Differential diagnosis between exudate and transudate in pleural effusion

We determined the relative contributions of endogenous gastrin, histamine and cholinergic tone to basal acid secretion in chronic fistula rats. Results were compared with those for acid secretion in pylorus-ligated rats. In chronic fistula rats, YM022 ?(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea? dose-dependently inhibited pentagastrin-stimulated acid secretion and abolished this secretion at 1 mumol/kg, s.c., but did not affect histamine- and carbachol-induced acid secretion even at 10 mumol/kg. In contrast, famotidine at 1 mumol/kg completely inhibited not only the acid secretion induced by histamine but also those by pentagastrin and carbachol. Furthermore, atropine abolished carbachol- and pentagastrin-stimulated acid secretion and significantly suppressed histamine-stimulated acid secretion at 0.1 mumol/kg. YM022 dose-dependently inhibited basal acid secretion. The YM022 dosage required to inhibit basal acid secretion is consistent with that required to suppress pentagastrin-induced acid secretion. Famotidine (1 mumol/kg) and atropine (0.1 mumol/kg) also abolished basal acid secretion. In pylorus-ligated rats, YM022 inhibited acid secretion in a dose-dependent manner; the inhibition at 1 mumol/kg, i.v. was 65%. No additional effect was observed when rats were dosed at 30 mumol/kg. Famotidine partially inhibited acid secretion in these rats, whereas atropine abolished this secretion. These results indicate that the major part of basal acid secretion in rats is attributable to endogenous gastrin via histamine- and cholinergic tone-dependent pathways. Moreover, pylorus ligation reduces the relative contribution of gastrin to acid secretion due to the activation of cholinergic tone.     

The mechanism of potentiation of the antitumor effect of 5-fluorouracil by methionine-free intravenous amino acid solution (AO-90) in rats

AO-90, a methionine-free intravenous amino acid solution (7.43%) showed to potentiate the antitumor effect of 5-fluorouracil (5-FU) when concomitantly used as the nitrogen source in total parenteral nutrition (TPN) in Yoshida sarcoma (YS)-bearing rats. In the present experiment, this potentiation mechanism was studied by determining the serum methionine level and tumor methylenetetrahydrofolate (CH2FH4) content in YS-bearing Donryu rats given AO-90 (nitrogen 0.73g/kg on the 1st day and 1.46g/kg for the remaining 6 days) by TPN for 1 week. The rats were subcutaneously inoculated with 10(4) YS cells in the dorsum 3 days before the start of TPN. Inhibition of thymidylate synthase activity in tumor tissue after dosing of AO-90 (nitrogen 0.68g/kg on the 1st day and 1.36 g/kg for the remaining 6 days) by TPN along with daily intraperitoneal dosing of 5-FU (10 mg/kg) was also evaluated with the inoculation of 10(6) tumor cells. The results were compared with those in tumor-bearing rats given TPN with a commercially available amino acid solution containing methionine. On day 5 of TPN, the tumor-bearing rats given AO-90 showed a significantly lower serum methionine level than the control rats: 101 +/- 11 mumol/l versus 29 +/- 14 mumol/l (p < 0.01); and a higher CH2FH4 content in tumor: 7.0 +/- 2.8 pmol/g protein versus 23.7 +/- 16.6 pmol/g protein (p < 0.05). Thymidylate synthase inhibition was 81.2 +/- 5.1% in the AO-90 group and 30.9 +/- 26.3% in the control group (p < 0.01). The results of the present study suggest that AO-90 potentiate the antitumor effect of 5-FU by biochemical modulation. AO-90 concomitantly given with 5-FU for 7 days was effective not only in the allogeneic tumor model, but also in WKAH and SHR rats previously inoculated with 10(6) of syngeneic KDH-8 hepatoma cells and SST-2 adenocarcinoma cells, respectively. Weight of SST-2 adenocarcinoma in SHR rats after the TPN period was significantly smaller in the AO-90 group than in the control rats given methionine-containing TPN and 5-FU: 2.66 +/- 0.91 versus 5.12 +/- 2.11 (p < 0.05).     

