bluuebunny/crossref_metadata_2025 huggingface dataset:
The Na+/H+ Exchanger SM-20220 Attenuates Ischemic Injury in in vitro and in vivo Models
Authors: Horikawa Naotsugu , Nishioka Mizue , Itoh Natsuko , Kuribayashi Yoshikazu , Matsui Kazuki , Ohashi Naohito
Published: April 2003

The aim of this study is to clarify whether the activation of a Na+/H+ exchanger (NHE) is tightly concerned with neuronal and glial cell injury induced by ischemia using a selective NHE inhibitor, SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate). Two hours of hypoxia followed by 24 h of reoxygenation induced lactate dehydrogenase (LDH) release, a marker of cell membrane damage, in cultured neurons and glia derived from rats. SM-20220 significantly reduced LDH release in both cells in a concentration-dependent manner, and this effect was statistically significant at concentrations of more than 10–8 mol/l for neurons and 10–7 mol/l for glia. A standard NHE inhibitor, 5-(N-ethyl-N-isopropyl)-amiloride, also reduced LDH release in neurons at concentrations of more than 10–7 mol/l. In a rat transient middle cerebral artery occlusion model, intravenous infusion of SM-20220 reduced cerebral infarction when the serum concentration of SM- 20220 was maintained at about 10–7 mol/l. These results suggest that the activation of the NHE plays an important role in ischemic neuronal and glial cell injury, and NHE inhibitor may have good therapeutic value for the treatment of ischemic stroke.
Characterization of Ascaris-Induced Biphasic Skin Allergic Reaction Model in Mice: Possible Roles of Mast Cells in Early-Phase and CD4-Positive T Cells in Late-Phase Reactions
Authors: Sengoku Takanori , Sato Sachio , Sakuma Shozo , Ogawa Toshikazu , Ohkubo Yoshitaka , Goto Toshio
Published: April 2003

We established an Ascaris-induced biphasic skin allergic reaction in mice. In the early-phase reaction (EPR), mast cell degranulation was observed, and tranilast inhibited ear edema. In mast-cell-deficient mice (WBB6F1-W/WV mice), ear edema in the EPR disappeared, whereas that in the late-phase reaction (LPR) remained. Eosinophils increased, and CD4-positive T cells tended to increase in the LPR. Anti-CD4 antibody, anti-IL-4 antibody and anti-IL-5 antibody all inhibited ear edema and had a tendency to inhibit eosinophil infiltration in the LPR. These data suggest that the EPR is induced by histamine released from mast cells, whereas the LPR is induced by IL-4 and IL-5 produced from CD4-positive T cells.
Angiotensin-Induced Enhancement of Excitatory Junction Potentials Evoked by Periarteriolar Nerve Stimulation and Vasoconstriction in Rat Mesenteric Arteries Are Both Mediated by the Angiotensin AT1 Receptor
Authors: Ziogas James , Vessey Kirstan
Published: April 2003

The aims of the present study were to determine the angiotensin II (AngII) receptor subtype(s) involved in vasoconstriction and enhancement of sympathetic neurotransmission in rat isolated mesenteric arteries. Vasoconstriction was assessed in mesenteric artery ring preparations suspended under 0.5 g of tension in a myograph. In control arteries, with an intact endothelium, AngII (1 nmol/l–3 µmol/l) caused a concentration-dependent contraction. The pEC50 for AngII was 7.6 ± 0.2 and the maximum response of 0.24 ± 0.07 g was reached with 100 nmol/l. In the presence of indomethacin (3.0 µmol/l) and Nω-nitro-L-arginine (NOLA) (100 µmol/l) to remove the influence of endothelium-derived prostaglandins and nitric oxide, the maximum response evoked by AngII was increased to 0.48 ± 0.1 g and the pEC50 was 7.6 ± 0.3. The AT1 receptor antagonist losartan (30 nmol/l) competitively blocked the AngII-induced contractions with an estimated pA2 of 8.2 in both the control arteries and in arteries treated with indomethacin and NOLA. The AT2 receptor antagonist PD 123319 (1 µmol/l) did not affect AngII-induced contractions under either condition. Conventional intracellular microelectrode recording techniques were used to investigate the effects of AngII on excitatory junction potentials (EJP) evoked by stimulation of periarteriolar sympathetic nerves. Stimulation with trains of 10 pulses delivered at 0.9 Hz evoked EJP which were blocked by tetrodotoxin (0.1 µmol/l), guanethidine (30 µmol/l) and the P2X receptor desensitizing agent α,β-methylene ATP (30 µmol/l) suggesting the EJP were mediated by ATP, or a related purine, released from sympathetic nerves. AngII (0.3– 100 nmol/l) did not affect the resting membrane potential or the amplitude of the first EJP, but did enhance the amplitude of the plateau EJP later in the train. A maximum 49.2 ± 3.9% enhancement of the plateau EJP amplitude was elicited by 10 nmol/l AngII and the pEC50 was 9.1 ± 0.1. The facilitatory effect of AngII on EJP amplitude was not altered in the presence of indomethacin and NOLA. Losartan (30 nmol/l) competitively blocked the AngII-induced enhancement of plateau EJP amplitude, with an estimated pA2 of 8.6. PD 123319 did not alter the enhancement of plateau EJP amplitude by AngII. The results from the present study show that both the vasoconstriction and enhancement of plateau EJP amplitude by AngII in rat mesenteric arteries are blocked by the AT1 receptor antagonist losartan and are unaffected by the AT2 receptor antagonist PD 123319.
Enhanced Relaxation to the Rho-Kinase Inhibitor Y-27632 in Mesenteric Arteries from Mineralocorticoid Hypertensive Rats
Authors: Weber Davis S. , Webb R. Clinton
Published: April 2003

