Naftidrofuryl protects the rat against chronic gastric ulceration

Intraperitoneal reserpine (5 mg/kg every day for 5 days) produced solitary chronic ulceration of the rat stomach after 2 weeks. Gavage with 1 mL/day of 1% naftidrofuryl oxalate for 2 weeks protected 30% of rats against ulceration and this protection extended to 70% of cases with a 2% solution. Similar gavage with a 5% solution protected all rats against ulceration without significantly influencing the basal H+ output (14.8 +/- 0.6 versus 15.4 +/- 0.5 mumol, mean +/- SEM, n = 10); that is, cytoprotection was achieved.     

The significance of removing oxygen-derived free radicals in the treatment of acute and chronic duodenal ulceration in the rat

Rats infused for 24 h with pentagastrin (4 micrograms kg-1 min-1) and carbachol (0.8 microgram kg-1 min-1) developed acute duodenal ulceration (100%) and hyperchlorhydria (69 +/- 5.3 mumol h-1 vs 14 +/- 0.9 mumol h-1, P less than 0.001, n = 10). The animals were then given daily by gavage, saline, allopurinol with dimethyl sulphoxide (DMSO) or cysteine with methyl methionine sulphonium bromide (MMSB). Two days after the infusion, 10 rats (100%) given saline and 7 rats (70%) given allopurinol and DMSO, or cysteine and MMSB, showed duodenal ulceration. Five days after the infusion, 8 rats (80%) given saline, 3 rats (30%) given allopurinol and DMSO, and 2 rats (20%) given cysteine and MMSB had duodenal ulceration. Seven days after the infusion, only 5 rats (50%) given saline still had duodenal ulceration. Daily intramuscular injection of reserpine (0.1 mg kg-1) for 6 weeks produced chronic duodenal ulceration (90%) and hyperchlorhydria (47 +/- 3.1 mumol h-1 vs 12 +/- 0.9 mumol h-1, P less than 0.001, n = 10). Animals were then given daily by gavage, saline, allopurinol and DMSO, or cysteine and MMSB. Five days after reserpine, 10 rats (100%) given saline, 8 rats (80%) given allopurinol and DMSO, and 7 rats (70%) given cysteine and MMSB showed duodenal ulceration. Ten days after reserpine, 9 rats (90%) given saline, 3 rats (30%) given allopurinol and DMSO, and 4 rats (40%) given cysteine and MMSB had duodenal ulceration. Fifteen days after reserpine, 8 rats (80%) receiving saline and only one rat (10%) receiving allopurinol and DMSO or cysteine and MMSB had duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of scavenging oxygen-derived free radicals to protect the rat against aspirin- and ethanol-induced erosive gastritis.

Oxygen-derived free radicals are cytotoxic and produce tissue damage. The effect of the radical scavengers allopurinol and dimethyl sulfoxide (DMSO) on aspirin- and ethanol-induced acute gastric mucosal injury was studied in the rat. Orogastric instillation of aspirin at 200 mg/kg produced, after 4 h, gastric mucosal injury in 30% of rats without pyloric ligation [score, 3.1 +/- 0.8 mm2, mean +/- standard error of the mean (SEM); n = 10] and in 80% of rats with this ligation (score, 10.4 +/- 1.2 mm2, mean +/- SEM; n = 10). Gavage with 1 mL of 2 or 5% allopurinol or DMSO at 24 h before and again just before aspirin administration completely protected rats with or without pyloric ligation against injury. Orogastric instillation of ethanol (1 mL of a 40% solution) produced, after 1 h, gastric mucosal injury in all rats with or without pyloric ligation (24.1 +/- 1.7 and 14.1 +/- 1.3 mm2, respectively, mean +/- SEM; n = 10). Gavage with 1 mL of 5% allopurinol or DMSO at 24 h before and again just before ethanol administration completely protected rats with or without pyloric ligation against injury. Protection against the aspirin- and ethanol-induced injury was not associated with any significant effect on the H+ output. The results suggest that oxygen-derived free radicals are directly implicated in the mechanism of aspirin- and ethanol-induced acute gastric mucosal injury and that scavenging these free radicals protects against injury by maintaining the integrity of the gastric mucosa.     

