bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of Neutral Endopeptidase Activity along the Rat and Rabbit Nephron
Authors: Edwards Richard M. , Pullen Mark , Nambi Ponnal
Published: April 2003

Neutral endopeptidase (NEP) activity was measured in various nephron segments dissected from rat and rabbit kidney. In the rat, only the proximal straight tubule and glomerulus had measurable NEP activity of 86 ± 11.3 pmol/min/mm tubule length and 5.8 ± 1.5 pmol/min/glomerulus, respectively. In the rabbit, significant activity was observed in both the proximal convoluted tubule (70.8 ± 7.2 pmol/min/mm) and proximal straight tubule (29.6 ± 2.3 pmol/min/mm) as well as in the glomerulus (12.8 ± 2.2 pmol/min/glomerulus). In the rat proximal tubule, phosphoramidon and thiorphan inhibited NEP activity, with IC50 values of 26.6 ± 6.0 and 6.9 ± 1.6 nmol/l, respectively. Incubation of rat proximal tubules with phorbol 12-myristate 13-acetate resulted in a 50% reduction in membrane-associated NEP activity. The results demonstrate that in both the rat and rabbit NEP is restricted to the glomerulus and proximal tubule. This localized distribution of NEP and its potential regulation by the protein kinase C pathway may play a key role in determining local concentrations of important regulatory peptides in the kidney.
An Individual Bioequivalence Approach to Compare the Intrasubject Variability of Two Ciclosporin Formulations, SangCyaTM and Neoral®
Authors: Canafax Daniel M. , Irish William D. , Berger Moran Hana , Squiers Elizabeth , Levy Ralph , Pouletty Philippe , First M. Roy , Christians Uwe
Published: April 2003

A novel bioequivalence testing approach was used to determine intrasubject variability and switchability of two ciclosporin formulations, SangCyaTM (test) and Neoral® (reference). Twenty healthy volunteers were enrolled into a single-dose, randomized, open-label, 4-period, 2-sequence study with a crossover replicate design. Subject-by-formulation interaction variances were compared using a mixed effects linear model. Intrasubject variability for ln AUC0–∞ and ln Cmax of SangCya and Neoral were not significantly different. The 95% confidence intervals of the intrasubject variability of AUC0–∞ (0.94) and Cmax (1.28) as determined using the bootstrap nonparametric percentile method (n = 2,000) were below the individual bioequivalence limit estimated at 2.25. We concluded equivalent intrasubject variability of ciclosporin pharmacokinetics and switchability between SangCya and Neoral.
Impairment of GABA-Mediated Contractions of Rat Isolated Ileum by Experimental Diabetes
Authors: Özdem Sadi S. , Şadan Gülay
Published: April 2003

The effect of diabetes induced by pretreatment with streptozotocin 6 weeks prior to the study on the responses induced by γ-aminobutyric acid (GABA), the GABAA agonist 3-aminopropane sulfonic acid (3-APS), and acetylcholine in the rat isolated ileum was evaluated. GABA, 3-APS, and acetylcholine showed a rightward shift in their concentration-dependent effects in the ileum that also attained a lower maximum in streptozotocin-diabetic rats as compared with control rats (p < 0.05). It is suggested that the reduced contractile responses of ileal smooth muscle to GABA and 3-APS might be due to a direct effect of diabetes on the GABAergic system or to its effect on the cholinergic system.
Effects of Mannitol and Dimethylthiourea on Helicobacter pylori-Induced IL-8 Production in Gastric Epithelial Cells
Authors: Kim Hyeyoung , Seo Jeong Yeon , Kim Kyung Hwan
Published: April 2003

The present study aims at investigating the effects of mannitol and dimethylthiourea, known hydroxyl radical scavengers, on lipid peroxidation as an indicative of oxidative damage, NF-κ B activation and IL-8 production by Helicobacter pylori in gastric epithelial cells. A human gastric epithelial cell line, AGS, treated with or without mannitol and dimethylthiourea, was incubated in the absence or the presence of H. pylori. As a result, H. pylori significantly stimulated the productions of lipid peroxide and IL-8. Treatment with H. pylori resulted in the activation of two species of NF-κ B dimers (a p50/p65 heterodimer and a p50 homodimer). Mannitol and dimethylthiourea significantly inhibited lipid peroxide production, NF-κ B complex formation and IL-8 production by H. pylori. In conclusion, mannitol and dimethylthiourea may attenuate H. pylori-induced gastric inflammation by inhibiting lipid peroxidation and NF-κ B activation and thereby decreasing IL-8 production.
Effect of Wood Creosote and Loperamide on Propulsive Motility of Mouse Colon and Small Intestine
Authors: Ogata Norio , Ataka Koji , Morino Hirofumi , Shibata Takashi
Published: April 2003

To elucidate a mechanism of the antidiarrheal activity of wood creosote, its effect on the propulsive motility of mouse colon and small intestine was studied using a charcoal meal test and a colonic bead expulsion test. The effect was compared with that of loperamide. At an ordinary therapeutic dose, wood creosote inhibited the propulsive motility of colon, but not of small intestine. On the other hand, loperamide inhibited the propulsive motility of small intestine, but not of colon. The results indicate that at least a part of the antidiarrheal activity of wood creosote and loperamide is attributable to their antikinetic effect predominantly on colon of the former and predominantly on small intestine of the latter.
Tamsulosin: Assessment of Affinityof 3H-P razosin Binding to Two Alpha-1- Adrenoceptor Subtypes in the Canine Aorta
Authors: Nakamura Takashi , Maruyama Keiko , Ohnuki Toshio , Hattori Kaoru , Watanabe Kenichi , Nagatomo Takafumi
Published: April 2003

