Cyclic GMP but not cyclic AMP prevents renal platelet accumulation after ischemia-reperfusion in anesthetized rats

Platelets have been implicated in the pathophysiology of ischemia-reperfusion injury. In this study, antiplatelet effects of cyclic GMP (cGMP)- and cyclic AMP (cAMP)-mediated agents were evaluated in renal ischemia in pentobarbital-anesthetized rats. Renal ischemia was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion (30 min) with the contralateral kidney serving as control. 111Indium-labeled platelets, drugs or vehicle were administered 30 min before induction of renal ischemia. Occlusion of the left renal artery for 20, 40 or 60 min resulted in a 100, 300 and 600% increase (over contralateral right kidney) in the platelet-associated 111indium activity in the ischemic kidney. In all subsequent studies the kidney was occluded for 40 min to test the antiplatelet activity of individual agents. 8-Br-cGMP (0.1 and 0.3 mg/kg/min i.v.), zaprinast (0.1 mg/kg/min i.v.) and sodium nitroprusside (0.003 and 0.01 mg/kg/min i.v.) significantly attenuated platelet accumulation in renal ischemia, whereas 8-Br-cAMP (0.3 mg/kg/min i.v.) or milrinone (0.1 mg/kg i.v. bolus, plus 0.01 mg/kg/min) did not. Minoxidil (0.01 and 0.03 mg/kg/min i.v.), a vasodilator which produced equihypotensive effects as the cGMP-mediated agents, and milrinone failed to prevent platelet accumulation. These results demonstrate that modulation of the platelet function by cGMP agents can be dissociated from their blood pressure lowering effects. cGMP is known to inhibit both platelet adhesion and aggregation, whereas cAMP is only active against aggregation. The present findings provide further evidence that cGMP-mediated drugs may afford effective antiplatelet action in an in vivo model of ischemia-reperfusion injury.     

Mobilization of hepatic cadmium in pregnant rats

Mobilization of hepatic cadmium (Cd) in pregnant rats was investigated. Female Sprague-Dawley rats (200-250 g) were injected subcutaneously, daily with 1.0 mg Cd/kg body weight as CdCl2 for 8 days. A group of these rats was made pregnant. Copper (Cu), zinc (Zn), Cd, and metallothionein (MT) concentrations in the liver, kidney, and plasma of the control and Cd-injected, pregnant and nonpregnant rats, were compared. The hepatic Cd concentration of the Cd-injected rats decreased by 40% during pregnancy and became significantly lower than that of the nonpregnant Cd-injected rats. On the other hand, there was a concomitant increase (60%) of Cd concentrations in the kidney of the Cd-injected pregnant rats. MT in the Cd-injected rats also showed a similar pattern of decrease in hepatic concentrations and increase in renal concentrations during pregnancy. Both Cd and MT contents in the placenta of the Cd-injected rats were higher than those of the control and there was a significant increase over the gestational period. Plasma Cd and MT concentrations of the Cd-injected pregnant rats were higher than those of Cd-injected nonpregnant rats. These results suggest that pregnancy can mobilize the hepatic Cd which can be transferred to the kidney and placenta through the blood plasma. Moreover, the blood urea nitrogen levels of the pregnant Cd-injected rats were increased on Gestation Day 21 and 7 days after delivery, indicating signs of Cd nephropathy. The hepatic Cd, Cu, Zn, and MT concentrations of the newborn rats, however, were unaltered by Cd injections. Therefore, it is possible that pregnancy may induce a high risk of Cd nephrotoxicity in women with chronic Cd exposure.     

Antiarrhythmic action of the new calcium antagonist [1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine dihydrochloride

Arrhythmias induced by coronary artery ligation in cats, by CaCl2 and epinephrine in rats, and by ouabain in guinea-pigs were used as experimental models for studying the effects of a new calcium antagonist AR-1 ([1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine, calcium channel blocker and calmodulin antagonist) on ventricular arrhythmias. Coronary ligation caused 90% lethality (ventricular fibrillation) with 12.5 min in untreated control cats, which was prevented by administration of AR-1 (4 mg/kg body weight (b.w.) before or after arrhythmia induction. Pretreatment with AR-1 afforded protection in a dose-related fashion. A dose of 1.5 mg/KG b.w. increased survival to 45%, and all cats dosed with 3 to 5 mg/Kg b.w. survived. CaCl2 (180 mg/Kg b.w., i.v.) induced ventricular fibrillation and 100% lethality. These effects were completely prevented by an anti-arrhythmic dose of AR-1 (3 mg/kg b.w.). Epinephrine-induced ventricular arrhythmias were also prevented by the same dose of AR-1. AR-1 (5 mg/kg b.w.) did not prevent ouabain (0.5 mg/kg b.w.)-induced arrhythmias that caused death within 17 +/- 3.7 min, but displayed protective effects during 67 +/- 7.7 min. The results from these animal studies, in conjunction with previously studies demonstrating coronarodilatory and anti-platelet efficacy of this compound, collectively suggest that AR-1 has a potential to become a useful antianginal and antiarrhythmic therapeutic agent.     

