Changes in body water compartments with diuretic therapy in infants with chronic lung disease

The effects of diuretic therapy on body water compartments were studied in preterm infants with chronic lung disease. Gestational age of the infants ranged from 24 to 28 weeks, while the median postnatal age at the time of study was 40 days. Infants were randomized to receive furosemide (1.0 mg/kg/day) alone (n = 5) or combined with metolazone (0.2 mg/kg/day, n = 7) for 4 consecutive days. Treatment in both groups produced a significant decrease (P < 0.05) in extracellular water (ECW) without changes in plasma volume, total body water or body weight. The decrease in ECW with furosemide (503 +/- 28 to 446 +/- 19 ml/kg initial body weight) was of similar magnitude to that seen with combined furosemide plus metolazone (522 +/- 30 to 454 +/- 15 ml/kg initial body weight). Water and electrolyte intakes were similar in both groups and unchanged over the course of the study. These findings suggest that in infants with chronic lung disease, diuretic therapy induces intercompartmental shifts in body water, ultimately decreasing interstitial water while preserving PV. Only combined treatment with furosemide plus metolazone produced a significant increase in urine output, confirming the increased efficacy of combination therapy in inducing diuresis.     

Addition of a thiazide: an effective remedy for furosemide resistance after cardiac operations

BACKGROUND: The frequent use of diuretic drugs in cardiac surgical practice contrasts with the lack of documentation regarding diuretic treatment in this setting. The aims of this study were to delineate the need for diuretic drugs in adult cardiac surgical practice and to evaluate the impact of adding a combination of 50 mg hydrochlorothiazide and 5 mg amiloride orally to patients responding poorly to furosemide. METHODS: Two hundred ten consecutive patients, 159 undergoing coronary artery bypass grafting procedures and 51 having valve operations, were studied. RESULTS: Seventy-seven patients received large doses of furosemide (> or = 80 mg/24 h) at some time during the postoperative course, and of these 20 responded poorly to furosemide (weight loss 0.3 +/- 0.2 kg) despite considerable fluid retention. The addition of hydrochlorothiazide and amiloride provided a prompt and effective remedy to relative furosemide resistance. Average weight loss was 2.3 +/- 0.2 kg (p < 0.01 compared with response to furosemide) and average diuresis was 2,949 +/- 156 mL in the following 24 hours. CONCLUSIONS: Relative furosemide resistance is common after cardiac operations. Thiazides, although they are mild diuretic agents, may serve as useful adjuncts in this setting.     

The use of antibiotic-impregnated cement in infected reconstructions after resection for bone tumours

Bone mobilization, lowering of bone mineral density (BMD), and osteoporotic fractures are recognized in postmenopausal women with weight loss. Because a high-calcium intake suppresses bone loss in peri- and postmenopausal women, the present randomized, double-blind, placebo-controlled study was designed to test the hypothesis that calcium supplementation prevents net bone mobilization and consequent bone mineral loss during voluntary weight reduction in obese postmenopausal women. Subjects were placed on a moderate energy-restricted diet and either calcium supplementation (1 g/day) or placebo for 6 months. Body weight, bone turnover markers (pyridinium cross-links), osteocalcin, and parathyroid hormone (PTH) were measured at treatment weeks 1-5, 7, 10, 13, 16, 20, and 25. Total body BMD, insulin-like growth factor, 25-hydroxyvitamin D, and sex hormone binding globulin (SHBG) were measured at baseline and week 25. The calcium supplemented (n = 15; age 60.9 +/- 9.4 years, body mass index [BMI] 33.2 +/- 4.6 kg/m2) and placebo (n = 16; age 55.8 +/- 8.3 years, BMI 32.9 +/- 4.5 kg/m2) groups lost similar amounts of weight over the study interval (10.2 +/- 5.3% vs. 10.0 +/- 5.2%) and both groups increased SHBG (p < 0.001). There was a statistical effect of calcium supplementation during weight loss to suppress pyridinium cross-links, osteocalcin, and PTH (p < 0.05, < 0.01, and < 0.05, respectively). Loss of BMD tended to be greater in the placebo group by 1.4% (p < 0.08) after weight loss. One gram per day calcium supplementation normalizes the increased calcium-PTH axis activity and the elevated bone turnover rate observed during moderate voluntary energy restriction in postmenopausal women.     