Increased vasoconstriction is characteristic of hypertension. In this study, we tested the hypothesis that changes in vascular responses during mineralocorticoid hypertension may be due to increased activation of the Rho/Rho-kinase pathway. To test this, relaxation responses to the Rho-kinase inhibitor Y-27632 were determined by measuring isometric force in deendothelialized mesenteric arteries from mineralocorticoid-hypertensive rats and sham-operated controls. Following agonist-induced contraction by serotonin (5-HT, 5-hydroxytryptamine), arteries from hypertensive rats demonstrated a greater relaxation to the Rho-kinase inhibitor Y-27632 (65 ± 5% vs. 28 ± 10%). Treatment with an EC50 concentration of Y-27632 following a KCl-induced contraction caused minimal relaxation of arteries in both groups of animals. These findings suggest that augmented Rho-kinase activity in the vasculature of mineralocorticoid hypertensive rats may contribute to the enhanced vascular reactivity of agonist-mediated stimuli characteristic of this model of hypertension.
Neuromuscular Blocking Effects of the Aminoglycoside Antibiotics Arbekacin, Astromicin, Isepamicin and Netilmicin on the Diaphragm and Limb Muscles in the Rabbit
Authors: Liu Mingji , Kato Masato , Hashimoto Yasuhiko
Published: April 2003

Aminoglycoside antibiotics are known to produce a depression of neuromuscular function which may cause prolonged paralysis of respiratory muscles. However, differences in the effects of aminoglycoside antibiotics on diaphragm and limb muscles have not been investigated. We determined the neuromuscular blocking effects of the aminoglycoside antibiotics arbekacin sulfate, astromicin sulfate, isepamicin sulfate and netilmicin sulfate on the diaphragm, tibialis anterior and soleus muscles in anesthetized rabbit nerve-muscle preparations. Neuromuscular block was assessed by mechanical response with single twitch stimulation. Cumulative drug dose-response curves were obtained for three different muscles in 24 rabbits. The mean ED50 and ED95 of the antibiotics in diaphragm, tibialis anterior and soleus muscles were calculated. The neuromuscular blocking effects of all the aminoglycosides on ED50 and ED95 values were in the order of soleus > tibialis anterior > diaphragm, and soleus > diaphragm > tibialis anterior, respectively. The ED50 ratios for the tibialis anterior and soleus muscles were approximately 1.5 and 2.7 times greater than that for the diaphragm.
Effects of Adenosine on Thrombosis and Thrombolysis in a Canine Experimental Preparation
Authors: Huang Jinbao , Feldbaum Victor M. , Lucchesi Benedict R. , Werns Steven W.
Published: April 2003

Intracoronary infusion of adenosine is reported to inhibit cyclic flow variations after coronary artery injury and stenosis. This study was performed in the anesthetized dog to determine if adenosine prevents arterial thrombosis and/or reocclusion after thrombolysis. Carotid and coronary arteries were instrumented with DopplerTM flow probes, a critical stenosis, infusion line and an anodal electrode. Two protocols were employed. In the thrombosis protocol, intracarotid infusion of adenosine (20 µg/kg/min for 3 h) did not alter cyclic flow variations or patency during induction of vessel wall injury. In the second protocol, occlusive arterial thrombi were induced by anodal current injury and lysed with local application of tissue plasminogen activator. Whereas adenosine prolonged the time to arterial occlusion, it did not affect cyclic flow variations or time to reocclusion after thrombolysis.
Muscarinic Receptor Subtypes Mediating Vasorelaxation of the Perforating Branch of the Human Internal Mammary Artery
Authors: Pešić S. , Jovanović A. , Grbović L.
Published: April 2003