Cadmium toxicity and distribution in metallothionein-I and -II deficient transgenic mice

To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the present study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metallothionein-I and -II deficient (MT-/-) mice and the parental strain carrying intact metallothionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT-/- mice expressed lower levels of cadmium-binding proteins relative to MT+/+ mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+ mice compared to zinc pretreated MT-/- mice. The cadmium LD50 was similar for MT-/-, MT+/+, and zinc-pretreated MT-/- mice (15-17 mumol CdCl2/kg body weight delivered i.p.). However, zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 mumol CdCl2/kg body weight. Over two-thirds of cadmium was found in liver, cecum, small intestine, and kidney in both MT+/+ and MT-/- mice; therefore, metallothionein levels do not appear to play a major role in the tissue distribution of cadmium. However, after zinc pretreatment, MT+/+ mice accumulated more cadmium in the liver and less in other tissues, whereas the amount of cadmium in the liver was not altered by zinc pretreatment in MT-/- mice. In general, the cytosolic/particulate ratio of cadmium was significantly higher in tissues of noninduced MT+/+ mice relative to MT-/- mice. This difference was accentuated after zinc pretreatment. Together these results indicate that basal levels of metallothionein do not protect from the acute toxicity of a single i.p. cadmium challenge. Furthermore, it does not appear that the cytosolic compartmentalization of cadmium is correlated with reduced toxicity.     

Modulation of erythropoietin production by selective adenosine agonists and antagonists in normal and anemic rats

Hypoxia or anemia is the fundamental stimulus for erythropoietin (EPO) production. Recent in vitro studies suggest that EPO secretion in response to hypoxia is regulated by adenosine in the kidney. In order to examine the in vivo effect of adenosine on EPO production, we determined the effects of adenosine receptor agonists and antagonists on serum EPO concentration in normal and anemic rats. In normal rats, intravenous injection of adenosine agonists (NECA, CHA and CGS-21680) dose-dependently stimulated EPO production. Pretreatment with KW-3902, an adenosine A1 antagonist with modest A2b antagonistic action, or KF17837, an adenosine A2a antagonist, inhibited the NECA (0.1 mg/kg, i.v.)-stimulated EPO production. Anemic hypoxia, induced by 2% (v/w body weight) blood withdrawal, increased serum EPO concentration from 38 +/- 2 to 352 +/- 76 mU/ml, with the increased serum adenosine concentration in the renal vein. KF17837 (0.1 mg/kg, i.v.), but not KW-3902 (0.1 mg/kg, i.v.), inhibited the anemic hypoxia-induced increase in EPO production. The present findings support the notion that adenosine mediates the EPO production in response to hypoxia in the kidney.     

Physical map of the Clostridium difficile chromosome

The present study was designed to investigate the effect of mercuric chloride administration on copper, zinc, and iron concentrations in the liver, kidney, lung, heart, spleen, and muscle of rats. The results showed that after dose and time exposure to mercuric chloride, the concentration of mercury in the six tissues was significantly elevated. Data showed that there were no interaction between mercury and tissue iron. There was a considerable elevation of the content of copper in the kidney and liver. The most significant changes in the copper concentration took place in the kidneys. About a twofold increase in the copper content of the kidney was noted after exposure to mercuric chloride (3 mg and 5 mg/kg). Only slight elevations in the copper content occurred in the liver especially in high dose and longer exposure time. In the remaining organs, the copper content was not changed significantly (p > 0.05). The most significant changes in the zinc concentration took place in liver, kidney, lung and heart (5 mg/kg). Marked changes in kidney zinc concentrations were observed at any of the specified doses. Zinc concentrations were significantly increased in kidney of rats sacrificed 9-48 h after s.c. injection of HgCl2 (5 mg/kg); in liver obtained from rats at 18, 24 or 48 h after injection; and in lung after 24 or 48 h of treatment. The heart and spleen zinc concentrations were elevated at 24 and 48 h after injection of HgCl2 (5 mg/kg), respectively. The results of this study implicate that effects on copper and zinc concentrations of the target tissues of mercury may play an important role in the pathogenesis of acute mercuric chloride intoxication.     

Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome

Recent studies have shown that tetrafluoroethylene is a renal and hepatic carcinogen in the rat. In this study, we have examined the ability of a single i.p. dose of 1,1,2,2-tetrafluoroethyl-L-cysteine (TFEC), a major metabolite of tetrafluoroethylene, to produce hepatic and renal injury in male and female rats. We have also examined the effect of blocking the renal organic anion transport system with probenecid and of inhibiting the activity of cysteine conjugate beta-lyase with aminooxyacetic acid on the extent of renal injury produced by TFEC. Doses of > or = 12.5 mg/kg TFEC produced renal tubular necrosis to the pars recta of the proximal tubules within 24 h in both male and female rats. This was associated with an increased kidney to body weight ratio and plasma urea at doses of > or = 25 mg/kg. No consistent evidence of liver injury was seen at doses up to 50 mg/kg TFEC in rats of either sex, although occasional vacuolation of hepatocytes and a small dose-related increase in liver to body weight ratio was observed. Prior treatment of female rats with probenecid completely prevented the renal injury produced by either 25 or 50 mg/kg TFEC as judged by plasma urea and histopathology. However, prior treatment of female rats with aminooxyacetic acid afforded no protection against the nephrotoxicity produced by either TFEC or the cysteine conjugate of hexachloro-1,3-butadiene. Thus no major sex difference in nephrotoxicity in the rat was seen with TFEC, while accumulation of TFEC, or its N-acetyl derived metabolite, into renal proximal tubular cells via a probenecid sensitive transport system appears to be a key event in the mechanism of nephrotoxicity. The lack of protection observed with the cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid, may reflect the inability to completely inhibit the mitochondrial form of this enzyme and thereby prevent the formation of the reactive metabolite. Our acute studies provide no insight concerning the liver carcinogenicity of tetrafluoroethylene.     

Epidermal growth factor (EGF) increases the renal amino acid transport capacity in amino acid loaded rats

In anaesthetized adult female rats, the influence of epidermal growth factor (EGF) on renal amino acid handling was investigated in glutamine, arginine (both 50 mg/100 g b.wt. per hour), or alanine (90 mg/100 g b.wt. per hour) loaded animals. Continuous infusions of the three amino acids were followed by an increase in the fractional excretion (FE) of the administered amino acids as well as of the other endogenous amino acids. Under load conditions (alanine, arginine or glutamine), EGF pretreatment (8 micrograms/100 g b.wt. subcutaneously for 8 days, twice daily 8 a.m. and 4 p.m.) was followed by a stimulation of renal amino acid reabsorption. The increase in the fractional excretion of the administered amino acids was significantly lower than in non-EGF-treated rats. These changes in amino acid transport were connected with a significant reduction of GFR after EGF pretreatment (0.96 +/- 0.10 vs. 0.62 +/- 0.07 ml/min x 100 g b.wt.) and a distinct increase in sodium excretion (2.98 +/- 0.55 vs. 4.97 +/- 0.71 muval/100 g b.wt. x 20 min). After loading with p-aminohippurate (PAH; 200 mg/100 g b.wt.), PAH excretion in EGF rats was increased by about 20%, whereas urinary protein excretion was lower in EGF pretreated rats (control: 0.45 +/- 0.04 vs. EGF: 0.18 +/- 0.03 mg/100 g b.wt. x 20 min). The PAH load reduced amino acid reabsorption as a sign of overloading of renal tubular transport capacity, but in EGF pretreated animals the amino acid excretion was only slightly increased under these conditions. Furthermore, EGF pretreatment depressed normal kidney weight gain significantly (874 +/- 18 vs. 775 +/- 32 mg/100 g b.wt.). EGF can improve the renal tubular transport capacity, but, compared to well-known stimulators of renal transport like dexamethasone or triiodothyronine, its effect is only of a moderate degree.     

