bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Binding Sites of Bopindolol and Its Two Metabolites with β1-Adrenoceptors by Molecular Modeling: Comparison with β2 Adrenoceptors
Authors: Hattori Kaoru , Ishiguro Masaji , Ohnuki Toshio , Nakamura Takashi , Muramatsu Ikunobu , Nagatomo Takafumi
Published: April 2003

This study was designed to examine the importance of interaction in the bindings of nonselective β-blockers to β1-adrenoceptors (β1-ARs) as compared with β2-ARs, using molecular modeling. The β-blockers used in this study were bopindolol [4-(benzoyloxy-3-t- butylaminopropyl)-2-methylindol hydrogen malomate], its two metabolites [18-502 – hydrolyzed bopindolol or 4-(3-t-butylamino-2-hydroxypropoxy)-2-methyl indole – and 20-785 – 4-(3-t-butylaminopropoxy)-2-carboxyl indole], and propranolol. Molecular modeling was performed on an Indigo2 workstation (Silicon Graphic) using Discover/Insight II (Molecular Simulations) software. Through molecular modeling, possible binding sites for these drugs were suggested to lie between helices 3, 4, 5, and 6 of the β1-AR. The amine, benzoic acid, indole methyl, t-butyl, phenyl, and indole functional groups of bopindolol possibly interact with Asp138 (transmembrane – TM – 3), Ser190 (TM 4), Ala343 (TM 6), Val137 (TM 3), Pro339 (TM6), Cys336 (TM 4), Leu237 (TM 5), and Pro236 (TM 5) of β1-AR, respectively, by either hydrogen bonding or hydrophobic interactions. In addition, 18-502, 20-785, and propranolol also interacted with sites at the same positions as those of β2-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of β1-AR among these amino acids were different from those of β2-AR, the interactions at the same sites between ligands and amino acids of β1-AR as those of β2-ARs may occur because these drugs are nonselective.
Inhaled Nitric Oxide Potentiates Actions of Adenosine but Not of Sodium Nitroprusside in Experimental Pulmonary Hypertension
Authors: Patterson Kenneth W. , Deb Bhaskar , Kavanagh Brian P. , Pearl RonaldG.
Published: April 2003

Inhaled nitric oxide (NO), a selective pulmonary vasodilator, increases intracellular cyclic guanosine monophosphate. In contrast, adenosine, another selective pulmonary vasodilator, increases intracellular cyclic adenosine monophosphate. There has been only limited study on effects of inhaled NO combined with other pulmonary vasodilators. The current study examined the hypothesis that inhaled NO would potentiate in vivo pulmonary vasodilator effects of adenosine, but not those of sodium nitroprusside (SNP). Like inhaled NO, SNP acts via cyclic guanosine monophosphate. Rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor NG-nitro-L-arginine methyl ester was administered. U46619, a thromboxane A2 mimetic, was infused to produce pulmonary hypertension. Rabbits then received either SNP at doses of 0.5, 1, 2, 4, 8, 16, and 32 µg/kg/min or adenosine at doses of 12.5, 25, 50, 100, 150, and 300 µg/kg/min. Hemodynamic measurements were obtained with or without inhaled NO (40 ppm) at each dose of SNP or adenosine. During U46619-induced pulmonary hypertension, inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance. Adenosine and SNP produced dose-related decreases in pulmonary artery pressure and pulmonary vascular resistance and increases in cardiac output. Inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance at all doses of adenosine, but had no significant pulmonary vasodilator effects at doses of SNP >0.5 µg/kg/min. We conclude that inhaled NO does not produce additional pulmonary vasodilation over that achieved at higher doses of SNP, but does produce additional vasodilation when combined with a vasodilator having different mechanisms of action. Since both inhaled NO and adenosine produce selective pulmonary vasodilation, such combination therapy may be effective in patients with pulmonary hypertension.
Voluntary Consumption of Amphetamine, Cocaine, Ethanol and Morphine by Rats as Influenced by a Preceding Period of Forced Drug Intake and Clozapine
Authors: Ufer M. , Dadmarz M. , Vogel W.H.
Published: April 2003

Forced nicotine intake was previously found to decrease a subsequent free choice selection, whereas clozapine (CL) caused a marked increase in its consumption. Here these findings are extended to ethanol, cocaine, morphine and amphetamine. Forced intake of ethanol, cocaine, morphine and amphetamine had no major effect on a subsequent voluntary intake. CL, a dopamine D4 antagonist, increased the voluntary consumption of amphetamine and morphine with no effects on ethanol or cocaine intake. Only for cocaine was it found that low-consuming rats increased but high-consuming rats decreased their voluntary cocaine intake by CL. Thus, forced drug exposure per se does not lead to subsequent enhancement of voluntary intake; CL exerts differential effects on intake of these drugs, and a specific dopaminergic set point may govern the voluntary intake of cocaine by individual rats.
Use of Diffusion-Weighted MRI and Neurological Deficit Scores to Demonstrate Beneficial Effects of Isradipine in a Rat Model of Focal Ischemia
Authors: Chandra Sudeep , White Ray F. , Everding Daryl , Feuerstein Giora Z. , Coatney Robert W. , Sarkar Susanta K. , Barone Frank C.
Published: April 2003