ATP-MgCl2 increases cisplatin toxicity in the dog and rat.

The purpose of this study was to examine if ATP-MgCl2, an agent that protects against acute cisplatin toxicity in vitro, protected against cisplatin toxicity in vivo. Baseline renal function measurements were obtained on dogs (n = 12) and rats (n = 20) on day -1. Dogs were given 90 mg m-2 cisplatin (n = 5), 90 mg m-2 cisplatin and 50 mumol kg-1 ATP-MgCl2 (n = 5), or 90 mg m-2 cisplatin and 150 mumol kg-1 ATP-MgCl2 (n = 2), in a slow bolus i.v. injection on day 0. Rats were given 4 mg kg-1 cisplatin i.p. (n = 6) and 25 mumol kg ATP-MgCl2 (n = 8) i.v. or 4 mg kg-1 cisplatin i.p. and 25 mumol kg-1 ATP-MgCl2 (n = 6) i.v. on day 0. Renal function was assessed on a routine basis for 14 days. All dogs had significantly decreased creatinine clearance following cisplatin administration. There were no significant differences in renal function tests between groups of dogs. One dog given 50 mumol kg-1 ATP-MgCl2 and both dogs given 150 mumol kg-1 ATP-MgCl2 in addition to cisplatin developed acute anuric renal failure and were euthanatized prior to completion of the study. Rats given 4 mg kg-1 cisplatin and 25 mumol kg-1 ATP-MgCl2 had significantly increased blood urea nitrogen and serum creatinine after drug administration, compared to rats given cisplatin alone. The results indicated that ATP-MgCl2 worsened in vivo cisplatin renal toxicity in the dog and rat.     

Gastric mucosal cytoprotection in the rat by naftidrofuryl oxalate

Ischaemic gastric mucosal injury was assessed in the rat by measurement of the area of the injury produced after 6 h by reserpine (5 mg kg-1 i.p.) or 5-hydroxytryptamine (5-HT) (50 mg kg-1 i.p.). Pretreatment with naftidrofuryl 1 mL, 1% by gavage significantly (P less than 0.001) protected the rat stomach against the reserpine (24 +/- 2.7 mm2 vs 40 +/- 4.7 mm2, mean +/- s.e.m., n = 10) and 5-HT injury (11.4 +/- 1.7 mm2 vs 27 +/- 4.1 mm2, mean +/- s.e.m., n = 10). Naftidrofuryl 1 mL 2% by gavage was more effective (P less than 0.001) in this respect and mucosal injury only developed in 50% of rats injected with reserpine (9.4 +/- 1.1 mm2) and 30% of those injected with 5-HT (3.2 +/- 0.4 mm2). Administration of naftidrofuryl 1 mL 5% by gavage completely protected the rat against both the reserpine- and 5-HT-induced acute gastric mucosal injury. This protection was not associated with any significant influence on the H+ output.     

Toxicity of gallium oxide particles following a 4-week inhalation exposure

To evaluate the inhalation toxicity of Ga2O3, F344 rats were exposed nose-only to 0.2 micron Ga2O3 particles 2 h/day, 5 days/week for 4 weeks. The exposure concentration was 23 +/- 5 mg/m3 (mean +/- SD) resulting in lung burdens of 0.8 +/- 0.1 mg Ga2O3/lung (mean +/- SE) at the end of 4 weeks of exposure. Analysis of bronchoalveolar lavage fluid of exposed rats showed marked responses. One day after termination of exposure, lactate dehydrogenase was increased 6-fold, and the lysosomal enzyme, beta-glucuronidase, was increased 38-fold in rats exposed to Ga2O3 compared to sham exposed controls. Alkaline phosphatase, glutathione reductase, glutathione peroxidase, white blood cells, acid proteinase, and protein were increased 3- to 4-fold. Responses remained elevated 6 and 12 months after exposure. Lung clearance of radiolabeled tracer particles was evaluated 4 days and 6 months after the end of 4 weeks of Ga2O3 exposures. Long-term clearance half-times were significantly longer (3-4 fold, P less than 0.01) in rats exposed to Ga2O3 than in the sham-exposed control rats at both 4 days and 6 months, indicating persistent impairment of particle clearance. Histopathological lesions consisted primarily of alveolar proteinosis 1 day after 4 weeks exposure, progressing in severity to large focal lesions of alveolar histiocytosis and septal fibrosis 6 and 12 months after exposure. Inhaled Ga2O3 produced cytotoxic, inflammatory, and fibrogenic responses of comparable or greater magnitude than those seen after similar exposures of rats to inhaled quartz particles in other studies. These data show that inhaled Ga2O3 particles produce considerable toxicity and exposures in the work place should be limited.     