The diuretic effect of borocaptate sodium in rats and in patients with brain tumors

Kidney function changes after single-dose administration of borocaptate sodium were studied in rats and in patients with brain tumors. Changes of glomerular filtration rate (GFR) measured as 14C-inulin clearance and urine flow rate (UFR) after a slow intravenous injection of BSH (25 and 50 mg/kg b.w., respectively) were investigated in rats under pentobarbital anesthesia. The effect of BSH has been compared with that of its disulfide (BSSB) which is spontaneously generated by oxidation of BSH during storage. It was found that BSH decreases GFR in relation to dose and, in the same way, causes a temporary increase of UFR. On the other hand, BSSB (50 mg/kg) induced a large reversible decrease of GFR as well as a decrease of urine excretion. Measurements of GFR (inulin clearance), renal plasma flow (PAH clearance) and urine excretion were taken in a group of patients with brain tumors in which boron disposition after an infusion of BSH (25 mg/kg b.w. over 1 h) had been studied. An increase in urine production was the dominant effect (up to 200% of the initial value), with the alterations of GFR and RPF being of minor significance except in one patient with a GFR reduction up to almost 50% the original value. Kidney function changes after BSH or BSSB administration are supposedly related to the high retention of BSH in kidney.     

Probenecid protects against In vivo acetaminophen-induced nephrotoxicity in male Wistar rats

Renal effects of acetaminophen (APAP) were studied in rats pretreated with probenecid to analyze whether acute APAP-induced nephrotoxicity could be related to a probenecid-sensitive transport system for APAP or its S-derived conjugates. The administration of probenecid (200 mg/kg b.wt. i.p.) 30 min before APAP administration (1000 mg/kg b.wt. i.p.) improved urine flow rate and protected against the alterations on glomerular filtration rate and urea and creatinine plasma levels induced by APAP. Fewer epithelial cells and granular casts and a decrease in the urinary excretion of protein and glucose were observed in rats pretreated with probenecid. Probenecid pretreatment promoted an elevation in the urinary 16-hr excretion of APAP and a diminution in the plasma levels attained by APAP. These results suggest that protection afforded by probenecid in vivo could be a consequence of the inhibition of APAP S-conjugate renal uptake and/or an increase in APAP renal clearance. The effects of APAP in presence of probenecid were studied with the isolated perfused kidney model. Perfusion with probenecid (0.1 mM) before APAP (10 mM) did not change APAP direct renal effects, APAP urinary excretion, or APAP renal clearance relative to glomerular filtration rate. Our results suggest that protection afforded by probenecid in vivo could be the result of the inhibition of the uptake of nephrotoxic APAP metabolites and/or a diuresis-induced enhanced APAP renal excretion.     

Repeated administration of alpha-hederin results in alterations in maternal zinc status and adverse developmental outcome in the rat

The administration of alpha-hederin, an inducer of metallothionein, results in a secondary zinc deficiency that may be an important maternally mediated mechanism of developmental toxicity. Previous studies have shown adverse developmental outcome with a single administration of alpha-hederin to rats on gestation day (GD) 8 or 11. The objective of this study was to determine whether dosing of alpha-hederin throughout organogenesis would result in a sustained elevation of maternal hepatic metallothionein and subsequent developmental abnormalities. Rats were administered dosage levels of 0 (vehicle only), 20, or 30 mumol/kg from GD 6-15. Maternal hepatic metallothionein levels were 10-fold higher on GD 16 in the treatment groups than the controls. Consequently, liver zinc concentrations increased 60% and 54%, whereas plasma levels decreased 23% and 33% in the 20 and 30 mumol/kg treatment groups, respectively. At GD 20, mean fetal weights of the treatment litters were 11% less than control litters. The administration of alpha-hederin resulted in a threefold increase in the number of offspring that exhibited developmental abnormalities, including visceral and skeletal malformations. Following an oral pulse of 65Zn subsequent to treatment with 0 or 20 mumol/kg of alpha-hederin, the distribution of 65Zn to the liver of treated dams was twice that of controls, whereas the radiolabeled zinc apportioned to the decidua and uterus decreased by 44%. Furthermore, the 65Zn detected in the embryos from treated dams was 70% lower than in embryos from control dams. In conclusion, low doses of a metallothionein inducer administered to the dam from GD 6-15 resulted in a sustained elevation of hepatic metallothionein and a subsequent redistribution of zinc leading to a decrease in the zinc available to the embryo and ultimately to adverse development of the offspring. Repeated dosing throughout organogenesis, as required in regulated safety assessment testing, increased the severity of the effects previously observed with single large dosages of the toxicant administered during midgestation.     