The neuroprotective effects of isradipine, a 2,4-dihydropyridine calcium channel blocker, has been well studied in the rat model of focal ischemia (induced by middle cerebral artery occlusion, MCAO). The present study was designed to evaluate whether isradipine pretreatment caused early (0–3 h after stroke) ischemic changes in diffusion- weighted magnetic resonance imaging (DWI) and if such changes were predictive of previously documented protection in brain infarction. An initial dose-response study using neurological deficit scores and estimates of protection from brain infarction (by histology) showed that isradipine reduced cortical infarctions compared to vehicle-treated animals at most doses (between 1.25 and 5 mg/kg/day s.c. for 6 days) with the best results obtained at 5 mg/kg/day, where a 78.5% reduction was observed. This dose was utilized to perform the DWI study. Early quantitative estimates of infarct size, as measured by DWI at 1, 2 and 3 h after MCAO, were similar to those obtained with late histology at 24 h. These data indicate that in pretreatment protocols, DWI can be used to quantitatively predict areas at risk of permanent damage. This work also demonstrates that neurological deficits, developing from the damaged forebrain following focal stroke, may provide an index of isradipine’s neuroprotective activity.
Influence of L-365,260, a CCK-B/Gastrin Receptor Antagonist, on Tetragastrin- Stimulated Mucin Metabolism in Rat Gastric Mucosa
Authors: Komuro Yuichi , Ichikawa Takafumi , Ishihara Kazuhiko , Saigenji Katsunori , Hotta Kyoko
Published: April 2003

The effect of L-365,260, a CCK-B/gastrin receptor antagonist, on gastric mucus metabolism induced by tetragastrin was investigated in rats. In vivo application of L-365,260 at a dose of 3 mg/kg p.o. significantly reduced the tetragastrin (12 μg/kg s.c.)-stimulated gastric acid secretion, but 0.3 mg/kg of L-365,260 did not affect the gastric acid secretion induced by the tetragastrin administration. A single administration of 12 μg/kg of tetragastrin caused an increase in gastric mucin content in the soluble mucus (175% of control), the mucus gel (155% of control) and the surface mucosa (125% of control). L-365,260 at the doses of 0.3 and 3 mg/kg considerably inhibited the tetragastrin-induced mucus secretion in the soluble mucus (70–80% of tetragastrin) and the mucus gel (45–70% of tetragastrin) and resumed the mucus accumulated in the surface mucosa to the control situation (80% of tetragastrin). In the in vitro incubation system of rat gastric mucosa, L-365,260 (0.1–10 μmol/l) caused no significant change in gastric mucin synthesis. An in vivo study also showed that the increase in total gastric mucin content and the distributional changes in mucin content induced by 12 μg/kg of tetragastrin reverted with 3 mg/kg of L-365,260 pretreatment to the control situation. It is evident from these results that the CCK-B/gastrin receptor is involved in the mechanism of the stimulation of mucus secretion and/or mucus accumulation in rat gastric mucosa and not directly concerned with the action of gastrin-induced gastric acid secretion.
Effects of a New Antiallergic Agent, VUF-K-8788, on Experimental Asthmatic Reactions in Guinea Pigs
Authors: Takizawa Toshiaki , Yamada Takatoshi , Takahashi Yoshimasa , Tanaka Hiroyuki , Wada Yasushi , Nagai Hiroichi
Published: April 2003

The effects of 7-[3-[4-(2-quinolinylmethyl)- 1-piperazinyl]propoxy]-2,3-dihydro-4H-1,4- benzothiazin-3-one (VUF-K-8788) on experimental asthmatic reactions in guinea pigs were investigated. VUF-K-8788 inhibited histamine-induced bronchoconstriction at the doses of 0.3 and 1 mg/kg per os (p.o.). VUF-K-8788 inhibited anaphylactic bronchoconstriction at doses between 0.01 and 1 mg/kg in passively sensitized guinea pigs. Terfenadine used as a reference drug also inhibited an antigen-induced bronchoconstriction. VUF-K-8788 at the doses of 0.3 and 1 mg/kg inhibited immediate- and late-phase asthmathic reactions in actively sensitized guinea pigs. Terfenadine inhibited only the immediate phase reaction. Moreover, VUF-K-8788 inhibited the infiltration of eosinophils and macrophages into bronchoalveolar lavage fluid in guinea pigs. These results indicate that VUF-K-8788 may be useful for the treatment of bronchial asthma.
Effects of Estrogen on Autotomy in Normal and Ovariectomized Rats
Authors: Tsao Cheng-Ming , Ho Chiu-Ming , Tsai Shen-Kou , Lee Tak-Yu
Published: April 2003

Gonadal hormones may modulate analgesia responses induced by acute stress in humans and rats. To evaluate the effects of gonadal hormones in modifying neuropathic pain, we measured autotomy changes following sciatic nerve resection in ovariectomized rats and in the presence of estrogen replacement. Two groups of female rats were subjected to ovariectomy and sham surgery. Each group was then divided into two subgroups receiving subcutaneously sesame oil with or without estradiol benzoate (5 μg/day/rat). All rats then underwent sciatic nerve resection in one hindlimb. Degree of self-mutilation was measured daily for 8 weeks. Estradiol treatment resulted in significantly lower autotomy scores in ovariectomized rats (3.6 ± 0.6 vs. 5.5 ± 0.3, p < 0.01) and in sham-operated rats (3.4 ± 0.7 vs. 5.1 ± 0.4, p < 0.05). The results of this study indicate that estrogen can modify the autotomy behavior, an indicator of neuropathic pain, in rats after nerve injury.
Is the Growth of Brown Adipocytes Necessary for Cold Acclimation in Mice?
Authors: Nishimura Masakazu , Moriya Masao , Saitoh Masaji , Murakoshi Naoko , Shimizu Yoshio
Published: April 2003

Chronic exposure to cold increases the growth of brown adipose tissue and the resistance to more severe cold, thus improving thermogenesis. The present study examined the possibility that dietary compounds can modify cold acclimation. Adenosine (ADO) or adenine (ADE) were administered in drinking water (0.05%, w/v) for 5 weeks to male ddY strain mice from 4 weeks of age. At 5 weeks of age, the mice were exposed to 4°C for 4 weeks. After termination of this period, the interscapular brown adipose tissue (IBAT) and rectal temperature on acute exposure to severe cold (–20°C) for 60 min were measured. Chronic exposure to cold increased the weight of IBAT and made mice resistant to a fall in rectal temperature on exposure to severe cold. The growth of IBAT and improvement in thermogenesis can be used as a cold acclimation profile in ddY mice. The growth of IBAT was selectively prevented by ingestion of ADO. The improvement in thermogenesis was reduced, but only a little, by the ingestion of either ADO or ADE. Thus, growth of brown adipocytes might not be necessary for cold acclimation in mice.
In vivo Receptor Occupancy and Plasma Concentration of Pranidipine, a Potent and Long-Acting Dihydropyridine Calcium Antagonist
Authors: Yamada Shizuo , Uchida Shinya , Urayama Akihiko , Kimura Ryohei
Published: April 2003