Effects of beta 1- and beta 1 + beta 2-antagonists on training-induced myocardial hypertrophy and enzyme adaptation

The effects of beta 1- and beta 1 + beta 2-antagonists on the myocardial adaptation to exercise training were investigated in male Sprague-Dawley rats randomly divided into trained (treadmill, 1 hr/day, 5 days/week for 10 weeks at 27 m/min, 15% grade) without drug (TC), sedentary without drug (SC), trained treated with atenolol (TA) (10 mg/kg body wt, i.p.), trained treated with propranolol (TP, 30 mg/kg body wt, i.p.), and sedentary propranolol. Doses of both beta-antagonists were titrated to decrease the exercise heart rate by 25% compared to the controls. The heart weight and heart/body weight ratio were significantly greater in TC (1.28 +/- 0.07 g (P less than 0.01); 296 +/- 12 mg/100 g body wt (P less than 0.05) respectively) than in SC (1.09 +/- 0.04 g and 268 +/- 11 mg/100 g body wt), or in TP and TA. Myocardial mitochondrial protein was unchanged by training or beta-blockade. Citrate synthase and beta-hydroxyacyl CoA dehydrogenase activities were not altered. Carnitine palmitoyltransferase activity was increased in SP compared to SC. Training increased hexokinase activity only in TC (5.22 +/- 0.12 vs 4.26 +/- 0.23 mumol/min/g wet wt, P less than 0.01). Lactate dehydrogenase activity increased significantly (P less than 0.01) in both TC (383 +/- 14 mumol/min/g wet wt) and TA (372 +/- 14 mumol/min/g wet wt) compared to SC (276 +/- 14 mumol/min/g wet wt), but not in TP versus SP. These data indicate that (1) beta-adrenergic blockade prevents training-induced cardiac hypertrophy; (2) beta-antagonists have little effect on the myocardial oxidative capacity; and (3) while the training induction of myocardial hexokinase is inhibited by both beta 1- and beta 1 + beta 2-antagonists, myocardium may increase its ability to utilize lactate during exercise with training despite beta 1-blockade.     

Early onset of cisplatin-induced nephrotoxicity in streptozotocin-diabetic rats treated with insulin

Mechanism of protection against cisplatin nephrotoxicity in streptozotocin-diabetic rats is unclear but is associated with decreased renal platinum accumulation. This study was designed to determine whether normalization of hyperglycaemia by insulin treatment to six week streptozotocin-diabetic rats reversed protection against cisplatin nephrotoxicity. Male Sprague-Dawley rats divided into 3 groups (n=10/group) (1) non-diabetic (2) untreated streptozotocin-diabetic and (3) insulin-treated streptozotocin-diabetic groups were rendered diabetic using streptozotocin (65 mg/kg body weight, intravenous). At the end of 6 weeks, Group 3 animals were treated with insulin (subcutaneously) for 21 days to normalize glucose. After 21 days of insulin treatment, the mean +/- S.D. plasma glucose (mg%) in Group 3 animals at 144.8 +/- 22.03, was significantly lower than Group 2 animals (412 +/- 24.69) and comparable to age-matched non-diabetic (Group 1) animals. Blood urea nitrogen at 24 hr after intraperitoneal administration of cisplatin (5 mg/kg body weight) increased by a factor 2.5 in Group 3 compared to 1.1 and 1.3 in Group 1 and Group 2 animals respectively. In the same animals, at 96 hr the blood area nitrogen increased by a factor of 3.2 and 2.9 in Group 1 and Group 3 respectively compared to 1.14 for Group 2 animals. Renal platinum levels in Group 1, Group 2 and Group 3 after 96 hr after cisplatin administration were 6.92 +/- 0.83, 3.46 +/- 0.77 & 6.20 +/- 0.64 (microg/g wet weight of tissue) respectively. Results indicate that 21 day insulin treatment to streptozotocin-diabetic animal reverses protection against cisplatin toxicity. Moreover, insulin treatment increased the susceptibility of streptozotocin-diabetic rats to cisplatin-induced renal toxicity.     