This study was performed to assess the affinity of tamsulosin to the α1L- in addition to α1B-adrenoceptor (α1-AR) subtypes coexisting in the canine aorta using the radioligand binding assay. The antagonistic effects of this drug on contraction of the rat aorta were also assessed, and the results were compared with those obtained with prazosin, amosulalol, labetalol, ketanserin, clonidine and propranolol. The pKi value of tamsulosin to the α1L-subtype was lower than those of prazosin and HV-723, but higher than those of amosulalol, ketanserin and labetalol. The pKi value of tamsulosin for the α1B-subtype in the canine aorta was similar to that of prazosin. However, this drug showed a higher pKi value than amosulalol, HV-723, labetalol and ketanserin. On the other hand, the order of inhibition potencies for contraction of the rat aorta by phenylephrine was as follows: prazosin > tamsulosin > amosulalol > HV-723 > labetalol > ketanserin > clonidine > propranolol. Thus, although the affinity of tamsulosin to the α1B-AR subtype in the canine aorta was as high as that in the bovine prostate reported in our previous study, the affinity (pKi 7.87) of this drug to α1L-AR in the canine aorta was lower than that (pKi 8.99) in the bovine prostate. These observations suggested that the pharmacological potencies of tamsulosin in the aorta and prostate may be different.
Effects of Organic Anions and Vinblastine on Biliary Excretion of Erythromycin in Rats
Authors: Sato Akihiro , Takikawa Hajime , Yamanaka Masami
Published: April 2003

Since little is known about the mechanism of biliary excretion of cationic drugs, biliary excretion of erythromycin was studied in rats. Infusion of sulfobromophthalein and taurocholate significantly decreased biliary erythromycin excretion, whereas infusion of dibromosulfophthalein, cefpiramide, ursodeoxycholate-3-O-glucuronide and taurolithocholate-3-sulfate had no effect on biliary excretion of erythromycin. Vinblastine significantly inhibited biliary erythromycin excretion. Phenothiazine treatment significantly increased biliary erythromycin excretion. However, erythromycin infusion did not affect biliary vinblastine excretion. These findings indicate a multiplicity of biliary excretory pathways for organic cations; at least one additonal pathway may exist for organic cations apart from P-glycoprotein.
Changes of Superoxide Dismutase in Cultured Rat Aortic Smooth Muscle Cells (A7r5) by an Incubation of Vitamin E
Authors: Huang Wen-Pin , Chan Paul , Chen Yi-Jen , Chen Chi-Ming , Liao Shue-Sen , Chin Wan-Tai , Cheng Juei-Tang
Published: April 2003

Supplementation of antioxidants such as vitamin E and vitamin C as health promotion food is popular recently. Epidemiological studies supported the beneficial effect of these antioxidants because oxygen free radicals have been linked to the process of diseases and aging. The present study evaluated the effect of α-tocopherol (vitamin E) on the changes of superoxide dismutase (SOD) in cultured rat aortic smooth muscle cells (A7r5) after a short-term (2 days) or long-term (7 days) incubation. Incubation of A7r5 cells with vitamin E at a concentration of 50 μmol/l for 2 days caused an increase of both the activity and mRNA level of SOD. At higher concentrations, such as 100 or 200 μmol/l, vitamin E failed to enhance SOD more effectively. However, after incubation for 7 days, vitamin E caused a decrease in both the activity and mRNA level of SOD in a concentration-dependent manner. Otherwise, the protein amount of SOD remained the same in these samples regardless of the concentration of vitamin E or the duration of incubation. The obtained results suggest that vitamin E can increase the effect of SOD to result in the beneficial influence of this antioxidant only at low concentration under a short-term supplementation because a down-regulation of SOD was observed in cells receiving a long-term incubation.
Pharmacological Analysis of Atypical β-Adrenoceptors in the Guinea Pig Gastric Fundus Using the β3-Adrenoceptor Antagonist Bupranolol
Authors: Horinouchi Takahiro , Koike Katsuo
Published: April 2003

Atypical β-adrenoceptor-mediated relaxations to catecholamines (isoprenaline, noradrenaline and adrenaline) and β3-adrenoceptor agonists, BRL37344 [(R*,R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]-propyl]phenoxyacetic acid sodium salt] and CGP12177A [(–)-4-(3-t-butylamino-2-hydroxy- propoxy)benzimidazol-2-one] in guinea pig gastric fundus were investigated. The five agonists induced concentration-dependent relaxation of the gastric fundus. In the presence of both atenolol and butoxamine only small rightward shifts of the concentration-response curves to these agonists were observed. Under this condition, however, bupranolol caused a concentration-dependent rightward shift of the concentration-response curve to catecholamines and β3-adrenoceptor agonists. Schild plot analyses of bupranolol against these agonists gave pA2 values of 6.08 (isoprenaline), 6.04 (noradrenaline), 5.90 (adrenaline), 6.50 (BRL37344) and 5.80 (CGP12177A), respectively. These results clearly suggest that the existence of functional atypical β-adrenoceptors in the guinea pig gastric fundus and the relaxation of these agonists in this tissue are mediated via atypical β-adrenoceptors.
Protein Kinase C-Dependent Coupling of α2A/D-Adrenergic Receptors to Phospholipase D
Authors: Jinsi-Parimoo Arti , Deth Richard C.
Published: April 2003