Metallothionein-I-transgenic mice are not protected from acute cadmium-metallothionein-induced nephrotoxicity

Mice pretreated with Zn have increased renal metallothionein (MT) levels and are protected from CdMT nephrotoxicity. To determine whether MT is important in this Zn-induced protection against CdMT-induced nephrotoxicity, MT-transgenic mice that have high levels of MT in their kidneys (10-fold over control mice) have been studied to determine whether they are resistant to CdMT-induced nephrotoxicity. Mice were injected with CdMT (0.1-0.6 mg Cd/kg, iv) and kidney injury was evaluated 24 hr later. CdMT produced renal toxicity in a dose-dependent manner. At a nephrotoxic dose of CdMT (0.4 mg Cd/kg), urinary protein and glucose excretion were increased 30- and 60-fold, respectively, in control mice. However, similar increases in protein and glucose excretion were also observed in MT-transgenic mice. CdMT also induced a similar dose-dependent proximal tubular cell necrosis in both control and MT-transgenic mice in a dose-dependent manner. Treatment of control mice with Zn (100 micromol/kg, sc x 2 days) increased renal MT to levels similar to those of untreated MT-transgenic mice and protected against CdMT-induced renal injury. Furthermore, when Zn (25-100 micromol/kg, sc) was given immediately before CdMT injection (i.e., without preinduction of MT), it was still effective in preventing CdMT nephrotoxicity. We conclude that Zn-induced protection against CdMT nephrotoxicity does not appear to be due to induction of renal MT.     

The cost of quality assurance

The relative importance of endothelial derived relaxing factor (EDRF)/nitric oxide (NO) in maintaining kidney function in normal condition and in acute renal failure (ARF) were evaluated in inactin anesthetized rats. ARF was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion, with the contralateral kidney serving as normal control. This protocol resulted in marked reductions in renal plasma flow (RPF), glomerular filtration rate (GFR) and increases in fractional sodium excretion (FENa) and urinary protein excretion in the post-ischemic kidney in comparison to the contralateral normal kidney. Administration of the nitric oxide (NO) synthase inhibitor NG--monomethyl-L-arginine (0.25 mg/kg per min, L-NMMA) exacerbated the ischemia-induced changes in renal functions as reflected by further reductions in urine flow (V), GFR, marked sodium wasting and renal edema. Pretreatment of the animals with NO precursor L-arginine (2.5 mg/kg per min, L-Arg) abolished the detrimental effects of L-NMMA in ARF. In contrast, D-Arginine (2.5 mg/kg per min, D-Arg) failed to reverse the detrimental effects of L-NMMA. Infusion of L-Arg alone also resulted in improvements in RPF and GFR in the ischemic kidney. The results of the present study suggest that the function of the ischemic kidney is sustained by EDRF/NO and is thus more sensitive to NO synthase inhibition.     

Effect of cisplatin administration on the electrochemical composition of endolymph in the rat cochlea

The effect of cisplatin on the electrochemical composition of the cochlear endolymph was studied in Long-Evans rats three days after a single intraperitoneal injection (8 mg/kg b.w.). A dose 2/3 of LD50 induced a decrease of the endolymphatic concentration of potassium whereas the endocochlear potential was unaffected. The discrepancy between these two findings indicated that cisplatin did not alter the mechanisms involved in the genesis of the endocochlear potential but modified the passive K transport into endolymph.     

Modification of vancomycin nephrotoxicity by other antibiotics in rats

Vancomycin (VCM) was intravenously administered to rats for 14 days at doses of 150 mg/kg/day and 250 mg/kg/day alone or in combination with 1,000 mg/kg/day of latamoxef (LMOX), flomoxef (FMOX) or cefpirome (CPR) or 250 mg/kg/day of fosfomycin (FOM), and the influences of combined antibiotics on the VCM-induced renal damage were studied. The renal impairment caused by VCM alone was, morphologically, demonstrated mainly as regeneration of tubular epithelium: slight regeneration was observed in a half of rats administered 150 mg/kg/day and slight to extensive regeneration in all the rats administered 250 mg/kg/day. Clinical examinations found apparent increases in urinary LDH and MDH activities in rats administered 250 mg/kg/day, thus showing a good correlation with renal pathological changes. In addition, increase in kidney weight and increase in urinary NAG activity were noted, while changes in plasma urea-N and creatinine were mild, and gamma-GTP activity and protein in urine could not be used as a parameter of the renal impairment. The slight renal impairment as noted in rats administered VCM 150 mg/kg/day alone was not observed at all when LMOX or FMOX was administered concomitantly, and less pronounced even when FOM was administered concomitantly. When CPR was administered concomitantly, the changes were the same as those observed with VCM alone. The renal impairment in rats administered VCM 250 mg/kg/day was apparently less severe when combined with LMOX, FMOX and FOM than that in rats administered VCM alone, and this was supported by apparent reduction of clinical examination values as the parameter of VCM-induced nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of ethanol on cadmium accumulation and its impact on lipid peroxidation and membrane bound functional enzymes (Na+, K(+)-ATPase and acetylcholinesterase) in various regions of adult rat brain