Effect of sodium tauroursodeoxycholate (UR-906) on liver dysfunction in bile duct-ligated rats

We investigated the effect of sodium tauroursodeoxycholate (UR-906) on cholestasis in common bile duct-ligated rats in comparison with the effect of dehydrocholic acid. UR-906 (30-180 mumol/kg) and dehydrocholic acid (180 mumol/kg) were intravenously given once daily for consecutive 20 days in rats and the common bile duct was ligated for the last 10 days. On the next day after the last test drug administration, serum biochemical and plasma hemostatic variables were determined. UR-906 significantly ameliorated the elevation of serum cholesterol, phospholipid, bilirubin and bile acid concentrations in bile duct-ligated rats. UR-906 significantly suppressed the prolongation of plasma prothrombin time and activated partial thromboplastin time. Furthermore, UR-906 significantly suppressed the decreases in plasma coagulation factor II and X activities. However, dehydrocholic acid did not cause significant changes in any of the variables examined in this model. These results suggest that UR-906 has a beneficial effect against cholestasis induced by bile duct ligation in rats and that this drug may be useful in the treatment of clinical cholestatic disorders.     

Detection and typing of hepatitis C RNA in liver biopsies and its relation to histopathology

The role of kainic acid (KA) (an agonist of non-NMDA receptors) in the control of GH secretion and the modulation of KA action by gonadal secretion were analysed in male rats. In the first experiment 4, 8, 12, 16, 20 and 30-day old males were sacrificed 15 min after injecting with vehicle or KA (2.5 mg/kg BW). In the second experiment, the effects of KA, 6,7-dinitroquinoxaline-2,3-dione (DNQX) and MK-801 were analysed in monolayer cultures of dispersed adenohypophyseal cells. In the third experiment, adult males were sham-operated or orchiectomized and decapitated seven days later, 15 min after injecting with vehicle or KA (2.5 or 15 mg/kg BW). In the fourth experiment, males neonatally injected with estradiol benzoate or vehicle were sacrificed on days 45, 60 or 90, 15 min after administration of vehicle or KA (2.5 or 15 mg/kg BW). We found that: (i) KA is a powerful secretagogue for GH in neonatal and postpubertal males but its releasing effectiveness decreases in adulthood; (ii) GH secretion by cultured pituitary cells remains unaffected in the presence of KA (1,10 or 100 mumol/l); (iii) the KA-stimulated GH secretion is increased after orchiectomy and abolished in males neonatally estrogenized. These results indicate that in male rats activation of non-NMDA receptors, probably those located in hypothalamus, increases GH secretion. The releasing properties of KA increases in orchiectomized males and completely disappears in males neonatally estrogenized.     

Inhibitory effect of selenium on biliary secretion of methyl mercury in rats

The inhibitory effect of sodium selenite on biliary secretion of methyl mercury was examined in rats. The biliary secretion of methyl mercury in rat treated with 1 mumol/kg of methyl mercury was significantly decreased by administration of selenite at doses of 0.05 mumol/kg or higher. In rats given 10 mumol/kg of methyl mercury, marked depression of biliary secretion of mercury was observed when selenite was injected at a dose of 0.2 mumol/kg. On the other hand, secretion of substantial amounts of selenium was observed when biliary secretion of mercury was depressed. When the concentration of selenium in the bile was higher than 5 nmol/ml, biliary secretion of mercury was markedly depressed independently of the dose of methyl mercury administered (1 mumol/kg or 10 mumol/kg). These results suggest that the degree of inhibitory effect of selenite may be determined by the selenium concentration in the liver or the bile after treatment with selenite rather than the molar ratio of the dose of methyl mercury and selenite. We concluded that the decrease in biliary secretion of methyl mercury induced by selenite may result from inhibition of pathway for secretion of methyl mercury from liver to bile rather than the direct formation of a complex between methyl mercury and selenium. Methyl mercury has been considered to be secreted from liver to bile as a complex with glutathione (GSH). However, administration of selenite did not affect biliary secretion of GSH or hepatic glutathione S-transferase activity. Moreover, gel filtration of liver cytosol demonstrated that the distribution pattern of hepatic methyl mercury between macromolecules and GSH was not significantly changed by administration of selenite. These results suggest that selenite does not affect complex formation of methyl mercury with GSH at least in the liver. Selenite might specifically inhibit the activity of the canalicular transporter(s) which transport complexes of methyl mercury and GSH from the liver to bile.     