The occupancy of 1,4-dihydropyridine (DHP) receptors by pranidipine was characterized in tissues of spontaneously hypertensive rats (SHR). Oral administration of pranidipine (1 and 3 mg/kg) in SHR produced significant (26–67%) decreases in the number of specific (+)-[3H]PN 200-110 binding sites (Bmax) with 2- to 4-fold increases in the apparent dissociation constant (Kd) in myocardial tissues at 1, 3 and 6 h later. In these rats, there was a reduction (16–37%) of Bmax in cerebral cortical (+)-[3H]PN 200-110 binding. Occupancy of myocardial DHP receptors after oral administration of pranidipine correlated well with its plasma concentration. Oral administration of nifedipine (10 mg/kg) in SHR caused significant increase in Kd values for (+)-[3H]PN 200-110 binding in myocardium and cerebral cortex at 1 h later. In vivo specific (+)-[3H]PN 200-110 binding in particulate fractions of SHR aorta was markedly (59–78%) reduced at 1, 3 and 12 h after oral administration of pranidipine (3 mg/kg), while myocardial (+)-[3H]PN 200-110 binding was decreased by 46–48% at 1 and 3 h later. In these rats, there was a significant decrease (34%) in cerebral cortical (+)-[3H]PN 200-110 binding at 3 h later. In contrast, nifedipine administration produced a similar degree of reduction (71–84%) of in vivo (+)-[3H]PN 200-110 binding in the myocardium, aorta and cerebral cortex. It is concluded that pranidipine may exert more selective and sustained occupation in vivo of DHP receptors in vascular tissues of SHR than in myocardial and brain tissues.
Sustaining Effects of Bopindolol on Inhibitory Chronotropic Actions in Guinea Pig Atria
Authors: Hattori Kaoru , Suzuki Jun , Hosohata Yoshiaki , Ohnuki Toshio , Nakamura Takashi , Watanabe Kenichi , Muramatsu Ikunobu , Nagatomo Takafumi
Published: April 2003

The dissociating and/or residual inhibitory effects of bopindolol from β-adrenoceptors (ARs) of atria strips pretreated with this drug and washed out with buffers on isoprenaline-induced chronotropic actions were determined. The effects of this drug were compared with those of its active metabolite 18-502, propranolol, and pindolol. Our results are as follows: (1) Lower concentrations of bopindolol (10–9 and 10–8 mol/l) and the active metabolite 18-502 (10–9 mol/l), propranolol (10–8 and 10–6 mol/l) and pindolol (10–8 mol/l) produced rightward shifts of concentration-response curves of isoprenaline. (2) Higher concentrations of bopindolol (10–7 mol/l) and 18-502 (10–8 and 10–7 mol/l) produced a reduced maximum response by isoprenaline. (3) Bopindolol (10–9–10–7 mol/l), 18-502 (10–9–10–7 mol/l) and propranolol (10–7 and 10–6 mol/l) did not recover to control levels at 180 min even after washout with buffers. In conclusion, bopindolol and 18-502 may slowly dissociate and act as noncompetitive β-antagonists rather than readily reversible β-AR antagonists. These effects may differ from those of propranolol and pindolol, although propranolol did not recover to control levels after washout with buffer.
Effects of in vivo Ischemia on Contractile Responses of Rabbit Bladder to Field Stimulation, Carbachol, ATP and KCl
Authors: Bratslavsky Gennady , Whitbeck Catherine , Horan Pat , Levin Robert M.
Published: April 2003

Rabbits were subjected to bilateral ischemia for 3, 6, or 18 h then euthanized and their bladders excised. Isolated strips of rabbit bladder detrusor were incubated in normal Tyrode’s solution and contractile responses to FS, carbachol, ATP, and KCl measured. Maximal contraction, maximal rate of tension generation, and length of time to maximal contraction were determined. These studies revealed that contractile responses to FS (neurogenic stimulation) were most affected by ischemia. Contractile responses to carbachol, ATP and KCl were all similarly sensitive to ischemia.
Antiarrhythmic Effect of Magnolol and Honokiol during Acute Phase of Coronary Occlusion in Anesthetized Rats: Influence of L-NAME and Aspirin
Authors: Tsai Shen Kou , Huang Cheng Hsiung , Huang Shiang Suo , Hung Li Man , Hong Chuang Ye
Published: April 2003

This study was designed to evaluate the in vivo effect of magnolol and honokiol on the acute phase of coronary ligation in the presence of nitric oxide inhibitor (L-NAME) or cyclooxygenase inhibitor (aspirin). After Sprague-Dawley rats were anesthetized with urethane, the changes of ventricular arrhythmia induced by coronary ligation for 30 min were determined with or without pretreatment with study medications. The incidence and duration of ventricular arrhythmia were significantly reduced after intravenous pretreatment (15 min before coronary ligation) with 10–7 g/kg magnolol or 10–7 g/kg honokiol. However, the antiarrhythmic effect of magnolol or honokiol could be abolished with the pretreatment of 1 mg/kg L-NAME, but not with pretreatment of 100 mg/kg aspirin. The abolishment of the myocardial beneficial effect of magnolol and honokiol by L-NAME, instead of aspirin, suggests an involvement of an increased nitric oxide synthesis in the protection offered by magnolol and honokiol against arrhythmia during myocardial ischemia.
Effect of Ozagrel on Locomotor and Motor Coordination after Transient Cerebral Ischemia in Experimental Animal Models
Authors: Ichikawa Kiyoshi , Tazawa Shigeki , Hamano Shuichiro , Kojima Masami , Hiraku Seiji
Published: April 2003