Effects of rilmenidine on rats made insulin resistant and hypertensive by a high fructose diet

This study was aimed to determine the effects of rilmenidine, an hypertensive drug, in an animal model of hypertension associated with insulin resistance, i.e. rats fed on a high fructose diet. Wistar rats were fed during four weeks either on a standard diet (S) or on a high fructose diet (F, 34.5% de fructose). In half of the F groups, rilmenidine (1 mg/kg/day) was added to the drinking water during the two last weeks of the diet (FR). Arterial blood pressure as well as insulin efficiency were determined at the end of the four weeks. Body weight gain was higher in F than in S rats (66 +/- 8 g versus 45 +/- 8 g; p < 0.05), this was prevented by rilmenidine treatment (32 +/- 2 g). Arterial systolic blood pressure was increased in F rats (162 +/- 2 vs 155 +/- 2 mmHg; p < 0.05), rilmenidine brought this value back to normal (149 +/- 3 mmHg). During the euglycemic hyperinsulinemic clamp, glucose utilization was lower (10 +/- 1 vs 14 +/- 1.5 mg/min/kg; p < 0.05) and hepatic glucose production higher (1 +/- 0.01 vs 0 mg/min/kg; p < 0.01) in F than in S rats. These changes in insulin action were totally abolished by rilmenidine. These data demonstrate that rilmenidine can ameliorate the deleterious effects of a high fructose diet, i.e. weight gain, hypertension and resistance to the effects of insulin Rilmenidine could represent a potential therapeutic agent for the treatment of hypertension associated with metabolic disorders such as syndrom X and obesity.     

Blood-to-brain glucose transport and cerebral glucose metabolism are not reduced in poorly controlled type 1 diabetes

Clinical and epidemiological studies suggest that thiazide diuretics can prevent bone loss and decrease the incidence of hip fractures. However, the mechanism of the effect of diuretics on bone is not clearly established. Indapamide (IDP), a sulfonamide diuretic related to thiazides, is used to treat hypertension. Sixty spontaneously hypertensive rats (SHRs) were divided into four groups and treated with or without IDP (1.5 mg/kg/day) during 8 weeks in the presence or absence of a high sodium load (8% NaCl supplementation in the diet). Sodium and calcium excretions were increased in the rats receiving the high sodium load (SHR + 8% NaCl) comparatively with control rats (SHR). IDP decreased and increased, respectively, calcium and sodium excretions. Serum parathyroid hormone (PTH) was unchanged in any group. Bone density was measured at the femur, tibia, and vertebrae, and bone morphometry was performed at the metaphysis of the femur to evaluate bone architecture. Rats fed a high sodium diet had an average 5.5% decreased bone density at every site except the femoral diaphysis. The trabecular bone volume was also decreased (SHR + 8% NaCl vs. SHR, 11.99+/-0.78 vs. 17.51+/-1.5%, p < 0.05). An increase in trabecular separation suggested that these changes were due to increased bone resorption. In the SHR + 8% NaCl + IDP group, IDP increased bone density and trabecular bone volume (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 16.52+/-1.04 vs. 11.99+/-0.78%, p < 0.05). Trabecular separation and pyridinoline/creatinine excretion (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 136.39+/-9.62 vs. 195.18+/-22.34 nmol/mmol, p < 0.05) were also decreased by IDP. These results show that in rats receiving a high sodium diet, IDP can reverse sodium-induced bone loss and increased bone resorption independently of changes in serum PTH.     