Stereological changes in rat parietal cells after vagotomy and antrectomy

Gastric parietal cells from 44 male adult Sprague-Dawley rats were studied in the electron microscope. The animals were divided into seven groups: normal fasted, normal nonfasted, 4 weeks after vagotomy, 10 weeks after vagotomy and pyloroplasty, 10 weeks after pyloroplasty, 4 weeks after antrectomy, and 10 weeks after antrectomy. Stereological data were obtained from 30 to 40 parietal cells in each animal. In the normal nonfasted rats the parietal cells high up in the glands had a larger secretory surface density than those at deeper levels of the mucosa. Neck parietal cells containing a few mucous granules constituted about 10% of the total number of parietal cells in the normal rats; they were most common in the midgland region. The average parietal cell volume in the normal fasted rats was calculated to be 1100 mu3; the cells were significantly smaller 10 weeks after vagotomy and pyloroplasty and still smaller 10 weeks after antrectomy. In this respect the results after vagotomy and pyloroplasty did not differ from those after pyloroplasty alone. The parietal cell density in the normal fasted rats averaged 144 X 10(3) cells per mm3; in the operated rats (except for the 4-week vagotomized rats) the cells became more numerous. The parietal cell volume density was about equal in all groups of animals, except for the 10-week antrectomized rats, where a significant reduction occurred.     

Kinetics of dodecanedioic acid and effect of its administration on glucose kinetics in rats

Dodecanedioic acid (C12), a saturated aliphatic dicarboxylic acid with twelve C atoms, was given as an intraperitoneal bolus to male Wistar rats, with the aim of evaluating C12 suitability as an energy substrate for parenteral nutrition. The 24 h urinary excretion of C12 was 3.9% of the administered dose. C12 kinetics were investigated by a one-compartment model with saturable tissue uptake and reversible binding to plasma albumin. The analysis of plasma concentration and urinary excretion data from different animals yielded the population means of the kinetic parameters: renal clearance was 0.72 ml/min per kg body weight (BW) (much smaller than inulin clearance in the rat), and maximal tissue uptake was 17.8 mumol/min per kg BW corresponding to 123.7 J/min per kg BW. These results encourage the consideration of C12 as a possible substrate for parenteral nutrition. To investigate the effect of C12 administration on glucose kinetics, two other groups of rats, one treated with an intraperitoneal bolus of C12 and the other with saline, were subsequently given an intravenous injection of D[-U-14C]glucose in a tracer amount. Radioactivity data of both control and C12-treated rats were analysed by means of a two-compartment kinetic model which takes into account glucose recycling. The estimates of glucose pool size (2.3 mmol/kg BW) and total-body rate of disappearance (82.1 mumol/min per kg BW) in control rats agreed with published values. In C12-treated rats, the rate of disappearance appeared to be reduced to 36.7 mumol/min per kg BW and the extent of recycling appeared to be negligible.     

Modulation of pentagastrin-induced histamine release by histamine H3 receptors in the dog

BACKGROUND: The histamine H3 receptor has been shown to inhibit pentagastrin-induced gastric acid secretion in dogs. Since pentagastrin releases histamine in dogs, we have now assessed whether the effects of H3-receptor ligands may be indirectly mediated by changes in gastric histamine release. METHODS: Pentagastrin infusions (1 or 6 micrograms/kg/h), alone or together with the H3-receptor agonist (R) alpha-methylhistamine (1.2 mumol/kg/h) or the antagonist thioperamide (0.1 mumol/kg/h), were performed in dogs. One group (anaesthetized) was used for enzyme immunoassays of plasma histamine and, when required. (R) alpha-methylhistamine in the gastrosplenic vein, and another group (non-anaesthetized) for measurement of gastric acid secretion. RESULTS: Histamine levels were increased five- and eight-fold after 1 and 6 micrograms/kg/h pentagastrin, respectively, whereas acid output was nearly maximal at the lower dosage. (R) alpha-methylhistamine, at a plasma concentration of 0.15 microM, inhibited histamine release by 78% (P < 0.007) and 37% (not significant) and the total acid output by 44% (P < 0.05) and 19% (not significant) after infusion of 1 and 6 micrograms/kg/h pentagastrin, respectively. Thioperamide, together with pentagastrin in low dose, significantly increased histamine release by 212% (P < 0.05), whereas acid output increased by 34% (not significant). CONCLUSIONS: The histamine H3 receptor mediates a negative feedback control of pentagastrin-induced release of gastric histamine. It is tonically activated by endogenous histamine after pentagastrin in low dosage. The control of acid secretion by the H3 receptor seems to involve modulation of endogenous histamine release, possibly by means of enterochromaffin-like cells.     