To clarify the role of protein kinase C (PKC) in regulating the coupling pathway of α2-adrenergic receptors, we examined receptor activation of phospholipase D (PLD) in PC12 cells overexpressing α2A/D receptors, using [3H]phosphatidylbutanol formation as an index of PLD activity. In intact PC12/α2A/D cells, the ability of either epinephrine or the α2-receptor-selective agonist UK14304 to stimulate PLD was completely dependent on concomitant PKC activation. Pretreatment with the PKC activator phorbol dibutyrate revealed an agonist-stimulated PLD activity which was blocked by the α2-receptor-selective antagonist rauwolscine and by pertussis toxin treatment. Removal of extracellular calcium or tyrosine kinase inhibition by genistein pretreatment also eliminated the ability of epinephrine to stimulate PLD. These results indicate that α2A/D-adrenergic receptors couple via pertussis toxin-sensitive G proteins to PLD in a PKC-requiring and tyrosine kinase regulated manner.
Renal Vascular Reactivity to P2-Purinoceptor Activation in Spontaneously Hypertensive Rats
Authors: Fernández Oscar , Wangensteen Rosemary , Osuna Antonio , Vargas Félix
Published: April 2003

This study was performed to determine the possible contribution of an imbalance between P2X (vasoconstriction) and P2Y (vasodilation)-purinergic reactivity to the increased vascular resistance of spontaneously hypertensive rats (SHR). The vasoactive responses to α,β-methylene ATP and 2-methylthio ATP specific agonists, respectively, for P2X and P2Y purinergic receptors were characterized in isolated perfused kidneys from Wistar Kyoto (WKY) and SHR. To analyze P2X- and P2Y-purinergic reactivity we used phenylephrine and barium chloride, or acethylcholine (ACh) and sodium nitroprusside (NP) as reference compounds, respectively. The renal vasculature from SHR showed markedly enhanced reactivity to α,β-methylene ATP, phenylephrine and barium chloride. The dose-response curves were characterized by a similar threshold, with a greater maximal response. There were no significant differences in the dose-response curves or in maximal vasodilation to 2-methylthio ATP, ACh or NP when both groups were compared, except at the dose of 10–6 g/g kidney weight of NP in which the SHR group showed an increased responsiveness. The results indicate that the increased responsiveness of kidneys from SHR to α,β-methylene ATP may be due to nonspecific functional changes in the renal vasculature rather than to a specific alteration in the activity of renal P2X-purinoceptors. Our results also indicate that P2Y-purinergic reactivity, nitric oxide-induced vasodilation and the cGMP-dependent mechanisms of vasodilation are well preserved in SHR.
Choline Is a Full Agonist in Inducing Activation of Neuronal Nitric Oxide Synthase via the Muscarinic M1 Receptor
Authors: Carriere Jason Lee , El-Fakahany Esam E.
Published: April 2003

The present study was designed to characterize the interaction of choline with the M1 subtype of the muscarinic acetylcholine receptor. Using Chinese hamster ovary cells transfected with neuronal nitric oxide synthase and the cloned human M1 receptor (CHO hM1/nNOS cells), we investigated choline’s effects on production of nitric oxide and elevation of intracellular [Ca2+]. Choline showed the properties of a full agonist in inducing the sustained plateau of increased intracellular [Ca2+], although it was only a partial agonist in inducing the larger, transient [Ca2+] peak. Choline was also found to act as a full agonist in stimulating the production of nitric oxide. These results have implications for efforts in the clinical treatment of dementia.
Differential Effect of Antiallergic Drugs on IgE-Mediated Cutaneous Reaction in Passively Sensitized Mice
Authors: Satoh Taku , Tahara Eiichi , Yamada Tomohiro , Watanabe Chie , Itoh Takashi , Terasawa Katsutoshi , Nagai Hiroichi , Saiki Ikuo
Published: April 2003

We investigated the effect of several antiallergic agents on murine IgE-mediated biphasic cutaneous reaction. Mice were passively sensitized by an intravenous injection of monoclonal anti-dinitrophenol (anti-DNP) IgE antibody. Skin reaction was elicited by an epicutaneous challenge of dinitrofluorobenzene (DNFB) and occurred biphasically with immediate-phase response (IPR) and late-phase response (LPR) at 1 and 24 h, respectively. Classical histamine H1 receptor antagonists and some chemical mediator-release inhibitors, such as diphenhydramine and terfenadine, inhibited IPR, but not LPR. In contrast, leukotriene B4 (LTB4) receptor antagonist (ONO-4057) inhibited LPR only. Antagonists for LTC4, D4, E4 receptor (ONO-1078) and platelet-activating factor (PAF) receptor (Y-24180) significantly inhibited both IPR and LPR, similarly to prednisolone. We recently found that a third-phase inflammatory reaction with marked infiltration of eosinophils (named very-late-phase response; vLPR), which is supposed to be a more important reaction in allergic diseases, was induced, peaking at day 8 following IPR and LPR in this model. The effect of these drugs on the triphasic skin reaction can be scored based on efficacy against IPR / LPR / vLPR; +/+/+ (prednisolone, a PAF receptor antagonist Y-24180, cyclosporin A and FK-506), +/–/– (diphenhydramine), +/+/– (azelastine and LT receptor antagonist ONO-1078), and –/+/+ (an LTB4 receptor antagonist ONO-4057). Thus the inhibitory effect on vLPR as well as LPR may relate to the inhibition of eosinophil function mediated by LTB4 and PAF and/or T cells. These findings may provide the basis for a treatment modality using various antiallergic agents in allergic disease.
In vitro Pharmacological Profile of SK-896, a New Human Motilin Analogue
Authors: Tsukamoto Katsura , Kuboyama Noboru , Yamano Masaya , Nakazawa Toru , Suzuki Tsunemasa
Published: April 2003