The effect of ozagrel, a selective thromboxane A2 (TXA2) synthetase inhibitor, on the obstruction after cerebral ischemia-reperfusion was studied in experimental animal models. The reduced spontaneously locomotor activity and the obstruction of motor coordination were improved by the administration of ozagrel in the conscious cerebral ischemia-reperfusion mouse model. Ozagrel suppressed the decrease in specific gravity of the brain tissue induced by the occlusion-reperfusion in the conscious cerebral ischemia-reperfusion SHR model, and recovered the postischemic decrease in cortical PO2 after middle cerebral artery occlusion-reperfusion in cats. The level of TXB2, a metabolite of TXA2, in the brain increased after the cerebral ischemia-reperfusion, and ozagrel prevented this increase. Additionally, ozagrel also increased the level of 6-keto-PGF1α, a metabolite of prostaglandin I2 (PGI2), in the brain tissue after cerebral ischemia-reperfusion, and the administration of PGI2 improved the reduced spontaneous locomotor activity in the conscious cerebral ischemia-reperfusion mouse model. Our data suggest that ozagrel suppressed the obstruction following cerebral ischemia-reperfusion by preserving the cerebral blood flow via preventing the increase in TXA2 and causing an increase in the PGI2 level.
Comparison of the Effects of Selective III, IV and Nonselective Phosphodiesterase Inhibitors on Isolated Tracheal Preparations in Streptozotocin-Diabetic Rats
Authors: Usta Coşkun , Şadan Gülay
Published: April 2003

The aim of the present study was to investigate the relaxant effects of selective III, IV and nonselective phosphodiesterase inhibitors, e.g. amrinone, rolipram and theophylline, respectively, on isolated tracheal preparations in streptozotocin (STZ)-diabetic rats. Six weeks before the experiments, the rats to be made diabetic were anesthetized with diethyl ether and diabetes was then induced by a single intravenous injection of STZ (65 mg kg–1) via the tail vein. All drugs produced concentration-dependent relaxations of tracheal preparations precontracted with 10–6 mol/l carbachol. The responses of phosphodiesterase inhibitors were marked in the diabetic groups compared to the control group, but it was found that only amrinone responses are significantly higher in the diabetic groups.
Autoradiographic Evidence of Delta-Opioid Receptor Downregulation after Prenatal Stress in Offspring Rat Brain
Authors: Sanchez M. Dolores , Milanés M. Victoria , Pazos Angel , Diaz Alvaro , Laorden M.L.
Published: April 2003

In order to visualize neuroanatomical alterations in specific brain regions, light microscopy autoradiography was carried out on offsprings (postnatal day 10) from female rats stressed in different periods of gestation and controls. Group 1 was subjected to restraint stress from day 2 to 6; group 2, from day 7 to 11; group 3, from day 12 to 16; group 4 from day 2 to 16. Group 2 showed decreases in δ-opioid receptor density in different hypothalamic regions. The decrease in δ-opioid receptor density was less marked in groups 1 and 3 whereas there was no modification in group 4. Present data suggest that the prenatal stress induces a downregulation of δ-receptors in different hypothalamic regions.
Dietary Taurine Decreases Hepatic Secretion of Cholesterol Ester in Rats Fed a High-Cholesterol Diet
Authors: Yamamoto Kyosuke , Yoshitama Ayako , Sakono Masanobu , Nasu Tetsuo , Murakami Shigeru , Fukuda Nobuhiro
Published: April 2003

The effects of dietary taurine on lipid secretion and ketone body production were examined in the livers of Wistar and Sprague-Dawley rats fed high-cholesterol diets. The weight gain of the Sprague-Dawley rats tended to be higher than that of the Wistar rats, although food intake was comparable between the strains. The concentration of hepatic triglyceride was significantly higher but that of phospholipid was significantly lower in the Sprague-Dawley rats. Ketone body production by livers of Sprague-Dawley rats was significantly higher than that by the livers of Wistar rats. Dietary taurine repressed the weight gain of Wistar rats, perhaps due to decreased food intake, but it had no apparent effect on these growth parameters in Sprague-Dawley rats. There was a significant reduction in the hepatic concentration of cholesterol ester, but not other lipid components following feeding of taurine. Taurine feeding resulted in a stimulation of hepatic ketogenesis, whereas it markedly reduced the hepatic secretion of cholesterol ester in both strains of rats. The effect of dietary taurine on the hepatic secretion of triglyceride, phospholipid and free-cholesterol was marginal in either strain. These results suggest that taurine feeding significantly ameliorated the dietary cholesterol-dependent increase in hepatic accumulation and secretion of cholesterol ester, regardless of strain differences, and the decrease in the hepatic secretion of this cholesterol ester appeared to be partly responsible for the observed reduction in the concentration of serum cholesterol following feeding of taurine in these cholesterol-fed rats.
Role of Leukotrienes on Coronary Vasoconstriction in Isolated Hearts of Arthritic Rats: Effect of in vivo Treatment with CI-986, a Dual Inhibitor of Cyclooxygenase and Lipoxygenase
Authors: Gök Şule , Ülker Sibel , Hüseyinov Afig , Hatip Funda Bölükbaşι , Çınar Mehtap Gülcihan , Evinç Akgün
Published: April 2003