Effect of furosemide on the renal excretion of digoxin

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin     

The human photoreceptor rim protein gene (ABCR): genomic structure and primer set information for mutation analysis

In order to evaluate the effect of thyroid replacement therapy on bone metabolism in congenital hypothyroid children, we studied 23 (10 girls and 13 boys) consecutive patients. Their age ranged from 3 to 8 weeks. One of these patients had familiar dyshormonogenesis, 21 had ectopic glands and one hemiagenesis. As a control group, we studied 46 sex- and age-matched healthy newborns. Before the beginning of therapy, the hypothyroid patients showed higher values of calcium (2.78 +/- 0.04 vs 2.65 +/- 0.07 mmol/l; p < 0.05) and of 1,25-dihydroxy-vitamin D (159.7 +/- 31.6 vs 90.5 +/- 33.1 ng/l; p < 0.01), while they showed lower values of osteocalcin (1.9 +/- 0.8 vs 2.9 +/- 0.9 ng/ml; p < 0.01) than controls. After 3 months of therapy, we found a complete normalization of all these parameters and a progressive increase of osteocalcin. Our data show that in congenital hypothyroid children there are abnormalities in calcium metabolism which seem to be transient and reversible after L-thyroxine replacement therapy.     

Diarrhea in young children associated with Escherichia coli non-O157 organisms that produce Shiga-like toxin

The aim of this study was to evaluate the way in which short-term protection declines and is eventually lost in preconditioning and to determine the efficacy of a second preconditioning at various reperfusion intervals. Male rabbits were divided into six groups. Forty-five minutes (sustained) ischemia followed by 120 minutes reperfusion was applied 60, 65, 70, 75, and 80 minutes after a 5 minute preconditioning (groups A, B, C, D, and E) and in a control group (F) after no preconditioning. The infarct to risk ratio (I/R) was 38.3 +/- 3.5% in group A, 46.0 +/- 7.8% in B, 61.6 +/- 9.7% in C, 68.1 +/- 4.2% in D, 64.5 +/- 7.8% in E, and 61.0 +/- 7.7% in F. Group A had a smaller I/R compared with groups C, D, E, and F (p < 0.05). In another series, groups G, H, and I were exposed to two 5-minute preconditioning stimuli, separated, respectively, by 45, 60, and 75 minutes of reperfusion; 10 minutes after the last preconditioning, the animals were exposed to 45-minutes ischemia and 120 minutes reperfusion. Groups A and D (with the smaller and higher I/R ratio) were also incorporated into this protocol in order to compare the effect of the additional preconditioning with the single one. The I/R ratio was 25.4 +/- 8.5% in group G, 22.8 +/- 7.0% in group H, and 14.7 +/- 4.0% in group I (p = NS). Group D showed a higher I/R compared with groups G, A, and H (p < 0.01), and group I had a smaller I/R compared with groups A (p < 0.01) and D (p < 0.001). Cardioprotection after a first preconditioning declines gradually and is eventually lost. An additional preconditioning is always effective, and the longer the interval from the first preconditioning, the more potent is the effect.     

Effect of furosemide oral solution versus furosemide tablets on diuresis and electrolytes in patients with moderate congestive heart failure

Oral furosemide solution was claimed to produce a greater diuretic response than furosemide tablets in patients with congestive heart failure. The aim of this study was to assess this observation and to further investigate the effects on the electrolyte balance. We compared the effects of oral furosemide in tablets versus oral furosemide solution on serum levels as well as on 4- and cumulative 24-hour urinary volume and sodium, potassium, calcium, magnesium and zinc excretions in 10 patients with moderate congestive heart failure due to ischemic heart disease. Oral furosemide (40-80 mg) was given at the usual once-daily dosage. No change in serum electrolyte levels has been found. All urinary parameters, except zinc, were significantly greater during the first 4 h following oral solution as compared with tablets (volume p < 0.001, sodium p < 0.001, potassium p < 0.05, calcium p < 0.003, magnesium p < 0.05). However, after 24 h, significant differences were found in urinary volume (p < 0.03) and sodium excretion (p < 0.004) only. We conclude that: (1) oral furosemide solution provides a more potent 24-hour diuretic and natriuretic effect than an identical dosage in tablet form, without entailing greater cumulative urinary losses of potassium, calcium, magnesium, and zinc; (2) following the first 4 h of furosemide solution, brisk diuresis, kaliuresis, and magnesiuria are produced, and (3) despite the urinary losses, serum electrolytes remained within normal limits at 4 and 24 h.     