The effect of acetylcholine (ACh) on the isolated perforating branch of the human internal mammary artery (HIMA) was investigated. ACh induced concentration- and endothelium-dependent relaxation of arterial rings precontracted with phenylephrine (pEC50 = 6.93 ± 0.01). The muscarinic receptor antagonist atropine (no selectivity), pirenzepine (M1), methoctramine (M2), and p-fluoro-hexahydro-siladifenidol (M1/M3) competitively antagonized the response to ACh. The pA2 values were 9.81 ± 0.15, 7.74 ± 0.08, 6.27 ± 0.08, and 7.88 ± 0.04, respectively. In conclusion, this study has shown that ACh induced an endothelium-dependent relaxation of the perforating branch of the HIMA by stimulation of muscarinic receptors on the endothelial cells. On the basis of differential antagonist affinity, we suggest that the muscarinic receptors involved in the ACh-induced relaxation of the isolated perforating branch of HIMA are predominantly of M1 subtype.
Thapsigargin-Induced Calcium Entry and Apoptotic Death of Neutrophils Are Blocked by Activation of Protein Kinase C
Authors: Lucas Miguel , Díaz Pilar
Published: April 2003

Intracellular free calcium ([Ca2+]i) concentration, free oxygen radical (FOR) production, DNA breakdown, and plasma membrane phosphorylation were studied in human neutrophils activated with thapsigargin and phorbol myrisate acetate (PMA). Thapsigargin produced a rapid and sustained rise of [Ca2+]i, activated the endonuclease, and caused the breakdown of the neutrophil’s DNA with a half-time close to 6 h. The protein kinase C activator PMA failed to inhibit the initial rise of [Ca2+]i, but inhibited the second phase of thapsigargin-induced calcium transient and completely blocked the activation of the endonuclease induced by thapsigargin. Thapsigargin induced a minor and delayed production of FOR, whereas PMA caused an abrupt and sustained FOR production that was enhanced by thapsigargin. Two plasma membrane proteins close to 50 and 64 kD were phosphorylated in PMA-activated neutrophils. These results suggest that the nonphosphorylated form of the membrane protein permits basal and thapsigargin-induced calcium entry. Phosphorylation by PMA of plasma membrane protein inhibits calcium uptake in both resting and thapsigargin-activated neutrophils and contributes to the block of the activation of the apoptotic endonuclease.
Ketoprofen-Induced Cyclooxygenase Inhibition in Renal Medulla and Platelets of Rats Treated with Caffeine
Authors: Sommerauer Martin , Ates Mehmet , Gühring Hans , Brune Kay , Amann Rainer , Peskar Bernhard A.
Published: April 2003

It has been suggested that caffeine can augment analgesic activity and aggravate side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of the present study was to investigate a possible interaction between ketoprofen and caffeine on prostaglandin (PG) biosynthesis and cyclooxygenase (COX) mRNA expression in the rat renal medulla ex vivo. Treatment of rats with ketoprofen (60 min before) resulted in a dose-dependent (estimated ID50 0.3 mg/kg p.o.) reduction of PGE2 biosynthesis in renal medulla ex vivo. Ketoprofen (0.3 mg/kg)-induced inhibition of PGE2 biosynthesis was stable between 30 and 180 min and still detectable 300 min after drug administration. Caffeine (10 mg/kg) did not cause a detectable effect on its own, nor did it significantly affect ketoprofen-induced inhibition of renal medullary PGE2 biosynthesis. Similar results were obtained with repeated daily drug administration for 1 week: there was no significant effect of caffeine on ketoprofen-induced inhibition of renal medullary PGE2 biosynthesis. The absence of significant caffeine effects on ketoprofen-induced inhibition of renal medullary PGE2 biosynthesis was paralleled by experiments showing no significant effect of caffeine on ketoprofen-induced inhibition of platelet thromboxane (TX)B2 biosynthesis. Additional experiments showed increased COX-2 mRNA expression in the renal medulla 60 min after ketoprofen administration, that was not significantly influenced by concomitant caffeine treatment. Treatment of rats with ketoprofen for 1 week had no significant effects on COX-2 mRNA expression. The present results show that ketoprofen caused inhibition of PGE2 biosynthesis in the rat renal medulla ex vivo with a potency similar to that reported for in vivo models suggesting that the ex vivo approach is a valid model to test a possible interference of caffeine with ketoprofen-induced COX inhibition. The absence of detectable effects of caffeine on time course or magnitude of ketoprofen-induced suppression of PGE2 biosynthesis in this model indicates, therefore, that possible adverse actions of co-administered caffeine on renal function are not related to interference with renal COX inhibition.
Progress in the Search for Ideal Drugs
Authors: Spector Reynold
Published: April 2003