Effects of chondroitin sulfate-C on bradykinin-induced proteoglycan depletion in rats.

Depletion of the proteoglycan content of articular cartilage was induced by injecting bradykinin (30-300 mumol/l, 50 microliters/knee) into the left knee articular cavities of rats 3 times a day for 2 days. The degree of the reduction in the intensity of histopathological safranin O staining was used as an index of proteoglycan depletion. Bradykinin reduced the cartilage proteoglycan contents of the knee joints of non-injected limbs in a dose-dependent manner and at 300 mumol/l markedly reduced these contents, but evoked no inflammatory changes. The extent of the reduction of the cartilage proteoglycan contents induced by bradykinin injection depended on the dose and injection frequency. Chondroitin sulfate-C (CAS 25322-46-7, Chondroitin ZS Tab) (30-1,000 mg/kg/day) administered orally to rats for 14 days inhibited the bradykinin-induced proteoglycan depletion of the articular cartilage in a dose-dependent manner. These results suggest that a reduction of the proteoglycan content of cartilage, like that associated with osteoarthritis, was induced by injecting bradykinin into the knee articular cavities of rats and chondroitin sulfate-C protected against this effect.     

PREVENTION OF ACUTE GASTRIC ULCERATION IN THE RAT BY CIMETIDINE, A HISTAMINE H2-RECEPTOR ANTAGONIST

1. Intraperitoneal injections of cimetidine into rats markedly reduced gastric acid production. When given at a dose of 50 mg/kg body weight, rate of acid production fell from a mean of 2.73 mumol/min (s.d. = 0.32) to a lowest level of 0.81 (s.d. = 0.28): the difference was highly significant (P less than 0.005). When given in a dose of 100 mg/kg, the rate of acid production further fell to 0.18 mumol/min (s.d. = 0.12;P less than 0.001). 2. Treatment with cimetidine in doses of 100 mg/kg 8-hourly during a 24 h period of restraint prevented the development of acute gastric ulceration in the rat. Pretreatment with cimetidine also protected against the ulcerogenic effects of intragastrically administered bile or lysolecithin. 3. The marked sustained reduction of acid production most probably accounts for the protective effects of cimetidine against ulcer production in the rat stomach.     

Serum level monitoring of a new slow release theophylline formulation in patients with chronic lung disease.

1 Serum theophylline levels were performed in 26 patients with chronic lung disease receiving rapid release theophylline (125 mg 6 hourly) and 28 patients receiving slow release theophylline (250 mg 12 hourly) under steady state conditions. 2 For rapid release theophylline the mean +/- s.d. serum theophylline levels at 0 and 2 h were 41.0 +/- 21.7 and 52.3 +/- 20.9 mumol l-1 respectively and for slow release theophylline at 0, 4 and 6 h 43.7 +/- 25.5, 50.9 +/- 23.0 and 51.7 +/- 26.4 mumol l-1 respectively. 3 Serum theophylline monitoring with slow release theophylline was performed in 70 patients with chronic lung disease. The initial dose was 250 mg administered 12 hourly. 4 The mean +/- s.d. steady state serum theophylline level achieved was 76.0 +/- 18.8 mumol l-1 and the mean +/- s.d. dose to produce this level was 9.4 +/ 2.3 mg kg-1 day-1. There was no correlation between dosage and serum theophylline level. 5 Sixty percent of patients required a dosage change for stabilization (375 to 1000 mg/day). Seventeen patients reported unwanted effects (nausea or tremor), which either settled quickly or resolved with dosage reduction. 6 Serum theophylline levels were obtained at different dosages in 44 patients and 18 patients demonstrated dose-dependent kinetics. 7 An initial dose of 500 mg/day is recommended and dosage increments should not exceed 125 mg/day with monitoring by serum theophylline levels.     

Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates

Hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and mercapturic acid derivative (HCBD-NAC) all produce acute necrosis of the pars recta of the proximal renal tubule in the rat. Previous studies have shown that radiolabel from administered HCBD appears to concentrate in the pars recta region. Renal uptake of radioactivity from HCBD-NAC was studied in rats by giving a single ip injection of the chemical and measuring its concentration in plasma and renal cortex 4 hr later. Cortex/plasma ratios (C/P) of HCBD-NAC were 4.35 +/- 0.21 (8 animals) at a dose of 64 mumol/kg and 10.4 +/- 0.55 (5) at a dose of 16 mumol/kg. These ratios were greater than that of inulin [C/P inulin = 1.5 +/- 0.2 (4)]. Thus cortical HCBD-NAC content was significantly greater than can be accounted for by glomerular filtration alone. Prior administration of probenecid (500 mumol/kg), a competitive inhibitor of organic acid transport, to animals receiving 16 or 64 mumol/kg of HCBD-NAC reduced the C/P to 1.03 +/- 0.09 (5) and 0.81 +/- 0.05 (8), respectively. Administration of probenecid in increasing doses (100, 200, 300, and 400 mumol/kg) to animals receiving 64 mumol/kg HCBD-NAC resulted in decreases of the C/P (2.59, 2.29, 1.35, and 0.84, respectively), suggesting a competitive inhibition of cortical HCBD-NAC uptake. The extent of covalently bound radioactivity from 64 mumol/kg HCBD-NAC was significantly greater in the renal cortex (1.11 +/- 0.2 nmol eq/mg protein) than in the liver (0.19 +/- 0.01 nmol eq/mg protein). Prior administration of probenecid (500 mumol/kg) reduced the renal cortical concentration of HCBD-NAC to 0.25 +/- 0.02 nmol eq/mg protein. Increasing doses of probenecid resulted in a progressive decrease in renal cortical covalent binding. When treatment with probenecid led to renal cortical concentrations of less than 120 nmol eq HCBD-NAC/g and an amount of covalently bound material less than 0.4 nmol eq/mg protein the animals were completely protected against the nephrotoxicity, as assessed by plasma urea and histopathological examination 24 hr after dosing. Prior administration of probenecid (500 mumol/kg) also protected rats against the nephrotoxicity produced by HCBD (192 mumol/kg), HCBD-GSH (47 mumol/kg), and HCBD-CYS (36 mumol/kg). It is suggested that the renal cortical accumulation and selective proximal tubular toxicity of HCBD and its conjugates is related to a carrier-mediated transport system.     

Comparison of administration of two standard intravenous amino acid formulas to severely brain-injured patients

Twenty severely brain-injured patients with Glasgow Coma Scale scores of 4-9 were prospectively randomized to receive one of two standard amino acid formulas, starting with the first day of hospital admission up to day 14 postinjury. Formula 2 (patient group 2) had 54 percent more leucine, 53 percent more isoleucine, 74 percent more valine, 28 percent less phenylalanine, 31 percent less methionine, 111 percent more proline, 38 percent less alanine, and 38 percent less glycine than formula 1 (patient group 1). Groups 1 and 2 received statistically equal overall mean parenteral nutrition calories and protein (2173 +/- 147 vs. 2059 +/- 143 kcal, and 77 +/- 12 vs. 83.1 +/- 6 g, respectively). There was a significant difference in overall mean urinary urea nitrogen excretion (group 1 = 24.6 +/- 1.3 vs. group 2 = 18.3 +/- 1.1, p = 0.02) and nitrogen balance (group 1 = -8.0 +/- 2.1 vs. group 2 = +1.8 +/- 1.2, p = 0.01). Mean overall isoleucine values were significantly higher in group 2 (overall mean 77 mumol/L vs. 62 mumol/L, p = 0.04). Phenylalanine levels were significantly higher in group 1 (107 mumol/L) versus group 2 (82 mumol/L) patients (p = 0.01). Arginine levels were significantly higher in group 1 (78 mumol/L) versus group 2 (49 mumol/L) patients (p = 0.0002). This observation suggests that some standard intravenous amino acid formulas may be more apt to promote positive nitrogen balance than others.     