Influence of ethanol on cadmium accumulation and its effect on metallothionein induction, binding of cadmium to metallothionein, lipid peroxidation and membrane bound functional enzymes such as (Na(+)-K+)-ATPase and acetylcholinesterase in various regions of adult rat brain was investigated. Ethanol (2 g/kg body wt) and cadmium (1 mg/kg body wt) were administered alone as well as in combination to different groups of rats, i.p., for a period of 1 week. It was observed that cadmium when co-administered with ethanol led to pronounced increase in cadmium accumulation in various regions of the brain. This ethanol induced accumulation of cadmium did not induce the synthesis of metallothionein and also did not bind to this protein in brain and mainly was present as non-metallothionein bound cadmium. It lead to a significant increase in lipid peroxidation and inhibition of membrane bound functional enzymes; (Na(+)-K+)-ATPase and acetylcholinesterase in various regions of the brain indicating functional impairment. The results of the present study imply that ethanol renders the adult brain more susceptible to cadmium neurotoxicity. Corpus striatum and cerebral cortex are more vulnerable regions than other areas of the brain.     

Accumulation of orally given cadmium in Long-Evans Cinnamon (LEC) rats with an inherently abnormal copper metabolism

An inherent defect of biliary Cu excretion and subsequent Cu deposition in the liver have been found in Long-Evans Cinnamon (LEC) rats, which are promising models of Wilson disease. LEC and Fischer rats were given water containing Cd (CdCl2) at a level of 5 ppm for 30 days. Regardless of drinking Cd water, LEC rats showed a very high concentration of Cu (200 to 250 microgram/g) and Cu-metallothionein (Cu-MT) (18 mg/g) in the liver. There was no difference of Cd accumulation in the liver between the two strains exposed to Cd (2.6 and 2.7 microgram/g in the Fischer and LEC groups, respectively). However, the renal Cd concentration was slightly but significantly higher in LEC rats (3.5 microgram/g) than in Fischer rats (2.0 microgram/g). The ratio of renal Cd contents to the sum of renal and hepatic Cd contents was significantly higher in LEC rats (0.25) than in Fischer rats (0.15). The serum Cd concentration in Cd-treated LEC rats increased threefold compared to Cd-treated Fischer rats. It seems likely that Cd from the liver is transported into the kidney in the form of Cd, Cu-MT. There was no difference in uptake of Cd in the hepatic MT fraction between the two strains. Although biliary Cu excretion in LEC rats was significantly lower than that in Fischer rats, reduced excretion of Cd into bile was not found in LEC rats. The gross amounts of Cu and Cu-MT influenced the accumulation of Cd in the kidney rather than in the liver when Cd was given orally at a low level to LEC rats. Our results suggest tht Cu and Cd do not share the same sites of hepatobiliary excretion in rats, although the main route of their excretion is via bile.     

Effects of diabetes and hyperglycemia on disaccharidase activities in the rat

BACKGROUND AND METHODS: To elucidate the effect of hyperglycemia on disaccharidase activities, the specific and total activities of the disaccharidases were measured in the intestinal mucosa and kidney cortex of diabetic and hyperglycemic rats. The diabetes was induced with an intraperitoneal injection of streptozotocin (60 mg/kg). The rats were made hyperglycemic with an intravenous instillation of a solution containing 40% dextrose monohydrate at a rate of 1.5 ml/h for 24 h. RESULTS: The blood glucose level was 387+/-45 mg/dl and 382+/-35 mg/dl (mean +/- standard deviation) in diabetic and hyperglycemic rats, respectively. In diabetic rats the intestinal maltase, sucrase, and lactase activities were significantly higher than those in control rats. Similarly, disaccharidase activities in hyperglycemic rats were significantly higher than those in control rats. The renal maltase activity in diabetic rats was significantly lower than that in control rats. The maltase activity in hyperglycemic rats, however, was not significantly different from that in control rats. CONCLUSIONS: These results suggest that 1) hyperglycemia directly increases the activities of intestinal maltase, sucrase, and lactase; 2) hyperglycemia does not influence renal maltase activity; and 3) hyperglycemia is partly responsible for increased activities of intestinal disaccharidases in diabetes mellitus.     