Two-chain factor VIIa generated in the pericardium during surgery with cardiopulmonary bypass : relationship to increased thrombin generation and heparin concentration

The effect of changes in medullary extracellular tonicity on mRNA expression for aldose reductase (AR), sorbitol dehydrogenase (SDH), Na+/Cl-/betaine (BGT) and Na+/myo-inositol (SMIT) cotransporter in different kidney zones was studied using Northern blot analysis and non-radioactive in situ hybridization in four groups of rats: controls, acute diuresis (the loop diuretic furosemide was administered), chronic diuresis (5 days of diuresis), and antidiuresis [5 days of diuresis followed by 24 h deamino-Cys1, d-Arg8 vasopressin (dDAVP)]. Acute administration of the loop diuretic furosemide significantly reduced AR, SMIT and BGT gene expression in the inner and outer medulla compared with controls. Administration of dDAVP to chronically diuretic rats raised the expression of these three mRNAs in the inner but not the outer medulla compared with the chronically diuretic rats. None of these alterations in medullary tonicity significantly changed SDH expression. The in situ hybridization studies showed AR, BGT and SMIT mRNAs to be expressed in both epithelial and non-epithelial cells of the outer and inner medulla. The various cell types (epithelial, endothelial and interstitial cells) differed in their expression pattern and intensity of AR, SDH, BGT and SMIT mRNA, but the inner medullary cells responded uniformly to a decrease in extracellular tonicity with a reduction, and to an increase with enhancement of their AR, BGT and SMIT expression.     

Daily variation in the urinary excretion of furosemide in young and aged rats

We have recently demonstrated that the time-dependent difference in urinary excretion of furosemide, a loop diuretic, diminishes during the aging process and disappears by 18 months of age in rats. The present study was undertaken to examine whether the amplitude of the daily variations in the urinary excretion of furosemide or their pattern, or both, are influenced in aged animals. Young (3 months of age) and aged (30 months of age) Wistar rats were maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Furosemide (30 mg/kg) was given orally at 4 am, 8 am, 12 am, 4 pm, 8 pm or 12 pm. Urine was collected for 8 hours after furosemide administration and urinary excretion of furosemide was determined. There were significant daily variations in the urinary furosemide and the urine volume with the peak at 8 am and the trough at 12 pm in both groups of rats. The differences in these parameters between the 8 am and 12 pm trials were significantly smaller in the aged than in the young rats. These results suggest that the age-related alteration in the time-dependent phenomenon of furosemide is caused by the decreased amplitude of the daily variation in the urinary furosemide excretion and its diuretic effect.     

Effect of exercise and tepary bean type diet on body composition and fat accretion in obese Zucker rats

OBJECTIVE: The effectiveness of a tepary bean high fat type diet, compared to a purified type high fat diet and exercise, on body composition in fatty Zucker rats was determined. SUBJECTS AND DESIGN: Approximately 6-week-old female fa/fa Zucker rats were divided into four groups of 10 rats each: TE, fed the tepary bean type diet and exercised; TN, fed the tepary bean type diet and not exercised; CE, fed the purified type control diet and exercised; CN, fed the purified type control diet and not exercised. The exercise modality was treadmill running and the experiment lasted 13 weeks. MEASUREMENTS: Body weight, cumulative food intake, body composition, weights of adipose tissues and liver, heart and gastrocnemius muscle. RESULTS: At the end of the 13 week experiment, TE rats weighed 511 +/- 22 g and were significantly lighter than TN, 588 +/- 15 g; CE, 606 +/- 22 g; and CN, 660 +/- 27 g. All are means +/- s.e.m. The carcass of CN rats had 58, 20 and 13% more fat than TE, TN and CE rats, respectively; P < 0.01. Lean body mass was the same for all the groups of rats and ranged from means of 216-228 g. However, TE rats had significantly more fat free dry mass (FFDM) than CN rats; 68 +/- 4 vs 58 +/- 2 (means +/- s.e.m.) and tended to have more FFDM than TN and CE rats. Inguinal fat depots weighed 20-30% less in T than in C rats (diet comparisons) and also 20-30% less in E than in N rats (exercise comparisons). Perirenal/retroperitoneal fat depots weighed 25% less in TN than in CN rats and 38% less in TE than in CE rats. Exercise did not reduce perirenal/retroperitoneal fat depot weights. Parametrial fat depot weights were not influenced by diet or exercise. CONCLUSIONS: In diets which provided 37% of the energy from fat, the incorporation of tepary beans attenuated weight gain, and subcutaneous and visceral fat gain compared to a purified type diet. Exercised rats gained less weight and subcutaneous, but not visceral fat, than non-exercised rats.     