SK-896 ([Leu13]motilin-Hse) is a new human motilin analogue synthesized by Escherichia coli using a biotechnological method. We investigated the binding of SK-896 to motilin receptors and the contractile effect of SK-896 on smooth muscle preparations isolated from the gastrointestinal tract and various regional organs in order to clarify its in vitro pharmacological profile. SK-896 inhibited the binding of 125I-human motilin to rabbit gastroduodenal motilin receptors with the same potency as unlabeled human motilin. The IC50 values of SK-896 and human motilin were 3.5 ± 1.5 and 3.1 ± 1.8 nmol/l, respectively. The Kd of human motilin was 3.0 ± 1.5 nmol/l, and the Ki of SK-896 was 3.4 ± 1.5 nmol/l. SK-896 induced contraction of smooth muscle preparations isolated from rabbit duodenum in a concentration-dependent manner. However, there was no effect of SK-896 on duodenal preparations isolated from the dog and the rat. SK-896 thus exhibited species specificity in its contractile effect. We next investigated the effect of SK-896 on various smooth muscle preparations isolated from rabbit gastrointestinal tract, trachea, bladder, gallbladder, uterus, vas deferens and artery. Results showed that SK-896 induced contraction of smooth muscle preparations isolated from gastrointestinal tract, with potencies in the order duodenum > gastric pylorus = jejunum = descending colon > ascending colon ≥ ileum. However, there was no effect of SK-896 on smooth muscle preparations from gastric fundus and other regional organs. SK-896 thus exhibited regional specificity in its contractile effect. Moreover, the effects of SK-896 on smooth muscle preparations from rabbit duodenum were the same as those of human motilin, and were not inhibited by pretreatment with tetrodotoxin and atropine but were inhibited by verapamil. These findings indicate that SK-896 has the same pharmacological profile as human motilin. They suggest that SK-896 acts on gastrointestinal smooth muscle isolated from rabbit directly and specifically.
Pharmacological Properties of the Gastric H+/K+ ATPase Inhibitor, AU-461
Authors: Cheon Hyae Gyeong , Kim Hyun Jung , Mo Hye Kyoung , Lee Byoung Ho , Choi Joong-Kwon
Published: April 2003

AU-461 (1-(2-methyl-4-methoxyphenyl)-4-[(2-hydroxyethyl)amino]-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline) was tested for its ability to act as an anti-ulcer agent. AU-461 inhibited gastric H+/K+ ATPase activities with IC50 values of 12.15 and 4.20 μmol/l for rabbit and pig enzymes, respectively. The inhibition was reversible, and competitive with respect to the activating cation K+. When AU-461 was examined for the in vivo antisecretory activity, we found that AU-461 reduced the histamine-stimulated acid secretion as well as the basal secretion in rat stomach. Duration of the antisecretory effect was about 6 h upon oral administration. AU-461 prevented dose-dependently the ulcer formation produced by either ethanol or NaOH. This protective effect was not altered by indomethacin pretreatment. In addition, the elevated plasma gastrin by the oral administration of AU-461 was returned to control by 12 h. Taken together, these results suggest that AU-461 could be developed as a new therapeutic agent for peptic ulcer disease.
Effects of Ba2+ on Norepinephrine-Induced Contraction of Rat Thoracic Aorta in vitro
Authors: Saito Kyoko , Kitajima Toshimitsu , Uchida Kohsuke , Kamikawa Yuichiro
Published: April 2003

The aim of this study was to examine the effect of exogenously applied BaCl2 on the norepinephrine-induced contraction of the rat thoracic aorta. Exogenously applied BaCl2 (0.3–1 mmol/l) slightly elevated the norepinephrine-induced sustained contraction of the rat thoracic aorta in the absence of nicardipine (1 μmol/l). In the aortic preparation pretreated with nicardipine (1 μmol/l), exogenous BaCl2 (0.1–3 mmol/l) did not elevate the norepinephrine-induced sustained contraction, but the high concentration of BaCl2 (10 mmol/l) slightly inhibited the norepinephrine-induced tone. In a Ca2+-free Krebs bi- carbonate solution (KBS) containing norepinephrine (1 μmol/l) or a Ca2+-free K+-rich (60 mmol/l) KBS, exogenously applied BaCl2 (1–30 mmol/l) caused a sustained contraction of the rat thoracic aorta, and this sustained contraction was completely inhibited by nicardipine (1 μmol/l). Exogenous CaCl2 (0.1–3 mmol/l) also caused a sustained contraction of the aortic preparation in a Ca2+- free KBS containing norephinephrine (1 μmol/l), but such a sustained contraction was partly inhibited by nicardipine (3 μmol/l). These results indicate that Ba2+ elevates the norepinephrine-induced tone of the rat isolated thoracic aorta by permeating voltage-dependent Ca2+ channels in the absence of nicardipine, but that Ba2+ has a minor modification on the norepinephrine-induced sustained contraction of the nicardipine-pretreated preparation.
Differences in Efficacy and Na+ Sensitivity between α2B and α2D Adrenergic Receptors
Authors: Tian Wang-Ni , Deth Richard C.
Published: April 2003

The ability of Na+ ions to modulate coupling of α2B- and α2D-adrenergic receptors to G proteins was investigated in isolated membranes from transfected PC12 and NIH 3T3 fibroblast cells. The initial rate of epinephrine-stimulated [35S]GTPγS binding was higher for α2D-receptors (the rat homolog of the α2A-receptor) in both cell types, whereas both α2B- and α2D-receptor responses were higher in PC12 cell membranes. Pertussis toxin completely blocked agonist-stimulated binding. Graded increases in Na+ caused a progressive loss of basal GTP binding, indicative of its ability to reduce the level of the active R* state of the receptor. This inhibitory effect of Na+ was more pronounced in PC12/α2B than PC12/α2D membranes. Epinephrine-stimulated GTP binding in PC12/α2B membranes was also more sensitive to Na+ inhibition than in PC12/α2D membranes. In saturation [35S]GTPγS binding studies, the presence of Na+ reduced apparent GTP affinity, and its effect was greater in PC12/ α2B membranes, consistent with a greater reduction in the active R* conformation of the receptor. The higher efficacy of epinephrine at α2D receptors and their lesser sensitivity to Na+ are both indicative of a more stable R* state. Together these results suggest that differences in the modulatory influence of Na+ within a family of Gi-coupled receptors may reflect differences in the stability of the active R* state.
Antithyroid Action of Tamoxifen in the Rat
Authors: Beyssen Marie-Laure , Lagorce Jean-François , Clédat Dominique , Jambut Anne-Catherine , Buxeraud Jacques
Published: April 2003