降钙素基因相关肽预适应对溶血磷脂酰胆碱抑制内皮依赖性舒张的…

目的：研究降钙素基因相关肽（ＣＧＲＰ）诱导预适应对溶血磷脂酰胆碱（Ｌｙｓ）抑制内皮依赖性舒张的作用。方法：用苯福林收缩兔与大鼠离体胸主动脉环，观察Ｌｙｓ对乙酰胆碱（ＡＣｈ）所致内皮依赖性舒张的影响。结果：ＣＧＲＰ预处理兔和大鼠离体胸主动脉环显著减轻Ｌｙｓ对ＡＣｈ舒血管效应的抑制，其作用可被蛋白激酶Ｃ（ＰＫＣ）抑制剂Ｈ－７所取消。结论：ＣＧＲＰ诱导预适应对所致内皮细胞损伤具有拮抗作用，此作用与激活Ｐ     

Characterization of hemoglobin adduct formation in mice and rats after administration of [14C]butadiene or [14C]isoprene

Occupational exposures to 1,3-butadiene or isoprene occur through their use in the manufacture of rubber and other related polymer products. The purpose of this study was to determine if butadiene or isoprene administration would result in the formation of adducts with blood hemoglobin (Hb), and if such adducts can be used as a measure of previous exposure(s). Male B6C3F1 mice and male Sprague-Dawley rats were injected intraperitoneally with 1, 10, 100, or 1000 mumol [14C]butadiene or 0.3, 3.0, 300, 1000, or 3000 mumol [14C]isoprene per kilogram body weight. Animals were killed 24 hr later. Globin was isolated from blood samples and was analyzed for 14C by liquid scintillation spectroscopy. Hb adduct formation was linearly related to administered doses up to 100 mumol [14C]butadiene or 500 mumol [14C]isoprene per kilogram body weight for mice and rats, respectively. For [14C]butadiene, the efficiency of Hb adduct formation in mice and rats within the linear response range was 0.177 +/- 0.003 and 0.407 +/- 0.019 (pmol of 14C-adducts/mg globin)/(mumol of retained [14C]butadiene/kg body wt), respectively (mean +/- SE; n = 18). For [14C]isoprene, these values for mice and rats were 0.158 +/- 0.035 and 0.079 +/- 0.016 (pmol of 14C-adducts/mg globin)/(mumol of retained [14C]isoprene/kg body wt), respectively (mean +/- SE; n = 12). Hb adducts also accumulated linearly after repeated daily administration of 100 mumol [14C]butadiene or 500 mumol [14C]isoprene per kilogram body wt to mice and rats, respectively, for 3 days. [14C]Butadiene-derived Hb adducts in blood showed lifetimes of approximately 24 and approximately 65 days for mice and rats, respectively, which correlate with the reported lifetimes for red blood cells in these rodent species. Thus, levels of butadiene- or isoprene-derived adducts on Hb in circulating blood may be a useful measure of prior repeated exposures to these compounds.     