Homologous up-regulation of vitamin D receptors is tissue specific in the rat

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) receptors (VDR) are expressed in multiple tissues within the body. VDR levels are increased by 1,25(OH)2D3 in intestine and kidney and in numerous cell models. The ability of 1,25(OH)2D3 to affect VDR levels in other target tissues in vivo was studied by assessing VDR levels by the 3H-1,25(OH)2D3 binding assay under varied physiological conditions in the rat. When compared with vitamin D-deficient (-D) controls, rats raised on a normal vitamin D-sufficient (+D) diet showed elevated VDR levels in kidney (391 +/- 53 vs. 913 +/- 76 fmol/g of tissue;p < 0.05), but not in testis, heart, or lung. Up-regulation of the VDR also occurred in kidney of +D rats 1 day after a single 100-ng dose of 1,25(OH)2D3 (454 +/- 43 vs. 746 +/- 113 fmol/mg of DNA; p < 0.05), but no changes were seen in intestine, testis, or lung. Because 1,25(OH)2D3-induced hypercalcemia may independently affect VDR regulation, 1,25(OH)2D3 was infused into -D rats, and normocalcemia was maintained by reduced dietary calcium intake. In this model, the renal VDR was again up-regulated (446 +/- 115 vs. 778 +/- 58 fmol/mg of DNA; p < 0.05), but VDR levels in testis and lung were unaffected. Scatchard analysis and tests of 1,25(OH)2D3 dose (1-100 ng/day for 7 days) and temporal (100 ng/day for 1-7 days) responsiveness further supported the tissue-specific nature of the homologous VDR regulation. Assay of VDR levels by L-1-tosylamido-2-phenylethyl chloromethyl ketone-3H-1,25(OH)2D3 exchange assay ruled out differences in endogenous 1,25(OH)2D3 occupancy as the basis for the observed differences in VDR regulation. Finally, coidentity of the VDR-like sites in kidney versus testis was confirmed by competitive binding analysis comparing their relative affinities for 25(OH)D3 versus 1,25(OH)2D3 (30.5 +/- 6.4 vs. 35.6 +/- 3.6 in kidney and testis, respectively) and by immunoblot analysis using a highly specific monoclonal anti-rat VDR antibody. Thus, under a wide variety of experimental conditions, homologous up-regulation of the VDR occurs in the rat kidney in vivo, but not in several other target tissues which do not regulate plasma calcium homeostasis. Moreover, this differential VDR regulation did not result from secondary changes in plasma calcium, from differential 1,25(OH)2D3 responsiveness in the various tissues, nor from differences in endogenous 1,25(OH)2D3 occupancy of the VDR. These studies thus establish that, in contrast to observations in vitro, the widely described phenomenon of homologous VDR up-regulation in kidney and intestine is not a universal property of 1,25(OH)2D3 target tissues in vivo in the rat.     

Reflex sympathetic function in cortisol-induced hypertension in humans

Nine healthy male subjects underwent measurement of reflex sympathetic function, pressor responsiveness and baroreflex sensitivity to phenylephrine (PE) and glyceryltrinitrate (GTN) before (C1) and following six days of treatment (E6) with cortisol (F), 200 mg/day. Seven subjects had washout studies (W) performed at least two weeks following the end of treatment. The BP responses to head tilt, isometric exercise and mental arithmetic were unaltered by F, however, there was a significant diminution of the diastolic BP response to cold pressor stimulus (delta DBP: 19 +/- 3 vs 25 +/- 5 vs 27 +/- 5 mmHg; E6 vs C1 vs W, p < 0.05 C1 vs E6 and W). Baroreflex sensitivity to PE was increased (28 +/- 3 vs 19 +/- 2 ms/mmHg, E6 vs C1, p = 0.03). These data demonstrate that increased BP during F treatment is not attributable to increased SNS activity, and suggest that SNS activity may be decreased by F.     