The influence of administration of tamoxifen (TAM) on thyroid metabolism was investigated. The potential action of TAM on iodine in the thyroid gland was evaluated by determination of the equilibrium constant of the charge transfer complex formed with molecular iodine and by computational studies. Adverse effects of TAM on thyroid function parameters were also investigated in female Wistar rats. Rats were treated for seven weeks with 5 mg/kg/day of TAM. Irrespective of the iodine content of the diet, administration of TAM led to goitre and a significant increase in levels of T4 and TSH. Similar results, albeit more marked, were observed after administration of an inhibitor of thyroid peroxidase. We also showed that TAM forms charge transfer complex with iodine (Kc = 876 liters/mol). We concluded that under our experimental conditions, TAM exerts antithyroid activity from an action on thyroid peroxidase. Nevertheless, when the exogenous iodine contribution is restricted, TAM may sequester iodine in the form of charge transfer complexes, thereby enhancing hypothyroidism.
Decreasing Cyclic GMP Exerts Similar Positive Functional Effects on Cardiac Myocytes Regardless of Initial Level
Authors: Yan Lin , Huang Mark W. , Scholz Peter M. , Weiss Harvey R.
Published: April 2003

We tested the hypothesis that lowering the level of cyclic GMP would have positive functional effects on isolated rabbit ventricular myocytes regardless of the basal cyclic GMP level. Cell shortening data were collected with a video detector; O2 consumption data were obtained with a Clark electrode; intracellular cyclic GMP levels were obtained by radioimmunoassay. Data were obtained: (1) at baseline; (2) after the addition of 1H-[1,2,4]oxadiazolo[4,3-α]quinoxaline-1-one (ODQ) 10–6 and 10–4 mol/l, a selective soluble guanylyl cyclase inhibitor, and (3) after zaprinast 10–6 mol/l, a cyclic GMP phosphodiesterase inhibitor, followed by ODQ 10–6 and 10–4 mol/l. We found that ODQ 10–4 mol/l significantly decreased the cyclic GMP level from 493 ± 75 to 301 ± 78 (fmol/100,000 myocytes) and increased percent shortening (Pcs, %; 4.9 ± 0.3 vs. 5.8 ± 0.6) and maximum rate of shortening (Rs, μm/s; 58.7 ± 5.7 vs. 73.6 ± 4.9). Zaprinast significantly increased the cyclic GMP level from 419 ± 140 to 599 ± 241 and decreased Pcs (6.2 ± 0.5 vs. 4.4 ± 0.4) and Rs (65.5 ± 5.3 vs. 49.6 ± 4.3). After zaprinast, ODQ 10–4 mol/l decreased the cyclic GMP level to 439 ± 139 and increased percent shortening and rate of shortening by a similar percentage compared to the non-zaprinast treated myocytes. We conclude that in rabbit ventricular myocytes, a reduction in the level of myocyte cyclic GMP increases myocyte function independent of the initial cyclic GMP level.
Applications of Genetically Manipulated Mice in Pharmacogenetics and Pharmacogenomics
Authors: Kimura Shioko , Gonzalez Frank J.
Published: April 2003

Gene knockout mice have proven to be very useful in understanding the role of xenobiotic-metabolizing enzymes in chemical toxicity and carcinogenesis. The combination of gene knockout technology with transgenic mouse technology should provide more versatile and suitable animal models to study the risks of chemical exposures in humans in terms of toxicity and carcinogenesis, as well as development and design of new therapeutic drugs. Recent studies using genetically manipulated mice are summarized.
Polymorphisms of Human Aldehyde Dehydrogenases
Authors: Vasiliou Vasilis , Pappa Aglaia
Published: April 2003

Aldehyde dehydrogenases (ALDHs), a superfamily of NAD(P)+-dependent enzymes with similar primary structures, catalyze the oxidation of a wide spectrum of endogenous and exogenous aliphatic and aromatic aldehydes. Thus far, 16 ALDH genes with distinct chromosomal locations have been identified in the human genome. Polymorphism in ALDH2 is associated with altered acetaldehyde metabolism, decreased risk of alcoholism and increased risk of ethanol-induced cancers. Polymorphisms in ALDH3A2, ALDH4A1, ALDH5A1 and ALDH6A1 are associated with metabolic diseases generally characterized by neurologic complications. Mutations in ALDH3A2 cause loss of enzymatic activity and are the molecular basis of Sjögren-Larsson syndrome. Mutations in ALDH4A1 are associated with type II hyperprolinemia. Deficiency in ALDH5A1 causes 4-hydroxybutyric aciduria. Lack of ALDH6A1 appears to be associated with developmental delay. Allelic variants of the ALDH1A1, ALDH1B1, ALDH3A1 and ALDH9A1 genes have also been observed but not yet characterized. This review describes consequences of ALDH polymorphisms with respect to drug metabolism and disease.
Effects of an Amphoteric Antiallergic Agent, HSR-609, on Antigen-Induced Late Phase Nasal Eosinophilia in Brown Norway Rats
Authors: Musoh Keiichi , Nakamura Nobuaki , Nagai Hiroichi
Published: April 2003