The search for ideal drugs to improve patient care requires applications of modern scientific methods to both discovery and development. Using these modern methods, the pharmaceutical industry with strong academic and government collaboration has introduced in the last 25 years many new drugs that approach the ideal. After reviewing Björnsson’s classification of drug action and the notion of contributory causality, this commentary defines an ideal drug from the perspectives of pharmacodynamics, pharmacokinetics, and therapeutics. Examples of new drugs for hypertension, heart disease, stroke, osteoporosis, asthma, ulcer, and migraine headaches are described. Finally, the profound implications of progress in developing ideal drugs not only for the patient but also for the academic, educational, and regulatory establishments are briefly reviewed.
Reduction of Submissive Behavior in Rats: A Test for Antidepressant Drug Activity
Authors: Malatynska Ewa , Goldenberg Rachel , Shuck Lucy , Haque Arif , Zamecki Paula , Crites Glenda , Schindler Nancy , Knapp Richard J.
Published: April 2003

Randomly paired rats were food deprived overnight and placed in an apparatus compelling them to compete for a food reward. About half of these pairs developed a dominant-submissive relationship measured as a significant difference in time spent on the feeder by each rat. This relationship developed over a 2-week period and remained stable for at least the next 5 weeks. Treatment of the submissive subjects, for at least 2 weeks, with imipramine, desipramine, or fluoxetine (10 mg/kg) significantly reduced submissive behavior. The effect faded after cessation of treatment with desipramine. Fluoxetine was further tested at 2.5- and 5-mg/kg doses and showed a dose-dependent reduction of submissive behavior. Treatment of submissive rats with the anxiolytic diazepam (1 mg/kg) was ineffective. The prevalence of dominant-submissive relationships and the effect of desipramine and imipramine on submissive behavior were gender independent. The predictive, face, and construct validity of the behavioral test is discussed.
Effect of Rebamipide on Cell Death Induced by Combined Treatment of Mild Heat Shock and Quercetin in RGM-1 Cells: A Role for HSP70 Induction
Authors: Tsukimi Yasuhiro , Fujishita Teruaki , Nakajima Kenji , Okabe Susumu
Published: April 2003

The mechanism by which rebamipide inhibits cell death induced by combined treatment of mild heat shock and quercetin in RGM-1 cells was examined. Cells were incubated at 42°C for 1 h with or without quercetin. Expression of HSP70 was detected by immunoblot analysis and cell viability was determined by the MTT method. Upon treatment of cells with heat shock in the presence of quercetin, cell viability was significantly decreased 24 h after heat shock, with strong inhibition of HSP70 expression. Rebamipide suppressed both cell death and a reduction in HSP70 induced by the combined treatment of heat shock and quercetin. The combination of heat shock and quercetin resulted in DNA fragmentation, but rebamipide managed to inhibit such fragmentation. The protective effect of rebamipide was eliminated by cycloheximide or actinomycin D. Based upon these findings, it was concluded that rebamipide inhibited cell death resulting from combined treatment of mild heat shock and quercetin. The protective action of rebamipide appears to be at least partially due to maintenance of the HSP70 level.
Cyclo-Oxygenase- and Capsaicin-Sensitive Afferent Fibres Affect Beta-Adrenoceptor-Evoked Response in the Rat Urinary Bladder
Authors: Tucci P. , Bartocci C. , Bolle P.
Published: April 2003