In this study, coronary perfusion pressure and force of contraction were investigated in isolated hearts removed from arthritic rats by using the Langendorff method. A strong coronary vasoconstriction was determined in arthritic hearts which was associated with elevated levels of arachidonate 5-lipoxygenase (5-LOX) products, leukotriene B4 (LTB4) and LTC4 in coronary effluents. In vivo treatment with the dual inhibitor of cyclooxygenase (COX) and LOX, CI-986 (2 and 10 mg/kg/day) on days 14– 26 following adjuvant injection, prevented the coronary vasoconstriction and the increased production of LTB4 and LTC4. These results suggest that the coronary vasoconstriction in the isolated arthritic hearts is associated with an increased activity of the LOX system and CI-986 could have a preventive effect on constriction of coronary arteries.
Effect of Antioxidants on Pyrogallol-Induced Delay in Gastric Emptying in Rats
Authors: Sharma Monisha , Rai Kamala , Sharma Shyam S. , Gupta Yogendra K.
Published: April 2003

The effect of a free radical generator pyrogallol on gastric emptying was studied in rats. Pyrogallol at doses of 25, 50, 100 and 150 mg/kg (i.p.) produced dose-dependent inhibition of gastric emptying. Pretreatment with vitamin C (100 and 500 mg/kg, p.o.), and vitamin E (100 and 500 mg/kg, p.o.) significantly reversed the inhibition in gastric emptying caused by pyrogallol 100 mg/kg. However, the combination of vitamin C and vitamin E (100 mg/kg) produced synergistic effect. Glutathione (100 mg/kg i.v.) 5-min pretreatment also reversed the inhibition of gastric emptying caused by pyrogallol 100 mg/kg. Ondansetron (3 mg/kg, p.o.) significantly reversed the pyrogallol effect. The effect of pyrogallol on malondialdehyde (MDA) levels and 5-HT levels in the stomach tissue was also studied. Pyrogallol at a dose of 100 mg/kg, i.p., significantly increased MDA levels and 5-HT levels in the stomach. Pretreatment with a combination of vitamin C and vitamin E (100 mg/kg, p.o.) and glutathione (100 mg/kg, i.v.) significantly ameliorated the rise in stomach tissue MDA caused by pyrogallol but had no significant effect on the rise in 5-HT levels caused by pyrogallol. The effect of different doses of 5-HT on gastric emptying was also studied. 5-HT had a differential effect on gastric emptying. The low and high doses (0.1, 0.3 and 30 mg/kg, i.p.) significantly inhibited the gastric emptying while doses ranging from 1 to 10 mg/kg, i.p., had no significant effect on the gastric emptying. The pretreatment with antioxidants, combination of vitamin C and vitamin E (100 mg/kg each, p.o.) and glutathione (100 mg/kg, i.v.) had no effect on the 5-HT (0.3 mg/kg, i.p.)-induced delay in gastric emptying. The result indicate the role of free radicals gastric emptying, and antioxidants may be of potential therapeutic value in disease conditions where free radicals are known to be released and the gastrointestinal effects are observed as symptoms or side effects of drug therapy.
Influence of Polyunsaturated Fatty Acids on Vasoconstrictions Induced by 8-iso-PGF2α and 8-iso-PGE2
Authors: Sametz Wolfgang , Jeschek Mirjam , Juan Heinz , Wintersteiger Reinhold
Published: April 2003

8-iso-PGF2α and 8-iso-PGE2, which are released in vivo by free radical catalyzed peroxidation of arachidonic acid, are equipotent vasoconstrictors in vivo and in vitro. It is assumed that they exert this effect via activation of the thromboxane A2 (TP) receptor or a TP-receptor-like isoprostane receptor. Increased levels of 8-iso-PGF2α have been detected in human cardiovascular diseases. It has been found that polyunsaturated fatty acids (PUFAs) have many beneficial effects in cardiovascular diseases, including antivasoconstrictor actions. Therefore, we investigated the influence of perfusions with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and dihomo-γ-linolenic acid (DGLA) at final concentrations of 3 and 30 μmol/l on vasoconstriction induced by 8-iso-PGF2α, 8-iso-PGE2 and the thromboxane A2 mimetic U 46619 in the vasculature of the isolated perfused rabbit ear. Additionally, the effect of indomethacin (final concentration 3 μmol/l) on the effects of the PUFAs was investigated. Our results show that the PUFAs at a concentration of 30 μmol/l caused a significant inhibition of the vasoconstrictions induced by 8-iso-PGF2α, 8-iso-PGE2 and U 46619. Furthermore, it can be assumed that a part of the inhibitory effect of DGLA is due to the effect of a cyclooxygenase product, probably PGE1, because indomethacin reduced the inhibitory effect of DGLA.
Animal Pharmacology of Reversible Antagonism of the Gastric Acid Pump, Compared to Standard Antisecretory Principles
Authors: Kromer Wolfgang , Postius Stefan , Riedel Richard
Published: April 2003

To define the basic antisecretory profile of a potassium-competitive antagonism of the gastric acid pump relative to other classes of acid-inhibitory drugs, they were compared to each other against all three major stimuli of acid secretion. Pumaprazole is an imidazo-pyridine derivative that was used in this investigation as an example of reversibly binding acid pump antagonists (APAs). It differs from covalently binding proton pump inhibitors (PPIs), such as omeprazole, both with respect to chemical structure and mode of interaction with the gastric H+/K+-ATPase (i.e., the acid or proton pump). The present data show that a single dose of pumaprazole is able to elevate intragastric pH in the dog with gastric fistula under pentagastrin or carbachol stimulation from pH 1 to about pH 7 while still displaying a dose-dependent, well-controlable duration of action of a few hours. Ranitidine at the same oral dose also shows a short duration of action, but combined with a far lower efficacy. By contrast, a single oral dose of the PPI omeprazole elevates intragastric pH for a longer time period, but this pH elevation is far lower compared to that of the APA. Regarding the less stringent parameter of inhibition of total acid output in the Heidenhain pouch dog, the modified Shay rat or the Ghosh-Schild rat, pumaprazole is, overall, slightly more efficacious than ranitidine. The M1-muscarinic antagonist pirenzepine is ineffective (against histamine stimulation) or far less effective than pumaprazole (against pentagastrin-stimulation), but as effective as pumaprazole against carbachol stimulation in the Ghosh-Schild rat. Basal acid output in the same model is more effectively inhibited by pumaprazole than by ranitidine. In conclusion, our data demonstrate the exceptional ability of a reversibly binding APA to elevate intragastric pH up to neutrality even upon a first administration while still displaying a limited, dose-dependent duration of action.
Effects of Centrally Applied Somatostatin on Pituitary Adrenocorticotropes in Female Rats
Authors: Starčević Vesna , Milošević Verica , Brkić Branislava , Severs Walter B.
Published: April 2003