The effect of a newly synthesized compound, HSR-609, on rat experimental rhinitis was investigated. In the first part of the study, a new experimental nasal allergic late phase eosinophilia model in Brown Norway (BN) rats was investigated. The increase in the number of antigen inhalations resulted in the proportional increase in the number of inflammatory cells such as macrophages, eosinophils and neutrophils in the nasal cavity lavage fluid (NCLF) at 5 h after each inhalation. The number of inflammatory cells reached a maximum 8 h after the antigen perfusion. Submaximum response was observed at 5 h after the antigen provocation. In this system, the serum IgG and IgE antibody titers measured by homologous passive cutaneous anaphylaxis were 160 and 640, respectively. In the second part of the study, the effects of prednisolone, cetirizine and a newly synthesized amphoteric antiallergic agent, HSR-609, on this allergic late nasal eosinophilia and neutrophilia in BN rats were investigated. Prednisolone and HSR-609 significantly inhibited the increase in the number of eosinophils in the NCLF but not cetirizine. Furthermore, prednisolone showed the inhibition of the increase in the number of macrophages and neutrophils in NCLF. These results suggest that this late phase eosinophilia model in the nose of BN rats may be useful for investigating the therapeutic drugs for nasal allergy and a newly synthesized amphoteric antiallergic agent, HSR-609, may be useful for the treatment of allergic rhinitis with eosinophilia.
Cardioprotective Effects of MET-88, a Gamma-Butyrobetaine Hydroxylase Inhibitor, on Cardiac Dysfunction Induced by Ischemia/Reperfusion in Isolated Rat Hearts
Authors: Hayashi Yukio , Tajima Kiyotaka , Kirimoto Tsukasa , Miyake Hidekazu , Matsuura Naosuke
Published: April 2003

Inhibition of fatty acid metabolite accumulation may be beneficial for treatment of cardiac dysfunction induced by ischemia. MET-88, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, inhibits γ-butyrobetaine hydroxylase which catalyzes conversion of γ-butyrobetaine to carnitine. In this study, we investigated whether MET-88 has cardioprotective effects against cardiac dysfunction induced by ischemia/reperfusion. Rats were divided into four groups: (1) control; (2) MET-88 at 50 mg/kg; (3) MET-88 at 100 mg/kg; (4) nifedipine at 30 mg/kg. MET-88 was administered orally once a day for 10 days, and nifedipine was administered orally 30 min before the experiments. Cardiac functions (heart rate, left ventricular systolic pressure and coronary flow) were measured in rat working heart preparations for 30 min under ischemia followed by 20 min under reperfusion. Myocardial carnitine levels were measured at the end of the experiments. Before ischemia, MET-88 did not affect cardiac functions, but nifedipine significantly increased only coronary flow. Under the ischemic condition, cardiac functions were markedly decreased in all groups. During reperfusion, MET-88 and nifedipine promoted recovery of cardiac functions and decreased the incidence of ventricular fibrillation. MET-88 also prevented the accumulation of long-chain acylcarnitine induced by ischemia. These results indicated that MET-88 protected against cardiac dysfunction in ischemia/reperfusion, and preventing the accumulation of long-chain acylcarnitine may be responsible for the cardioprotective effects.
Mechanisms Underlying Contraction and Relaxation Induced by Nerve Stimulation in Monkey Uterine Arteries
Authors: Okamura Tomio , Ghoneim Hamdy A. , Ayajiki Kazuhide , Ammar El-Sayed M. , Toda Noboru
Published: April 2003

We investigated the mechanisms of contractile and relaxant responses to nerve stimulation by electrical pulses and nicotine in isolated monkey uterine artery strips denuded of the endothelium. In the strips contracted with prostaglandin F2α, transmural electrical stimulation (5 Hz, 40 s) produced a contraction which was partially attenuated by prazosin and abolished or reversed to a relaxation by additional treatment with α,β-methylene ATP. The relaxation was abolished by NG-nitro-L-arginine (L-NA) and restored by L-arginine but not by D-arginine. Atropine, D-NA, aminophylline and suramin, an inhibitor of P2Y purinoceptors, were without effect. The neurogenic relaxation was abolished by 1H-(1,2,4)oxadiazolo(4,3)quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Nicotine (10–4 mol/l) elicited contraction or relaxation of uterine arteries; the contraction was reversed by combined treatment with prazosin and α,β-methylene ATP. Nicotine-induced relaxations were abolished by L-NA and restored by L-arginine. The relaxation induced by exogenously applied NO (acidified NaNO2 solution) was not influenced by L-NA but abolished by ODQ. It is concluded that contractions induced by nerve stimulation are mediated by norepinephrine and ATP liberated from sympathetic nerves that stimulate α1-adrenoceptors and P2x purinoceptors, respectively. The neurogenic relaxation seems to be mediated exclusively by nitric oxide synthesized from L-arginine in perivascular nerves that activates guanylate cyclase and produces cyclic GMP in smooth muscle.
An Acoustic Study of the Tongue Root Contrast in Degema Vowels
Authors: Fulop S.A. , Kari E. , Ladefoged P.
Published: April 2003

Degema is an Edoid language of Nigeria whose ten vowels are organized phonologically into two sets of five. The two sets are thought to be differentiated by the degree of tongue root advancing. This paper examines the acoustic nature of these vowels as represented in field recordings of six speakers. The most consistent acoustic correlate of the tongue root contrast was found to be the first formant frequency which consistently distinguishes four of the five vowel pairs, the exception being the two low vowels. Three of the five pairs could also be distinguished by F2, though the direction of the difference was not consistent. Additionally, a comparison of corresponding advanced and retracted vowels using a normalized measure of relative formant intensity demonstrated that this correlate could also distinguish them in general, but only operated reliably in two of the five vowel pairs. The pair of low vowels could not be distinguished from each other by any of these measures. Finally, a perceptual study was conducted which demonstrates that Degema speakers do not classify their vowels very well using formant frequencies as the sole acoustic variable; only the two pairs of mid vowels were reliably singled out by native listeners from an array of synthesized vowels.
Effects of Contrastive Emphasis on Jaw Opening
Authors: Erickson Donna
Published: April 2003

