the asymmetric apical plaques decreased in numbers and in their morphologic specialization in each successive region. The epithelium surrounding the inner medulla (zone 6-7) was completely devoid of this transitional cell type. Judging from the morphologic characteristics of the epithelia, one could surmise that little exchange of urea, water, and salts would occur with the extrarenal connective tissue or the cortical parenchyma. Recycling of urea might become more important physiologically with the outer stripe parenchyma, and even more so with the increased surfaces of the inner stripe parenchyma that lined the secondary pyramid, as well as with the epithelium lining the medulla.

Animals↗
PubMed1982

Carbonic anhydrase histochemistry in rabbit and mouse kidneys.

The presence of carbonic anhydrase activity in rabbit and mouse kidneys was examined using a histochemical procedure with plastic embedded sections stained by the modified version of the cobalt-phosphate method (Hansson, 1967, 1968; Ridderstrale, 1976). Proximal convoluted tubules (S1 and S2 segments) in both species were strongly positive for carbonic anhydrase activity on the membranes of the luminal, lateral, and basal surfaces. The apical cytoplasm beneath the brush border and the nuclei also stained positively for carbonic anhydrase. The S3 segment (pars recta) of the proximal tubule in the rabbit was positive on the luminal membrane, with somewhat less intensity seen on the lateral and basal surfaces. This segment in the mouse was completely negative. The first part of the thin limbs of long-looped nephrons exhibited strong staining in the mouse. Faint luminal staining was present on descending thin limbs of short-looped nephrons in the mouse. In the rabbit, both the medullary and cortical ascending thick segments of the limb of Henle were completely negative. In contrast, the medullary and cortical ascending thick limbs in the mouse kidney showed staining on all plasma membranes. The intercalated cells in the cortical and medullary portion of the collecting tubules stained positively for carbonic anhydrase in both species. The principal cells of the collecting duct in the cortex were negative in the rabbit and faintly positive in the mouse. The principal cells in the upper medullary collecting tubules in both species stained intensely along the luminal, lateral, and basal cell membranes. The papillary collecting ducts were largely negative in both the rabbit and the mouse. Some interstitial cells in the rabbit in the region of the papillary tip were strongly positive. We conclude that there is a marked difference in carbonic anhydrase activity within and between the renal tubular segments of the rabbit and the mouse. In addition, these distinct differences that exist between the two species correlated with known physiological roles in ion transport.

Animals↗
PubMed1982

The long-term effects of uranyl nitrate on the structure and function of the rat kidney.

Studies were undertaken to determine the long-term effects of the nephrotoxin, uranyl nitrate, on the function and structure of the rat kidney. Animals were injected with 10 mg/kg B.Wt. of uranyl nitrate and renal function studies were performed one, two, four and eight weeks after drug administration. Light microscopy and scanning and transmission electron microscopy were used to characterize the morphologic changes at each time interval. Glomerular filtration rate was significantly reduced (P less than 0.01) one week (0.18 +/- 0.06 ml/min/100 gm B.Wt.) and two weeks (0.54 +/- 0.09 ml/min/100 gm B.Wt.) after drug treatment compared to controls (1.01 +/- 0.4 ml/min/100 gm B.Wt.) and returned to normal values by four weeks. The fractional excretion of sodium was significantly increased (P less than 0.01) one week after uranyl nitrate treatment (2.45% +/- 0.82) compared to controls (0.29% +/- 0.11). No further differences in this parameter were noted after one week. At all time intervals studied the pars recta of the proximal tubule (S2 and S3 segments) was the most consistently damaged region of the nephron. Acute tubular necrosis and tubular regeneration of these segments were evident one and two weeks after drug administration. Many of the tubules were widely dilated and lined by low-lying squamous epithelial cells. By four weeks some of these pars recta segments could be classified as microcysts and this type of lesion persisted as long as eight weeks after treatment. Regeneration of most injured proximal tubules was complete by eight weeks. Atrophic proximal tubules, marked interstitial fibrosis and a mononuclear cell infiltration, consistent with a chronic type of injury, were noted at the later time intervals. These results suggest that uranyl nitrate induces a persistent injury to the kidneys of rats causing lesions as long as eight weeks after injection.

Animals↗
PubMed1982

Renal carbonic anhydrase.

Carbonic anhydrase is a zinc metalloenzyme widely distributed throughout the tissues of the body. This enzyme exists in a number of isozymic forms in most mammalian species. Significant advances over the past decade have been made in characterizing the nature of renal carbonic anhydrase. In the kidney, this enzyme is thought to play a pivotal role in urinary acidification and bicarbonate reabsorption. Two distinct isozymes of carbonic anhydrase have now been identified in the mammalian kidney. A soluble cytoplasmic form, similar if not identical to human erythrocyte carbonic anhydrase C, accounts for the bulk of the renal carbonic anhydrase activity. In addition, a membrane-bound form constituting only about 2--5% of the renal activity has been found in the brush border and basolateral fractions of kidney homogenates. The histochemical and immunocytochemical localization of these isozymes along the nephron and collecting duct system of various mammalian species suggests that marked heterogeneity exists. The Editorial Review examines the biochemical and morphological approaches that have been used to elucidate the nature of renal carbonic anhydrase and to assess its distribution along the urinary tubule. Possible physiological roles for the renal carbonic anhydrases are considered for the different segments of the nephron and collecting duct system.

Animals↗