Effects of intracerebroventricular (i.c.v.) application of somatostatin (SRIH-14 or SRIH-28) on growth and function of pituitary adrenocorticotropes (ACTH cells) were examined in adult female Wistar rats. Animals were subjected to i.c.v. administration of three 1-μg doses of SRIH-14 or SRIH-28 dissolved in 5 μl saline every second day. Controls were treated in the same way with the same volume of saline only. ACTH-producing cells were studied using the peroxidase-antiperoxidase (PAP) immunohistochemical procedure; blood samples were collected for hormone analyses 5 days after the last injection. SRIH-28 treatment decreased (p < 0.05) all morphometric parameters compared to control rats. Volume of ACTH cells decreased by 10%, nuclei by 36% and volume density by 13%. No significant changes (p > 0.05) in these parameters occurred after SRIH-14 treatment. Plasma concentration of ACTH in SRIH-28-treated rats was significantly lower (p < 0.05) than in control rats by 35%. In SRIH-14-treated rats, plasma concentration of ACTH was slightly, but not significantly (p > 0.05) increased by 13% compared to saline treatment. These observations suggest that centrally administered somatostatin-28, but not somatostatin-14, is specifically involved in the control of growth and secretory activity of ACTH cells in female rats. Thus, selective pharmacological manipulation of SRIH-28 receptors reached from CSF may affect ACTH activity without altering actions usually attributed to receptors sensitive to SRIF-14.
Effect of Am-80, a Retinoid Derivative, on 2,4-Dinitrofluorobenzene-Induced Contact Dermatitis in Mice
Authors: Niwa Satoru , Ochi Takashi , Hirano Yousuke , Wang Ting , Inagaki Naoki , Shudo Koichi , Nagai Hiroichi
Published: April 2003

Retinoids have many pharmacological activities, including anti-inflammatory action and antiangiogenesis, effected through the regulation of various gene transcriptions. In this study, we investigated the effect of Am-80, one of the retinoic acid derivatives, on hapten-induced contact hypersensitivity in BALB/c mice. After application of 2,4-dinitrofluorobenzene (DNFB) to the ears of the mice, severe contact hypersensitivity with marked infiltration of inflammatory cells and hypertrophy of the epidermis was caused. The thickness of the ears increased biphasically and reached a peak 3 and 24 h after the DNFB challenge. Am-80 significantly inhibited ear thickness in the late-(24 h), but not the early-phase (3 h) reaction in a dose-dependent manner. In a histopathological study, obvious depression of edema and infiltration of inflammatory cells was observed in the ears of mice treated with Am-80. Am-80 inhibited the levels of expression in mice ears of interferon-γ (IFN-γ) and interleukin-6 (IL-6), but not tumor necrosis factor-α (TNF-α) or interleukin-4 (IL-4). Furthermore, Am-80 inhibited the antigen-induced production of some cytokines, including IFN-γ and IL-6, but not IL-4, in vitro. Therefore, Am-80 inhibited hapten-induced contact hypersensitivity through the direct inhibition of inflammatory cytokines such as IFN-γ and IL-6.
M2 and M4 Muscarinic Receptor Subtypes Couple to Activation of Endothelial Nitric Oxide Synthase
Authors: Waid David K. , Chell Mellisa , El-Fakahany Esam E.
Published: April 2003

In this report we studied coupling of M2 and M4 muscarinic acetylcholine receptors to activation of endothelial nitric oxide synthase (eNOS). Chinese hamster ovary cells that co-express the individual receptor subtypes and eNOS in a stable fashion were used as a model. Activation of eNOS was assayed by measuring increasing levels of cyclic GMP in admixed cells that contain guanylate cyclase. Activation of both M2 or M4 muscarinic receptors resulted in marked activation of eNOS, in a time- and concentration-dependent manner. The time course of the response exhibited a transient peak, followed by a sustained lower plateau. While the sustained phase was dependent on influx of extracellular calcium, the transient response showed dependency on both mobilization of intracellular calcium and extracellular influx.
On the Cardiac Contractile, Electrophysiological and Biochemical Effects of Endothall, a Protein Phosphatase Inhibitor
Authors: Bokník P. , Vahlensieck U. , Huke S. , Knapp J. , Linck B. , Lüss H. , Müller F.U. , Neumann J. , Schmitz W.
Published: April 2003