This paper examines the effect of contrastive emphasis on the amount of vertical jaw displacement, as measured from X-ray microbeam data, for 3 American English speakers. Jaw opening in short utterances with one word emphasized (in initial, middle, and final positions) was compared with that of similar utterances with no words emphasized. The results suggest that emphasis involves not only a significant increase in jaw opening on the word emphasized but also possibly a reduction of jaw opening on the word following emphasis. Emphasis in addition may affect the amount of jaw opening of the utterance as a whole, in terms of a decrement in jaw opening on all the remaining words in the utterance following the emphasized word. The relationship between jaw opening and hierarchical levels of prosodic structure is tentatively discussed.
Acoustic Characteristics of Greek Vowels
Authors: Fourakis Marios , Botinis Antonis , Katsaiti Maria
Published: April 2003

Five male speakers produced the vowels of Greek at slow and fast tempo, in lexically stressed and unstressed syllables, and in lexically stressed syllables of words appearing in focus position. Duration, fundamental frequency (F₀), amplitude, and the frequencies of the first (F1) and second formant (F2) were measured. The effects on these variables of the phonemic category of the vowel, tempo, stress, and focus were examined. The results indicated that the vowel system of Greek follows universal tendencies in terms of duration but not in terms of F₀ and amplitude. Vowels in focus position, when plotted by their F1 and F2 frequencies, defined a vowel space larger than that defined by vowels in any other condition.
A Cross-Language Comparison of Speaking Rate Effects on the Production of Voice Onset Time in English and Spanish
Authors: Magloire Joël , Green Kerry P.
Published: April 2003

Of interest in the current study was how voice inset time (VOT) was influenced by changes in speaking rate across Spanish and English. Three groups of subjects (English monolinguals, Spanish monolinguals and early Spanish-English bilinguals) produced sentences containing voiced and voiceless bilabial stops at different speaking rates. As in previous research, English monolinguals showed rate-dependent effects on their VOT productions: VOT increased as speaking rate decreased. Spanish monolinguals showed a large effect of speaking rate on the duration of prevoicing of the voiced stops. However, they showed only a small effect of rate on the VOT of their voiceless stops. The bilinguals produced VOT values in each language that were nearly identical to their monolingual counterparts. The results from this study indicate that short-lag stops experience minimal variation as a function of speaking rate regardless of the other contrasting phonetic categories within a particular language. In addition, early bilinguals showed evidence of separate representations for voiced and voiceless stops for English and Spanish.
Emotive Transforms
Authors: Sundberg Johan
Published: April 2003

Emotional expressivity in singing is examined by comparing neutral and expressive performances of a set of music excerpts as performed by a professional baritone singer. Both the neutral and the expressive versions showed considerable deviations from the nominal description represented by the score. Much of these differences can be accounted for in terms of the application of two basic principles, grouping, i.e. marking of the hierarchical structure, and differentiation, i.e. enhancing the differences between tone categories. The expressive versions differed from the neutral versions with respect to a number of acoustic characteristics. In the expressive versions, the structure and the tone category differences were marked more clearly. Furthermore, the singer emphasized semantically important words in the lyrics in the expressive versions. Comparing the means used by the singer for the purpose of emphasis with those used by a professional actor and voice coach revealed striking similarities.
Adaptive Dispersion in Vowel Perception
Authors: Johnson Keith
Published: April 2003

The ‘hyperspace effect’ in vowel perception may be taken as evidence that adaptive dispersion is an active perceptual process. However, a previous study tested for adaptive dispersion in isolated vowel stimuli spoken in a voice unfamiliar to the listeners. The experiment reported in this paper addressed both of these potential concerns and found that both consonant context and talker familiarity modulate the hyperspace effect. However, the reductions induced by context and familiarity were slight. Listeners’ preferred perceptual spaces remained hyperarticulated relative to the production vowel space.
Clonal Cytogenetic Abnormalities in Pediatric Brain Tumors: Cytogenetic Analysis and Clinical Correlation
Authors: Thangavelu M. , Turina J. , Tomita T. , Chou P.M.
Published: April 2003

The use of contemporary techniques in genetics has resulted in identifying a number of recurring abnormalities in pediatric brain tumors. This information has potential significance in the diagnosis and subtyping of these tumors. Although recurring genetic alterations have been identified in specific tumor types, there are some indications that pediatric brain tumors may be different cytogenetically from adult tumors. In addition, cytogenetic aberrations in certain tumors are associated with unfavorable outcome. In this report we present the cytogenetic characteristics of 14 brain tumors. The clinical outcome is correlated with cytogenetic abnormalities. Clonal abnormalities were observed in 6 of 14 (43%) tumors. All 7 cases had abnormalities specific to histologic subtype. Five of 6 cases with clonal abnormalities (83%) and 2 of 8 with a normal karyotype (25%) were observed in patients with poor prognosis. We also describe the cytogenetic aberrations associated with progression in a rare pediatric brain tumor. This data suggests that cytogenetic analysis of pediatric brain tumors may not be entirely different from their adult counterpart and like the latter may be clinically relevant not only in diagnosis but also as a prognostic indicator.
Intraparenchymal Clear Cell Meningioma of the Brainstem in a 2-Year-Old Child
Authors: Teo Jennifer G.C. , Goh Keith Y.C. , Rosenblum Marc K. , Muszynski Cheryl A. , Epstein Fred J.
Published: April 2003