The lipid peroxidation inhibitor indenoindole H290/51 protects myocardium at risk of injury induced by ischemia-reperfusion

OBJECTIVE: Elevated blood ammonia is an important pathogenic factor of hepatic encephalopathy. Although colonic bacteria are considered the main source of ammonia, the stomach in subjects with urease-producing Helicobacter pylori (H. pylori) is an alternative site. The objective of this study was to determine whether H. pylori is associated with this complication. METHODS: After assessing liver function and portal hypertension, 55 cirrhotics were evaluated for encephalopathy and H. pylori infection. Response to 2 weeks of amoxicillin (2 g/day) and omeprazole (40 mg/day) was then assessed in 17 (13 H. pylori-positive, four H. pylori-negative) encephalopathic subjects. RESULTS: H. pylori infection was more common (67 % vs 33%, p = 0.004) among encephalopathic patients. Additional factors associated with encephalopathy included older age (60.1 +/- 1.5 vs 49.8 +/- 2.4 yr, p = 0.001), lower albumin (3.17 +/- 0.08 vs 3.69 +/- 0.12 g/dl, p = 0.001), higher total bilirubin (2.24 +/- 0.20 vs 1.53 +/- 0.23 mg/dl, p = 0.034), greater ascites score (0.8 +/- 0.1 vs 0.3 +/- 0.1, p = 0.01), greater diuretic score (1.1 +/- 0.1 vs 0.3 +/- 0.1, p = 0.002), and greater modified Child score (6.7 +/- 0.3 vs 5.1 +/- 0.3, p = 0.001). When adjusted for severity of cirrhosis and age, H. pylori continued to demonstrate a statistical association (p = 0.039). After anti-H. pylori therapy, symptomatology in infected encephalopathic patients appeared to improve, whereas noninfected subjects were unaffected. CONCLUSION: In cirrhotic patients, H. pylori infection is associated with hepatic encephalopathy, especially in younger patients with decompensated liver disease.     

Pharmacokinetics of acetaminophen after intravenous and oral administration to spontaneously hypertensive rats and normotensive Wistar rats

In our previous study, we reported the faster metabolism of intravenously administered furosemide, hence the smaller diuretic effect of furosemide in spontaneously hypertensive rats (SHRs) of 16 weeks of age than in the age-matched normotensive Wistar rats. In present study, in order to evaluate whether there is some alteration of the phase II metabolism including glucuronide and sulfate conjugations in 16-week-old SHRs and the age-matched Wistar rats, the pharmacokinetic parameters of acetaminophen (A), A-sulfate, and A-glucuronide were investigated after intravenous (iv) and oral 100 mg/kg administration of A to 16-week-old SHRs and the age-matched Wistar rats. After iv administration of A, the mean fraction of iv dose excreted in 24-h urine as A-sulfate (75.6 versus 67.8%) and the partial clearance of A to A-sulfate (8.10 versus 6.89 mL/ min/kg) were significantly greater in SHRs than in Wistar rats. Conversely, the mean fraction of iv dose excreted in 24-h urine as A-glucuronide (9.39 versus 15.0%) and the partial clearance of A to A-glucuronide (1.01 versus 1.49 mL/min/kg) were significantly smaller in these SHRs. Similar results were also obtained after oral dosing of A. The in vitro sulfotransferase activity toward A was significantly smaller (0.397 versus 0.331 microg/min/mg of protein) in 16-week-old SHRs than in the age-matched Wistar rats, whereas, the glucuronyltransferase activity toward A was not significantly different between these SHRs and Wistar rats. On the other hand, there was no significant difference in the both sulfotransferase and glucuronyltransferase activity toward A between 6-week-old SHRs and age-matched Wistar rats. Therefore, the alterations in sulfation and perhaps glucuronidation of A between 16 -week-old SHRs and normotensive Wistar rats suggested that some physiological factors derived from the chronic hypertensive status in SHRs might affect the disposition of drugs.     