Protein phosphatase inhibitors, e.g. cantharidin, exert positive inotropic effects in mammalian heart preparations. Endothall, a synthetic herbicide which is chemically related to cantharidin, inhibits protein phosphatase activities in mouse liver preparations. However, the cardiac effects of endothall have hitherto not been studied. In guinea pig papillary muscles, endothall (1–100 μmol/l) failed to affect force of contraction, whereas cantharidin (1–100 μmol/l) increased force of contraction maximally to 313.4 ± 32% of control at 10 μmol/l. In isolated guinea pig ventricular cardiomyocytes, endothall did neither change the free intracellular calcium concentration nor the amplitude of calcium current nor the phosphorylation state of regulatory phosphoproteins like phospholamban. In contrast, cantharidin (30 μmol/l) increased the free intracellular calcium concentration and the L-type calcium current to 149.6 ± 9% and to 157.6 ± 12% of control, respectively. Furthermore, cantharidin (1–100 μmol/l) augmented the phosphorylation of phospholamban maximally to 140.8 ± 7% of control. Nevertheless, in guinea pig ventricular homogenates, both endothall and cantharidin inhibited phosphatase activity with EC50 values of 1.92 and 0.32 μmol/l, respectively. Thus, in contrast to cantharidin, endothall failed to increase force of contraction, though it inhibited protein phosphatase activity. Clearly, endothall is not an appropriate tool to study the function of protein phosphatases in the mammalian heart.
Effect of FRG-8813, a New-Type Histamine H2-Receptor Antagonist, on the Recurrence of Gastric Ulcer after Healing by Drug Treatment in Rats
Authors: Ajioka Hirofusa , Miyake Hidekazu , Matsuura Naosuke
Published: April 2003

We investigated the recurrence of ulcers in rats after treatment with FRG-8813, (±)-2-(furfurylsulfinyl)-N-[4- [4-(piperidinomethyl)-2-pyridyl] oxy-(Z)-2-butenyl] acetamide, a novel histamine H2-receptor antagonist. Chronic gastric ulcers were induced by serosa-searing with a hot metal bar, and the ulcer healing and recurrence after treatment with FRG-8813 or famotidine were evaluated by endoscopy for 160 days. At the dose of 30 mg/kg p.o., once daily, the treatment with FRG-8813 or famotidine for 60 days, which was stopped earlier if the ulcer had healed, accelerated the ulcer healing significantly. A subsequent follow-up study on the healed rats showed that the cumulative recurrence rate of rats healed by FRG-8813 was lower than that of naturally healed rats or rats healed by famotidine. In many cases of rats healed by FRG-8813, the regenerated mucosa was normal in contrast with the control of famotidine-healed animals. The mucosal regeneration index of the gastric ulcer after 10 days’ administration of FRG-8813 was significantly higher than that obtained with famotidine. After cessation of the treatment with famotidine for 7 days, rebound hyperacidity was induced; but such rebound did not occur with FRG-8813. Considering the low recurrence rate of ulcers after FRG-8813 treatment, we suggest that FRG-8813 treatment may provide additional benefits in peptic ulcer therapy.
Role of Nitric Oxide in Gastric Injury Induced by Hemorrhagic Shock in Rats
Authors: Denizbaşı Arzu , Yegen Cumhur , Öztürk Melek , Yegen Berrak
Published: April 2003

The aim of this study was to investigate the effect of nitric oxide (NO) on the gastric injury induced by hemorrhagic shock. Hemorrhagic shock was created by withdrawing 3 ml blood/200 g body weight of the rats. Before the hemorrhage, NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg i.v. bolus), D-NAME (10 mg/kg i.v. bolus), or L-arginine (100 mg/kg i.v. bolus and 10 mg/kg/min infusion) + L-NAME were administered. At the end of the 1-hour hypovolemic shock period, histological analysis, gastric ulcer index, gastric myeloperoxidase (MPO) activity, and gastric protein oxidation (PO) levels were determined. In histological analysis a destructive effect of L-NAME (NO synthase inhibitor) was demonstrated. L-NAME treatment increased gastric MPO activity, L-arginine reversed this effect and D-NAME had no effect. Tissue PO activity was found to be increased in L-NAME-treated rats; L-arginine treatment reversed this activity. It is concluded that gastric barrier function is altered after hemorrhagic shock, and L-arginine (NO precursor) can prevent mucosal injury in the stomach. This effect of NO may be on gastric blood flow and can be mediated by tissue neutrophils.
Pharmacogenetics of the Alcohol Dehydrogenase System
Authors: Jörnvall Hans , Höög Jan-Olov , Persson Bengt , Parés Xavier
Published: April 2003

Alcohol dehydrogenase (ADH) constitutes a complex enzyme system with different forms and extensive multiplicity. A combination of constant and variable properties regarding function, multiplicity and structure of ADH is highlighted for the human system and extended to ADH forms in general. Future perspectives suggest continued studies in specific directions for distinction of metabolic, regulatory and pharmacogenetic roles of ADH.
The Role of Pharmacogenetics and Pharmacogenomics in Cancer Chemotherapy with 5-Fluorouracil
Authors: Diasio Robert B. , Johnson Martin R.
Published: April 2003

There is increasing evidence supporting the important role of genetics in determining the effect (response and toxicity) to cancer chemotherapy. This has included both pharmacogenetics, where the alteration of a gene coding for an important drug metabolizing enzyme results in increased toxicity (and occasionally altered efficacy), and pharmacogenomics, where knowledge of the expression of genes critical to the action of the cancer chemotherapy drug can be used to individualize therapy. This manuscript focuses on the widely used cancer chemotherapy drug 5-fluorouracil (5-FU) to illustrate the following concepts: (1) The effect of the pharmacogenetic syndrome known as dihydropyrimidine dehydrogenase (DPD) deficiency on 5-FU pharmacology; (2) the role of pharmacogenomics in individualizing 5-FU therapy, and (3) the potential value of pharmacogenomics in designing new drugs.
Prospects for Gene Therapy in Pediatric Neurosurgery
Authors: Kaplitt Michael G. , Darakchiev Borimir , During Matthew J.
Published: April 2003