We report an unusual case of an intraparenchymal clear cell meningioma of the brainstem, occurring in a 22-month-old girl. She presented with bulbar dysfunction and a right hemiparesis due to an intrinsic tumor of the medulla, which was confirmed by radiologic imaging to be focal and with an exophytic component. At surgery, a partial resection was achieved and no dural attachment was found. Pathologic examination revealed a clear cell meningioma. In reviewing the literature, there have been fewer than 20 reported cases of clear cell meningioma, none of which were intraparenchymal, involved the brainstem or occurred in such a young patient. The pathologic findings, treatment options and present understanding of this tumor are discussed.
Clinical Manifestations of Childhood Ependymoma:A Multitude of Syndromes
Authors: Allen Jeffrey C. , Siffert Joao , Hukin Juliette
Published: April 2003

Over 90% of childhood ependymomas arise within the cranium, two-thirds below and one-third above the tentorium, and they comprise 8–10% of all childhood CNS neoplasms. This is in contradistinction to the presentation in adults where over 75% of the ependymomas arise within the spinal canal. The incidence of 2.2 cases per million appears to be increasing over the past 30 years. The biology of the disease resembles that of a low-grade glioma where local control measures are most important and less than 5% of children present with metastatic disease. Thus, total resection is the optimum therapy. The value of adjuvant therapy for children with no postoperative residual disease is unclear. Adjuvant radiotherapy is reserved for children with postoperative residual disease and appears to prolong survival. A brief review of our current understanding of the incidence, sites of origin, clinical presentations, prognostic factors and controversial treatment issues will be presented.
Radiation Exposure in the Myelomeningocele Population
Authors: Gaskill Sarah J. , Marlin Arthur E.
Published: April 2003

Radiation-induced carcinoma is known to occur with lower doses of radiation exposure than previously recognized. The myelomeningocele population, because of its complex medical problems, is exposed to relatively high doses of radiation from diagnostic radiographs performed throughout their lives. To quantify the amount of exposure, we have calculated the total lifetime radiographic exposure for patients in a myelomeningocele clinic. Out of a myelomeningocele clinic of 248 patients, 112 were identified who had been followed in the clinic since birth. A retrospective history of radiographic exposure was obtained for each patient by reviewing the hospital X-ray jackets. Using standard radiographic dose tables, calculations of total radiation exposure were performed for each patient. The total skin dose exposure ranged from 3.96 to 171.29 rad with a mean of 42.99 rad (SD 33.58). The total skin dose per year of life ranged from 0.79 to 37.81 rad/year of life with a mean of 6.38 rad/year of life (SD 5.72). The total red marrow dose ranged from 0.3 to 29.04 rad with a mean of 7.02 rad (SD 6.24). The total red marrow dose per year of life ranged from 0.1 to 5.35 rad/year of life with a mean of 1.01 rad/year of life (SD 1.06). These data suggest that the radiation burden from diagnostic radiographs in the myelomeningocele population may ultimately contribute to carcinogenesis, mutagenesis and other radiation damage. Specific strategies for reducing the lifetime radiographic exposure in these patients are discussed in detail.
Intraventricular Pressure Dynamics in Patients with Ventriculopleural Shunts: A Telemetric Study
Authors: Munshi Ilyas , Lathrop Dawn , Madsen Joseph R. , Frim David M.
Published: April 2003

Extracranial CSF shunting to the pleural absorptive surface is sometimes used as an alternative to ventriculoperitoneal shunting. The pressure dynamics of this type of shunt would be expected to differ from peritoneal shunting due to active changes in pleural pressures caused by the ventilatory cycle. We have had opportunity to examine the in vivo intraventricular pressure (IVP) dynamics of ventriculopleural shunts utilizing a commercially available implantable telemonitor (Telesensor; Radionics, Burlington, Mass.). Four patients with ventriculopleural shunts were monitored telemetrically while supine and at increments of head elevation to 90°. Two patients with ‘medium’ grade differential pressure valves exhibited IVPs which were never greater than zero. One patient with an in-line antisiphoning device in the shunt system appeared to have IVPs closely resembling those seen in shunting to the peritoneal space. Another patient with valve opening pressure set at 19 cm of water consistently had supine intraventricular pressures less than 10 cm of water that readily fell to zero with minimal head elevation. We conclude that the negative intrapleural pressures generated by the ventilatory cycle tend to cause IVPs in ventriculopleural shunts to be lower than those expected in peritoneal shunting. This observation suggests that ventriculopleural shunts may be appropriate for patients requiring very low intraventricular pressures in order to resolve their hydrocephalic symptoms.
Pediatric Brain Tumors in a 10-Year Period from 1986 to 1995 in Yamaguchi Prefecture: Epidemiology and Comparison with Adult Brain Tumors
Authors: Nomura Sadahiro , Nishizaki Takafumi , Yamashita Katsuhiro , Ito Haruhide
Published: April 2003

The epidemiology of pediatric brain tumor was studied in a 10-year period from 1986 to 1995 in Yamaguchi prefecture. The total number of pediatric brain tumors was 83, and the incidence was 2.5/100,000/year, which did not change during the period. The sign most frequently seen was intracranial hypertension, whereas focal signs were less frequent. Although asymptomatic cases increased in this period, outcomes did not improve. Significant differences between pediatric and adult cases were the percentage of male patients (70.0 vs. 43.7%), tumor location on the midline (59.0 vs. 20.8%) and tumor location in the posterior fossa (44.6 vs. 26.3%). The midline location of many pediatric brain tumors results in the absence of focal signs, which delays the diagnosis and makes surgery difficult.