Ochratoxin A impairs "postproximal" nephron function in vivo and blocks plasma membrane anion conductance in Madin-Darby canine kidney cells in vitro

Ochratoxin A (OTA) is a widespread nephrotoxin which causes porcine nephropathy and is supposed to have caused the human Balkan endemic nephropathy. We performed experiments in vivo and in vitro to elucidate the mechanism of OTA action in renal epithelium. Application of OTA to male Wistar rats [1.25 mumol/(kg.day)] for 6 days led to a reduction of glomerular filtration rate (to 63% of control), an increased fractional water (194% of control), Na+ (199% of control), K+ (147% of control) and Cl- (270% of control) excretion and an increased dependence of the osmole clearance on urine flow. Acute application of OTA to rats (3 mumol/kg) increased urinary pH from 6.0 +/- 0.2 to 6.6 +/- 0.1 and urinary NaCl excretion, but decreased titratable acid excretion to 47% of control. As these in vivo findings may be the result of an action of OTA beyond the proximal tubule ("postproximal") we investigated the effect of OTA on cultured Madin-Darby canine kidney (MDCK) cells, regarded as a model of collecting duct epithelium. In confluent monolayers formed by MDCK cells OTA reduced the number of domes in a dose-dependent manner and impaired the formation of a transepithelial Cl- gradient. Electrophysiological measurements in giant MDCK cells revealed that OTA blocks fractional anion conductance of the plasma membrane with an IC50 value of 30 +/- 5 nmol/l, unmasking OTA as a naturally occurring anion conductance blocker about 20-times more effective than the most potent synthetic blocker 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) (IC50 = 600 +/- 50 nmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of biliary lipid secretion in the rat: a role for bile acid-independent bile flow?

Bile acid-induced lipid secretion was compared in unanesthetized normal control and Groningen Yellow Wistar rats during variations in endogenous bile acid output. Groningen Yellow rats express a genetic defect in the biliary secretion of various organic anions. During a 5-hr period after interruption of the enterohepatic circulation, bile acid secretion decreased from 36.4 +/- 1.8 to 1.9 +/- 0.3 mumol per 30 min in normal control rats and from 37.1 +/- 2.8 to 1.8 +/- 0.2 mumol per 30 min in Groningen Yellow rats, respectively (mean +/- S.E.M., n = 5). The relationship between bile acid secretion and bile flow showed similar slopes (normal control, 8.74 +/- 0.44 microliter/mumol and Groningen Yellow rats, 7.71 +/- 0.42 microliter/mumol) but different y-intercepts (normal control, 243 +/- 8 and Groningen Yellow, 127 +/- 4 microliters per 30 min; p < 0.001), corresponding to a 47% reduction of the bile acid-independent fraction of bile flow in Groningen Yellow rats. During the course of the experiment, the ratio of lipids (phospholipids plus cholesterol) to bile acids increased in both strains more than threefold but was permanently higher in Groningen Yellow than in normal control rats (p = 0.035), implying that Groningen Yellow rats continuously secreted more lipid per bile acid. No differences in bile acid pool composition or in bile canalicular membrane composition and fluidity between the two strains were detected. The results indicate that apart from previously demonstrated factors (bile acid concentration, bile acid composition and hydrophilic organic anion concentration in bile), another parameter affects the efficacy of bile acids to induce biliary lipid secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

201Tl-myocardial scintigraphy (1974-1992): from perfusion defect to detection of viability