CHLORIDE ION INGESTED WITH SODIUM AFFECTS THE DEVELOPMENT OF CEREBRAL LESIONS IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. To determine the effect of chloride ion on the development of hypertension and the incidence of cerebral lesions in stroke-prone spontaneously hypertensive rats (SHRSP), groups of 10 rats were administered chronically with either 171 mmol/L sodium chloride or equimolar sodium provided as sodium citrate in the drinking water from the age of 12 weeks. 2. The life span was significantly extended in SHRSP given sodium citrate (336 +/- 28 vs 246 +/- 26 days, mean +/- s.e.m., P less than 0.05) but their development of hypertension was not different from SHRSP given sodium chloride. 3. In order to determine the role of calcium homeostasis, calcium in urine was collected. Urinary calcium in SHRSP given sodium citrate was significantly decreased (1.0 +/- 0.12 vs 1.8 +/- 0.18 mg/24 h urine, P less than 0.05). 4. If the normal life span is 320 +/- 35 days, this suggests that chloride ion ingested with sodium accelerates the development of cerebrovascular diseases, and that increased urinary calcium excretion may be related to this adverse chloride effect on the development of hypertension in SHRSP.     

Characterization of the renal action of pranidipine in the rat

Although calcium antagonists elicit predominant dilation of afferent arterioles that might be associated with glomerular hypertension, there have been reported diverse observations demonstrating the effect of calcium antagonists on the progression of renal injury. The present study examined the effect of pranidipine (CAS 99522-79-9) on the renal microvascular tone in the isolated perfused hydronephrotic rat kidney, and the progression of renal insufficiency in subtotally nephrectomized spontaneously hypertensive rats. In the hydronephrotic kidney, angiotensin II caused marked constriction of both afferent and efferent arterioles. The subsequent addition of pranidipine (10 nmol/l, 100 nmol/l, 1 mumol/l) elicited dose-dependent afferent arteriolar dilation, with 97 +/- 3% reversal at 1 mumol/l. In contrast, efferent arterioles were resistant to pranidipine, with only 20 +/- 4% reversal at 1 mumol/l. In subtotally nephrectomized rats, 10-week treatment with pranidipine (3.0 mg/kg/day) markedly decreased blood pressure (from 270 +/- 6 to 158 +/- 8 mmHg) and improved renal histopathological changes, including glomerular and arteriolar sclerosis. Proteinuria was also less than than in the control rats (233 +/- 5 vs. 305 +/- 26 mg/day). Thus, although glomerular hypertension might develop as a consequence of preferential afferent arteriolar dilation, pranidipine actually improved the renal injury in subtotally nephrectomized SHR. These ostensibly discrepant observations could be attributed to the simultaneous reduction in blood pressure and the salutary actions of this agent mediated by non-hemodynamic mechanisms.     

Effects of icatibant on the ramipril-induced decrease in renal lithium clearance in the rat

The interaction between an inhibitor of angiotensin I converting enzyme (ramipril) and renal lithium handling was analysed in conscious, normotensive Wistar rats in the absence or the presence of a specific bradykinin B2 receptor antagonist, icatibant. The rats were treated for 5 days with ramipril (1 mg/kg/day p.o.) or its vehicle, alone or together with icatibant (0.1 mg/kg/day, s.c. infusion). Lithium chloride (8.3 mg/kg i.p.) was given as a single dose on day 5. Systolic blood pressure and heart rate were measured by tail plethysmography on day 3 (3, 9 and 15 h after ramipril administration) and renal function on day 4 (0-6 and 6-24 h urine sampling) and day 5 (0-6 h urine sampling). In another group of rats, 24 h sodium excretion was assessed during the first 4 days of ramipril treatment. Ramipril decreased renal lithium clearance (90+/-8 vs. 142+/-10 microl/min/100 g, P<0.001, n=24) and increased the fractional lithium reabsorption (74.3+/-1.9 vs. 66.7+/-1.7%, P<0.05) and plasma lithium concentration (0.108+/-0.006 vs. 0.085+/-0.004 mM, P<0.01). Alteration of renal lithium handling by ramipril was associated with a decrease in systolic blood pressure (-15% 3 h after ramipril administration) and sodium excretion (0-6 h after ramipril). The 24-h sodium excretion, however, tended to increase. Icatibant had no effect per se on renal function but attenuated the ramipril-induced decrease in renal lithium clearance (118+/-16 vs. 90+/-8 microl/min/100 g, n=12 and 24 respectively, P<0.05 one-tailed test) and systolic blood pressure. These results suggest that endogenous bradykinin contributes to the ramipril-associated alteration in renal lithium handling. Bradykinin B2 receptor-mediated vasodilation seems to be involved.     