An experimental study of PAH clearance in chronic unilateral and completely obstructed kidney

The following experiment was performed to estimate PAH clearance of chronic unilateral and completely obstructed kidney and to explore its change during obstruction period. Thirty adult male mongrel dogs were used. Unilateral complete ureteral obstruction was made by ligation of the left ureter proximal to the bladder. After 3, 5, 10, 20 and 40 days of obstruction, an experiment was performed. Under laparotomy, the left kidney was exposed and polyethylene catheter was inserted into the renal pelvis. Intrapelvic pressure was monitored by pressure transducer. In a condition that PAH (p-aminohippurate) was constantly infused intravenously, intrapelvic urine of the obstructed kidney was exchanged for physiological saline. After the exchange, intrapelvic PAH concentration was measured at hourly intervals for 4 hours. At each midpoint of the measurements, plasma PAH concentration was measured. At the end of the experiment, the obstructed kidney was resected and pelvic capacity was measured. PAH of the obstructed pelvis increased at hourly intervals after the exchange. The result showed that the clearance ability was maintained in the completely obstructed kidney. PAH clearance values were 16.3, 13.6, 1.0, 0.9, 0.9 ml/hr/kg b.w. at 3, 5, 10, 20 and 40 days obstruction respectively. PAH clearance decreased sharply during early stage of obstruction and tended to reach a fixed low value at over 10 days of obstruction. Our experimental method seemed to be available to estimate the clearance ability of chronically, unilaterally and completely obstructed kidney.     

Varicella-zoster virus Fc receptor gE glycoprotein: serine/threonine and tyrosine phosphorylation of monomeric and dimeric forms

Recently, it has been shown that large doses of all-trans-retinol (vitamin A) can potentiate the hepatotoxicity of several organic chemicals in the rat. Whether retinol pretreatment can alter the acute hepatotoxicity of an inorganic chemical, such as cadmium, is unknown. Therefore, the objective of this study was to determine how retinol might affect the acute toxicity of cadmium chloride (CdCl2) and to elucidate possible mechanisms. Cadmium exposure can induce acute, lethal hepatocellular necrosis in rodents, as well as lesions in the lung, kidney, testis, and gastrointestinal tract. In the present studies, male Sprague-Dawley rats were pretreated with retinol (75 mg/kg/day, po) for 7 consecutive days. One day after the last dose of retinol, animals were given a single injection of CdCl2 (2.5 to 4.0 mg/kg, iv). Cadmium chloride administration to unpretreated control rats caused extensive hepatic, renal, pulmonary, and testicular toxicity at 6, 24, and 48 hr postdosing as evaluated by plasma enzymes and/or histopathology. In retinol-pretreated rats, a significant attenuation of CdCl2-induced tissue injury was observed. Since the inducible cadmium-binding protein metallothionein (MT) is often an essential aspect of cadmium tolerance, its content in tissue was assessed using the cadmium-hemoglobin assay. Interestingly, retinol pretreatment significantly increased MT in the liver by sevenfold, but had no effect on lung, kidney, testicular, or pancreatic MT content. Although this increase in hepatic MT was much less than that induced by CdCl2, it was additive to the induction of CdCl2. Furthermore, the tissue distribution of cadmium was significantly altered by retinol pretreatment. The liver accumulated more cadmium, while less cadmium was found in the lung, kidney, and testis in retinol-pretreated rats than in controls. In monolayers of primary isolated hepatocytes, CdCl2-induced toxicity was significantly reduced in cells isolated from retinol-pretreated rats compared to those isolated from control rats. The dose response was shifted to the right and the in vitro cadmium LC50 was increased by in vivo retinol exposure from 1.1 +/- 0.1 to 2.4 +/- 0.04 microM. From these data it is concluded that the induction of hepatic MT is an essential aspect of retinol-induced tolerance to CdCl2 hepatotoxicity, as well as toxicity in other tissues.