Metalloporphyrin inhibitors of heme oxygenase have been studied for use in the prevention of hyperbilirubinemia of the neonate. One report has suggested that incorporation of these drugs into liposomes can increase their localization to the spleen, dramatically reducing heme oxygenase activity in that important heme-degrading organ. We sought to further increase porphyrin delivery to the spleen by using reticuloendothelial blockade with blank liposomes 2 h before injection of 0.3 microns extruded zinc protoporphyrin liposomes (L-ZnPP). Control adult rats without hemolysis had splenic heme oxygenase activity of 1.07 +/- 0.09 nmol carbon monoxide (CO)/h/mg protein. Rats treated with L-ZnPP alone had splenic heme oxygenase activity of 0.53 +/- 0.16 nmol CO/h/mg protein 6 h after L-ZnPP dosing. However, rats treated with 1000 mumol of blank liposomes per kg to saturate the reticuloendothelial system 2 h before L-ZnPP administration had splenic heme oxygenase activity of 0.25 +/- 0.16 nmol CO/h/mg protein at t = 6 h, which is significantly less than that of the L-ZnPP alone group (p < 0.05). In adult rats treated with heat-damaged red blood cells (RBC) to simulate hemolysis, treatment with 10 mumol of aqueous ZnPP per kg or 10 mumol of untargeted L-ZnPP per kg did not produce a difference from control in total body bilirubin production as estimated by CO excretion. However, RBC-treated rats given 1000 mumol of blank liposomes per kg 2 h before L-ZnPP administration produced significantly less CO than control, aqueous ZnPP-treated, and untargeted L-ZnPP-treated rats from 8 to 12 h after RBC treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phosphatidylcholines as mediators of adaptive cytoprotection of the rat duodenum

BACKGROUND/AIMS: Surfactant phospholipids impede diffusion of acid through the gastric mucus, but their relevance in the defense of the duodenum against luminal acid is not known. METHODS: Duodenal resistance to acid was tested in anesthetized rats by instillation of HCl using a tube implanted in the proximal duodenum. The effects of a detergent (Brij 35; Sigma, St. Louis, MO) and a lipid mixture flushed through the luminal surface on duodenal resistance to acid were studied. The lipid content in the mucus and the effects of acid, prostaglandins, and indomethacin on the lipid layer were also analyzed. RESULTS: Instillation of 100 mumol HCl or 5 micrograms/kg 16,16-dimethyl prostaglandin E2 increased resistance to acid, preventing duodenal lesions induced by 500 mumol HCl. However, 100 mumol HCl or 16,16-dimethyl prostaglandin E2 did not prevent lesions induced by 500 mumol HCl in rats undergoing perfusions with 5% Brij 35. Indomethacin suppressed acid-induced protection. A mixture of tripalmitin and dipalmitoyl-phosphatidylcholine protected against 500 mumol HCl, and the effect was also observed in rats receiving indomethacin. Finally, 100 mumol HCl increased the phosphatidylcholine content in the duodenal mucus but not in rats receiving 5% Brij 35 or indomethacin. CONCLUSIONS: Surface-active phospholipids are critical for adaptive cytoprotection to acid in the rat duodenum.     

Changes of plasma osmotic pressure during lactation in rats

It is known that blood and plasma volume increase during lactation. The present paper examines whether an increase in plasma volume is accompanied by the change in plasma composition or attributed to hydro-dilution. Six dam-nursed pups and six dam-removed pups housed individually were designated as lactating rats and control rats, respectively. The plasma osmotic pressure and hematocrit value (Ht) were measured in the rats on days 3, 5, 7, 10, 13 and 18 of lactation. The total plasma protein (TP) and serum sodium concentration were also measured as they are factors affecting the plasma osmotic pressure. In addition, milk yield was estimated by the Morag technique. On day 5 and after day 10, the osmotic pressure of the lactating rats was found to be significantly lower than that of the control rats. The serum sodium concentration (days 5 and after day 10) and Tp values (days 3, 10 and 18) of the lactating rats were significantly lower than those of the control rats. Except on day 5, the Ht values of the lactating rats were significantly lower than those of the controls. During the period between days 3 and 10, milk yield was increased and it become steady (18 g/12 hr) on days 10 and 18. On and after day 10 when rats secreted a large amount of milk, it is considered that a decrease in the plasma osmotic pressure was mainly attributed to the reduction of sodium concentration by hydro-dilution. The Ht values indicate that an increase in blood volume is mainly through plasma volume rather than blood cell volume in lactating rats.     