Ischemic and reperfusion injury of cyanotic myocardium in chronic hypoxic rat model: changes in cyanotic myocardial antioxidant system

OBJECTIVE: The objective was to evaluate the effect of left ventricular function on cyanotic myocardium after ischemia-reperfusion and to determine the effect of cyanosis on the myocardial antioxidant system. METHODS: Cyanotic hearts (cyanotic group) were obtained from rats housed in a hypoxic chamber (10% oxygen) for 2 weeks and control hearts (control group) from rats maintained in ambient air. Isolated, crystalloid perfused working hearts were subjected to 15 minutes of global normothermic ischemia and 20 minutes of reperfusion, and functional recovery was evaluated in the two groups. Myocardial superoxide dismutase, glutathione peroxidase, glutathione reductase activity, and reduced glutathione content were measured separately in the cytoplasm and mitochondria at the end of the preischemic, ischemic, and reperfusion periods. RESULTS: Mean cardiac output/left ventricular weight was not significantly different between the two groups. Percent recovery of cardiac output was significantly lower in the cyanotic group than in the control group (56.1% +/- 5.7% vs 73.0% +/- 3.1%, p = 0.001). Mitochondrial superoxide dismutase, mitochondrial and cytosolic glutathione reductase activity, and cytosolic reduced glutathione were significantly lower in the cyanotic group than in the control group at end-ischemia (superoxide dismutase, 3.7 +/- 1.3 vs 5.9 +/- 1.5 units/mg protein, p = 0.012; mitochondrial glutathione reductase, 43.7 +/- 14.0 vs 71.0 +/- 30.3 munits/mg protein, p = 0.039; cytosolic glutathione reductase, 13.7 +/- 2.0 vs 23.2 +/- 4.2 munits/mg protein, p < 0.001; and reduced glutathione, 0.69 +/- 0.10 vs 0.91 +/- 0.24 microgram/mg protein, p = 0.037). CONCLUSIONS: Cyanosis impairs postischemic functional recovery and depresses myocardial antioxidant reserve during ischemia. Reduced antioxidant reserve at end-ischemia may result in impaired postischemic functional recovery of cyanotic myocardium.     

Effect of pancreas transplantation on the prevention of nephropathy in alloxan-induced diabetic rats

We studied the effects of pancreas transplantation on kidney lesions of rats with alloxan-induced diabetes. Ninety inbred male Lewis rats were randomly assigned to 3 experimental groups: group NC included 30 non-diabetic control rats, group DC included 30 alloxan-induced diabetic control rats, and group PT included 30 alloxan-induced diabetic rats that received pancreas transplants from normal donor Lewis rats. Each group was further divided into 3 subgroups of 10 rats which were sacrificed at 1, 3, and 6 months of follow-up, respectively. Clinical and laboratory parameters during these periods were documented. The kidneys of 5 rats in each subgroup were studied and 50 glomeruli and tubules from each kidney were analyzed by light microscopy by two different investigators in a double-blind study. There was progressive glomerular basement membrane thickening (GBMT), mesangial enlargement (ME), and Bowman's capsule thickening (BCT) in kidneys of rats in the 3 experimental groups during follow-up. These alterations were significantly higher in DC rats (GBMT: 1.99 +/- 0.31; ME: 2.00 +/- 0.33; BCT: 1.88 +/- 0.27) when compared to NC (GBMT: 1.54 +/- 0.30; ME: 1.56 +/- 0.47; BCT: 1.36 +/- 0.35) and PT rats (GBMT: 1.49 +/- 0.29; ME: 1.57 +/- 0.36; BCT: 1.35 +/- 0.28) at 6 months (P < 0.01). The extent of GBMT, ME, and BCT observed in DC rats at 1 and 3 months was not significantly different from NC and PT rats. The amount of kidney lesions in PT rats was similar to that of NC rats and lower than those of DC rats at 6 months (P < 0.01). In addition, Armanni-Ebstein lesions of the tubules (AE) and tubular lumen protein (PRO) observed in DC rats were not present in NC or PT rats. We conclude that pancreas transplantation in alloxan-induced diabetic rats prevents the development of kidney lesions beginning at 6 months after transplantation.     