Gene therapy represents a powerful tool for both the study and potential treatment of pediatric neurological diseases. The majority of strategies for brain gene therapy have focused upon the use of modified viruses as vehicles for efficient delivery of genes into cells of the central nervous system. Retroviruses were originally the most popular vehicles for gene transfer outside the brain; however, these only function in actively dividing cells and have thus been limited to developmental neurobiology and treatment of brain tumors. Viruses with DNA-based genomes can transfer genes to both dividing and nondividing cells such as neurons, and these include adenovirus, adeno-associated virus and herpes simplex virus. Each system has special features, and the choice of vehicle may be based upon a variety of factors including toxicity or immunogenicity of the vector in vivo, size of the gene which can be inserted, titer of virus which can be obtained and technical difficulty in generating reagent grade viruses. Pediatric patients present unique opportunities for gene therapy, and inherited genetic defects and brain tumors are among the pediatric disorders which would most benefit from this new field. Preclinical studies using each of these systems in a variety of models of pediatric CNS disease have proven promising. Several ongoing studies have been initiated for treatment of pediatric brain tumors, and a protocol for treatment of an inherited neurological defect has recently achieved approval for initial clinical trials. Continued advances in gene therapy technology and delivery systems combined with the explosion of available genetic information should make gene therapy an increasingly important tool for the future of pediatric neurosurgery.
Appendicitis in Children with a Ventriculoperitoneal Shunt
Authors: Pumberger W. , Löbl M. , Geissler W.
Published: April 2003

The presentation of an acute abdomen in children with a ventriculoperitoneal shunt requires skilful diagnostic workup. Apart from complications caused by the shunt, primary abdominal pathological conditions must be taken into consideration, particularly in the older child. A series of 6 children with a ventriculoperitoneal shunt had to be treated surgically for appendicitis. Their medical records were analyzed retrospectively. Despite difficulties with the initial diagnosis, the time from admission to final diagnosis and operation was relatively short. An accurate history, careful evaluation of the clinical signs and, above all, ultrasound of the abdomen were helpful in decision making. During the operation the shunts were left in place. Only 1 patient developed a cerebrospinal fluid pseudocyst in the early postoperative period, which made a conversion into a ventriculoatrial shunt necessary. No ascending infection occurred, even when the abdominal tip of the shunt came in close contact with the focus of inflammation. An acute abdomen due to shunt infection should be managed conservatively and by removal of the shunt from the abdomen, thus avoiding an unnecessary laparotomy. On the other hand, a primary intra-abdominal disease requires surgical treatment, during which the shunt system can be left in place.
Pediatric Oligodendrogliomas
Authors: Razack Nizam , Baumgartner James , Bruner Janet
Published: April 2003

Pediatric oligodendrogliomas are infrequently occurring brain tumors and frequently thought of as benign. The literature examining treatment and outcome in this select population is sparse. A retrospective analysis of pediatric oligodendrogliomas treated at MD Anderson Cancer Center between 1973 and 1992 was performed. Oligodendrogliomas were histologically graded according to the method of Smith. Survival data were estimated with Kaplan-Meier curves. Mean follow-up was 39.7 months. Nineteen children had histologically verified oligodendrogliomas and mixed oligodendroglioma/astrocytoma (M:F = 11:8; age range 1–18 years, mean = 13.1). Presenting symptoms included seizures (n = 10), headache (n = 3), visual field defects (n = 2), weakness (n = 2), cranial nerve palsy (n = 1) and decreased school performance (n = 1). All patients underwent craniotomy: 13 subtotal resections, 5 gross total resections and 1 biopsy. Twelve children had adjuvant therapy including radiation (n = 12), chemotherapy (n = 5) or both (n = 5). The 5-year survival was 65%. Seizure frequency was reduced in 30%. Children with oligodendrogliomas do not have a benign course, but younger children (<12 years) have a better prognosis. Histologic classification correlates with survival. Completeness of resection was not found to be a factor relating to survival. No conclusions can be drawn concerning adjuvant therapy because of selection bias.
C2/3 Instability in a Child with Down’s Syndrome
Authors: Citow Jonathan Stuart , Munshi Ilyas , Chang-Stroman T. , Sullivan Christopher , Frim David M.
Published: April 2003

Down’s syndrome patients are prone to cervical ligamentous laxity, the vast majority of which is at the C1/2 level. We describe the case of a 2-year-old girl with Down’s syndrome who was found to have cervical instability at the C2/3 level on screening cervical spine radiographs with 9 mm of anterolisthesis of C2 on C3. She was without clinically evident neurological deficit from this condition; however, T2-weighted magnetic resonance imaging of her cervical spine revealed high intensity signal changes within the spinal cord at and above that level. She underwent posterior fusion that was complicated by poor tolerance of her Minerva-type cervical brace. She eventually developed a stable fusion with 5 mm of anterolisthesis at the C2/3 level. This is the only Down’s syndrome patient with instability at the C2/3 level that we have found reported. Our experience suggests that Down’s syndrome patients can have instability at C2/3 that can be successfully treated with posterior fusion.
Myelomeningocele Repair in utero: A Report of Three Cases
Authors: Tulipan Noel , Bruner Joseph P.
Published: April 2003

Background: Evidence accumulating over the last 10 years suggests that the exposed spinal cord tissue in a myelomeningocele sustains a secondary injury as the result of prolonged exposure to the intrauterine environment. These data suggest that early closure of the myelomeningocele sac might prevent such injury and in turn improve the neurologic outcome in the affected infant. Methods: Three patients with fetuses carrying the ultrasonic diagnosis of myelomeningocele elected to enter a study of the feasibility of repairing myelomeningocele in utero. At approximately 28 weeks of gestation each patient underwent laparotomy and hysterotomy, thus exposing the myelomeningocele defect. The defect was closed in a routine surgical fashion, and the hysterotomy was then closed. Results: The 3 patients recovered from surgery without incident. Early premature contractions subsided, and they were discharged by the 5th postoperative day. At between 33 and 36 weeks of gestation, each infant was delivered via cesarean section. The observed neurologic deficits were within the range expected from the anatomic level of the defects. Two of the infants have not required ventriculoperitoneal shunting. Conclusions: This limited series of patients suggests that myelomeningocele can be repaired in utero with minimal morbidity to either the mother or her fetus. A larger study will be needed to substantiate this low morbidity and to determine the extent of any neurologic benefit of early surgery.