Inhibition of parietal cell acid secretion is mediated by the classical epidermal growth factor receptor

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) inhibit gastric acid secretion both in vivo and in vitro. Previous studies have indicated that EGF and TGF-alpha bind to the same EGF/TGF-alpha receptor. Nevertheless, we and others have previously demonstrated that inhibition of acid secretion by these growth factors requires concentrations of the peptides that are 10-fold higher than those necessary for induction of mitogenesis. Therefore, we have sought to investigate whether gastric parietal cells may possess a second EGF/TGF-alpha receptor class. Two systems were studied: First, [125I]TGF-alpha was cross-linked to the receptor in isolated rabbit parietal cell membranes, and labeled species were resolved on SDS-PAGE. Second, acid secretion was evaluated in pylorus-ligated waved-2 mutant mice, which carry a disabling point mutation in their classical EGF/TGF-alpha receptor. In isolated parietal cells, [125I]TGF-alpha was cross-linked into a single species of 170 kDa. Cross-linking was inhibited in the presence of unlabeled TGF-alpha with an IC50 of 80 nM. In the pylorus-ligated mice, control littermate mice demonstrated a dose-dependent inhibition of acid secretion by EGF with an IC50 of 20 micrograms/kg. In contrast, EGF had no inhibitory effect on acid secretion in waved-2 mice at concentrations up to 100 micrograms/kg. No alterations in parietal cell or gastrin cell numbers were observed. These results in both isolated rabbit parietal cells and waved-2 mice support the existence of only a single class of EGF/TGF-alpha receptors in parietal cells. Differences in growth factor affinity are likely due to the modification of the receptor or one of its coordinate regulators.     

Retinoid-X receptors and the effects of 9-cis-retinoic acid on insulin secretion from RINm5F cells

OBJECTIVE: We evaluated the influence of chronic blockade of the renin-angiotensin system on hypertension induced by long-term thyroxin (T4) administration. To this end, we determined the effects of chronic treatment with captopril on blood pressure, cardiac hypertrophy and other renal and metabolic variables of hypertensive hyperthyroid rats. METHODS: T4 was administered s.c. at 0.38 mumol/kg per day and captopril was given in the drinking water (1.38 mmol/l). Both treatments were maintained for 6 weeks. Control rats received tap water. After the treatment period, the rats were placed in metabolic cages. Later, blood pressure was measured in conscious rats by intra-arterial determination. RESULTS: T4-treated rats showed an increased mean arterial pressure (MAP) whereas, in rats treated with T4 plus captopril, MAP was similar to that of the control group. Captopril did not affect the increased heart rate or ventricular weight/body weight ratio of hyperthyroid rats, but it improved the reduced creatinine clearance of these animals. CONCLUSIONS: The elevation in blood pressure produced by long-term T4 administration was prevented by chronic blockade of the renin-angiotensin system. Captopril improved the renal function of hyperthyroid rats, but did not affect the relative cardiac hypertrophy of these animals.     

Chronic desipramine treatment desensitizes the rat to anesthetic and antinociceptive effects of the alpha2-adrenergic agonist dexmedetomidine

INTRODUCTION: The effects of long-term administration of the tricyclic antidepressant agent desipramine on the hypnotic, antinociceptive, anesthetic-sparing, and central norepinephrine turnover suppressant action of short-term dexmedetomidine, a highly selective alpha2-adrenergic agonist, were studied in rats. METHODS: Rats were given a 3- or 4-week course of twice daily administration of desipramine, 10 mg/kg, or saline. The effect of a hypnotic dose of dexmedetomidine, 250 microg/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 microg/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 microg/kg dexmedetomidine. Changes in the affinity and density of the alpha2-adrenergic receptor in locus coeruleus and spinal cord also were determined. RESULTS: Treatment with desipramine decreased dexmedetomidine-induced loss of righting reflex duration by 67% and eliminated the antinociceptive effect of dexmedetomidine. Dexmedetomidine produced a 55% decrease in minimum anesthetic concentration in the control group but no reduction in desipramine-treated rats. Desipramine did not change the receptor density or binding affinity of alpha2 receptors at the site for hypnotic (locus coeruleus) or antinociceptive (spinal cord) responses. No decrement in the central norepinephrine turnover rate was noted in the locus coeruleus of dexmedetomidine after 3 weeks of treatment with desipramine. The alpha1-adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal. CONCLUSIONS: These data indicate that treatment with desipramine induces hyporesponsiveness to the hypnotic, analgesic, and minimum anesthetic concentration-reducing, but not to the suppression of central norepinephrine turnover, properties of dexmedetomidine. The hyporesponsiveness appears to involve an alpha1-adrenergic mechanism.     