Analysis of growth in five-sixths-nephrectomized rats

The present study was designed in an attempt to better define the pattern of growth in five-sixths-nephrectomized rats. Male Sprague-Dawley rats underwent two-stage (days 0 and 7) five-sixths nephrectomy (NX, n = 16) or sham surgery (SHAM, n = 9). At the time of sacrifice (day 21), renal failure (CRF) of NX rats was confirmed by elevated (p < or = 0.0001) serum concentrations (X +/- SEM) of urea nitrogen (SUN) (56 +/- 5 vs. 20 +/- 1 mg/dl) and creatinine (0.7 +/- 0.04 vs. 0.4 +/- 0.02 mg/dl) and reduced SUN (0.13 +/- 0.02 vs. 0.44 +/- 0.05 ml/min/100 g) and creatinine clearances (0.23 +/- 0.02 vs. 0.58 +/- 0.05 ml/min/100 g). As shown by lower cumulative gains of weight (41 +/- 6 vs. 74 +/- 4 g) and length (5.0 +/- 0.4 vs. 6.8 +/- 0.3 cm), NX rats grew subnormally. Detailed analysis of growth data revealed: (1) In spite of being identically matched in weight and length on day 0, at day 7, NX rats already weighed less than SHAM animals (147.1 +/- 2.3 vs. 153.4 +/- 1.9 g, p = 0.03). (2) From day 7 on, daily gain of weight was lower in the NX group only on days 8 (-6.08 +/- 0.52 vs. -1.60 +/- 0.69 g/100 g body weight) and 9 (-0.41 +/- 1.73 vs. 5.18 +/- 0.63 g/100 g body weight). (3) Following the early post-second-nephrectomy period, two subgroups of NX rats were clearly differentiated according to whether or not their daily growth rate was lower than that of SHAM animals. Maintained subnormal growth rate was observed in rats with severe CRF (SUN 73 +/- 5 mg/dl, range 54-90) but not in rats having milder uremia (42 +/- 3 mg/dl, range 31-51). Thus, growth in five-sixths-nephrectomized rats should be reported based on daily weight increments (g/100 g body weight). Subnormal growth can be attributed to CRF provided SUN is at least 3 times as high as normal while growth impairment of rats with less marked reduction of renal function is likely related to transient acute renal failure and postsurgical catabolic state.     

Thrombus age as a determinant of lysis efficacy of in vitro produced platelet-fibrin thrombi

Thrombus age as a determinant of lysis efficacy has rarely been investigated. We developed an in vitro model to study the lysis of collagen induced platelet-fibrin-thrombi of different ages. Histologically, the thrombi were similar to those found in coronary vessels of patients deceased from acute myocardial infarction or unstable angina. After 10 (TA10), 30(TA30) und 60 (TA60) min of thrombus aging thrombolysis over 30 min with urokinase alone or in combination with prostaglandin E1 was started. The efficacy of lysis with urokinase alone decreased with increasing thrombus age. After 30 min of lysis with urokinase alone weight of TA10-thrombi was reduced by 16.4 +/- 1.2 mg, of TA30-thrombi by 11.5 +/- 0.9 mg (p < 0.001 vs TA10-thrombi) and of TA60-thrombi by 7.8 +/- 1.1 mg (p < 0.001 vs TA30, p < 0.0001 vs TA10-thrombi). The addition of prostaglandin Ei augmented lysis of TA10-thrombi, after 30 min of lysis thrombus weight was reduced by 17.3 +/- 1.2 mg (p < 0.01 vs urokinase alone). Lysis of 30 and 60 min old thrombi was nearly unaffected. Thus, thrombus age is a strong predictor of lysis efficacy of in vitro collagen induced platelet-fibrin-thrombi.