Stability of an ofloxacin injection in various infusion fluids.

The stability of ofloxacin was evaluated in 10 different infusion fluids under various storage conditions. Solutions of ofloxacin (0.4 mg/mL and 4.0 mg/mL) were prepared in (1) 0.9% sodium chloride injection; (2) 5% dextrose injection; (3) 5% dextrose and 0.9% sodium chloride injection; (4) 5% dextrose and lactated Ringer's injection; (5) 5% sodium bicarbonate injection; (6) Plasma-Lyte 56 and 5% dextrose injection; (7) 5% dextrose, 0.45% sodium chloride, and 0.15% potassium chloride injection; (8) 1/6 M sodium lactate injection; (9) water for injection; and (10) 20% mannitol injection. Each solution was injected into polyvinyl chloride bags and stored at (1) 24 degrees C for 3 days, (2) 5 degrees C for 7 days, (3) 5 degrees C for 14 days, (4) -20 degrees C for 13 weeks and then 5 degrees C for 14 days, or (5) -20 degrees C for 26 weeks and then 5 degrees C, for 14 days. Samples were assayed initially and after storage by high-performance liquid chromatography and examined for visual clarity, pH, turbidity, and particulates. Ofloxacin was stable in all solutions and under all storage conditions. All of the solutions were clear, pH was stable, and particulate-matter counts were acceptable under all storage conditions (except for the 20% mannitol solution, which formed crystals at 5 degrees C and -20 degrees C). An injectable formulation of ofloxacin was stable for at least 3 days at 24 degrees C, 14 days at 5 degrees C, and 26 weeks at -20 degrees C in all tested infusion fluids. Crystals formed in refrigerated or frozen solutions prepared with 20% mannitol injection.     

Membrane potential changes induced by 5-hydroxytryptamine in the rabbit superior cervical ganglion.

1. Changes in resting membrane potential induced by 5-hydroxytryptamine (5-HT) have been measured in the excised ganglion by the sucrose-gap technique. 2. 5-HT produced a rapid depolarization, the threshold concentration for depolarization being around 10 muM. With concentrations of 100 muM or greater, repolarization began during the course of the superfusion; this was followed by prolonged tachyphylaxis. 3. Tachyphylaxis was largely avoided by making injections into the superfusion stream. Standard injections of 0.2 mumol 5-HT dissolved in 0.2 ml of Krebs solution were used routinely and could be given at 20-30 min intervals to evoke relatively constant responses. 4. The response to an injection consisted of a rapid depolarization, followed by a rapid repolarization and subsequent after-hyperpolarization. The threshold quantity for depolarization was around 0.01 mumol, while the ED50 estimated from 6 dose-response curves was 0.12 +/- 0.02 mumol (mean +/- s.e. mean). 5. Injections of 5-HT (0.2 mumol), choline (10 mumol) and acetylcholine (9.9 mumol) produced depolarizations of similar magnitude. 6. Monoamine oxidase inhibitors failed to alter substantially the amplitude of depolarizations to 5-HT. 7. 5-HT depolarizations were unaltered in amplitude when the impermeant anion benzenesulphonate was substituted for the chloride ion in Krebs solution, but were initially markedly reduced in amplitude in a sodium-deficient medium; some recovery of the response subsequently occurred. The depolarization which persisted in sodium-deficient solutions was much reduced or abolished when calcium ions were then removed from the superfusion medium. Removal of either calcium ions alone or potassium ions from the superfusion fluid did not reduce depolarization amplitude. 8. The after-hyperpolarization was abolished in sodium-deficient solutions, usually increased in potassium-free solutions, reduced or abolished by ouabain or nicotine, but unaffected by calcium free solutions. 9. A depolarizing action of 5-HT on presynaptic terminals in the ganglion appears probable.