Uremia in the rat affects gastric cell growth and differentiation

The aim of this study was to determine if hypertrophy of different tissues seen in uremic rats included gastrointestinal hypertrophy and an increase in parietal cell mass that might explain the increased acid secretion we previously reported. Chronic renal failure was induced by subtotal nephrectomy. Despite a lower total body weight, uremic rats had a significantly greater stomach weight (33%), corpus area (13%), corpus mucosal height (19%), and parietal (32%) and enterochromaffin-like (ECL, 54%) cell density, but a 16% decrease in mucous neck cell region height. These findings suggest that uremia leads to gastric stem cell stimulation with differentiation favoring parietal and ECL cells over mucous cells. In addition, in uremic rats there was an increase in height of the duodenal mucosa, but not of the ileal or transverse colon mucosa. In conclusion, the present study shows that uremia in the rat promotes hypertrophy of the stomach with cell differentiation favoring parietal cells over mucus cells. The increase in parietal cell mass may explain the increased acid secretion in these rats.     

Morphology of liver stellate cells and liver vitamin A content in 3,4,3',4'-tetrachlorobiphenyl-treated rats

BACKGROUND/AIMS: Because xenobiotics decrease the vitamin A stores localized in the liver stellate cells, we investigated morphological alterations in the liver of rats exposed to 3,4,3',4'-tetrachlorobiphenyl. Special attention was given to the morphology of the liver stellate cells and to their relationship to the liver vitamin A content. METHODS: Six rats received an intraperitoneal injection of 3,4,3',4'-tetrachlorobiphenyl (300 mumol/kg) in soyabean oil. A further six rats received the vehicle alone. After 7 days, all rats were killed and their livers assayed for vitamin A. Liver stellate cells were examined and counted on liver sections, stained with toluidine blue or immunocytochemically for desmin and, for some animals, for alpha-smooth muscle actin. RESULTS: In the livers of 3,4,3',4'-tetrachlorobiphenyl-treated rats, we found spotty and bridging necrosis, with inflammation and accumulation of desmin-positive liver stellate cells. Steatosis and mild portal inflammation were also observed. 3,4,3',4'-Tetrachlorobiphenyl decreased the liver vitamin A content by 38%, whereas morphometric analyses showed a 40% decrease of the number of toluidine blue-detected liver stellate cells and an 11% increase of desmin-detected liver stellate cells, indicating a likely differentiation of liver stellate cells into myofibroblast-like cells. 3,4,3',4'-Tetrachlorobiphenyl treatment did not modify the expression of alpha-smooth muscle actin. Morphological alterations were more pronounced in periportal than in pericentral areas. The liver vitamin A content was positively correlated (r = 0.56, p < 0.005) with the number of toluidine-blue detected liver stellate cells. CONCLUSIONS: 3,4,3',4'-tetrachlorobiphenyl administration results in an accumulation of liver stellate cells that start differentiating into myofibroblast-like cells. The 3,4,3',4'-tetrachlorobiphenyl-induced decrease in liver vitamin A probably results from this differentiation, although other mechanisms cannot be excluded.     

In vivo induction of tyrosylprotein sulfotransferase by ethanol: role of increased enzyme synthesis

Tyrosine sulfation is a posttranslational modification involved in the synthesis, secretion, and biological activity of proteins and peptides. Our previous studies have demonstrated that the enzyme activity was induced by ethanol. In the present work, the induction was studied in detail. Initial experiments were conducted to examine the time course of tyrosylprotein sulfotransferase (TPST) induction in rats pair-fed liquid diets containing either ethanol or carbohydrate substitute (controls). Marked elevation of TPST activity (3-fold) was measured on day 10 in the liver and gastric mucosa of ethanol-fed rats. Ethanol-mediated enhancement was also noticed by Western-blot analysis with anti-TPST antibody in both the liver and gastric mucosa on days 5 and 10. We then determined the steady-state TPST protein turnover in ethanol-fed and control animals that were given 35S-methionine after 10 days of pair-feeding with liquid diet. The rates of TPST synthesis assessed by measuring initial rates of incorporation of 35S-methionine into TPST was increased in the liver and gastric mucosa of animals fed with ethanol. Monophasic exponential decay curves showed that TPST protein half-lives for liver (control: 34 hr, ethanol: 32 hr) and gastric mucosa (control: 52 hr, ethanol: 48 hr) did not differ between control and ethanol groups. Our overall results indicate that the in vivo induction of TPST by ethanol involves increased enzyme synthesis rather than decreased enzyme degradation.