As reported previously, the beta-adrenoceptor-evoked response in the in vitro rabbit detrusor is inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins can restore this response. This study was designed to better define physiological influences on beta-adrenoceptors in the urinary bladder and to ascertain whether the observations made in the rabbit urinary bladder in vitro were valid in vivo, as well as in a different animal species, i.e. in the rat. The NSAID indometacin partially inhibited the isoproterenol-evoked response in the rat detrusor muscle. When the neurokinin A (NKA) antagonist MEN-10376 was administered after indometacin, the beta-adrenoceptor-evoked response was completely abolished. The isoproterenol-evoked beta response was dose dependently reduced following treatment with the capsaicin antagonist ruthenium red. Taken together, these data indicate an involvement of prostanoids, NKA- and capsaicin-sensitive fibres in the beta-adrenoceptor-evoked response in the rat urinary bladder.
Effect of 17β-Estradiol on Intracellular Ca2+ Levels in Renal Tubular Cells
Authors: Chen Wei-Chuan , Cheng Jin-Shiung , Chou Kang-Ju , Tang Kwong-Yui , Huang Jong-Khing , Tseng Li-Ling , Wang Jue-Long , Lee Kam-Chung , Jan Chung-Ren
Published: April 2003

The effect of 17β-estradiol on intracellular Ca2+ concentrations ([Ca2+]i) in Madin Darby canine kidney cells was investigated by using the fluorescent dye fura-2. 17β-Estradiol (5–100 µmol/l) induced instantaneous increases in [Ca2+]i in a concentration-dependent manner. Ca2+ removal inhibited 45 ± 15% of the Ca2+ signal. In Ca2+-free medium, pretreatment with 50 µmol/l 17β-estradiol abolished the [Ca2+]i increases induced by 2 µmol/l carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler), 1 µmol/l thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) and 50 µmol/l brefeldin A (an antibiotic which disperses the Golgi complex), but pretreatment with brefeldin A, CCCP and thapsigargin only partly inhibited the 17β-estradiol-induced [Ca2+]i signal. Adding 3 mmol/lCa2+ increased [Ca2+]i in cells pretreated with 5–100 µmol/l 17β-estradiol in Ca2+-free medium. Pretreatment with 1 µmol/l U73122 to abolish the formation of inositol-1,4,5-trisphosphate inhibited 50% of the Ca2+ release induced by 50 µmol/l 17β-estradiol. 17β-Estradiol (20 µmol/l) also increased [Ca2+]i in human bladder cancer cells and prostate cancer cells. Collectively, this study shows that 17β-estradiol evoked a significant internal Ca2+ release and external Ca2+ entry possibly in a nongenomic manner.
Cyclic GMP-Induced Reduction in Cardiac Myocyte Function Is Partially Mediated by Activation of the Sarcoplasmic Reticulum Ca2+-ATPase
Authors: Zhang Qihang , Yan Lin , Weiss Harvey R. , Scholz Peter M.
Published: April 2003

We tested the hypothesis that the mechanism through which cyclic GMP reduces cardiac function is mediated by activation of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Cardiac myocytes were isolated from New Zealand white rabbits (n = 11). Individual ventricular cells were stimulated by electrical field stimulation. The maximal rate of cell shortening and percentage shortening were measured with a video edge detector. Thapsigargin (10–8 mol/l) was used as a specific inhibitor of SERCA. When 8-bromo-cyclic GMP (8-Br-cGMP, 10–7, –6, –5 mol/l) was added to cells, the maximal rate of myocyte shortening (Rmax, µm/s) and percentage shortening were both decreased in a concentration-dependent manner. Rmax decreased 27% from 117 ± 12 at baseline to 85.2 ± 13 when 10–5 mol/l of 8-Br-cGMP was present, and percent shortening was reduced 28% from 6.0 ± 0.5 to 4.3 ± 0.5%. Thapsigargin (10–8 mol/l) increased the maximal rate of myocyte shortening and percent shortening. Addition of thapsigargin prior to 8-Br-cGMP reduced the negative effects of cGMP on myocyte function. The percent shortening decreased only 11% and Rmax decreased 14% with 10–5 mol/l 8-Br-cGMP, which was not significant. Cyclopiazonic acid, another SERCA inhibitor, was also used to test whether 8-Br-cGMP reduced myocyte function through SERCA. The results were similar to those when thapsigargin was used. These results indicated that the cyclic GMP-induced reduction in cardiac myocyte function was partially mediated through the action of the sarcoplasmic reticulum Ca2+-ATPase.
Nitric Oxide Stimulates Adrenomedullin Secretion and Gene Expression in Endothelial Cells
Authors: Dötsch J. , Schoof E. , Hänze J. , Dittrich K. , Opherk P. , Dumke K. , Rascher W.
Published: April 2003

Adrenomedullin, a peptide with vasorelaxant activity, stimulates nitric oxide (NO) synthesis. We tested whether or not NO regulates the function of the adrenomedullin system. Human umbilical vein endothelial cells (HUVEC) were incubated with the NO donors sodium nitroprusside (SNP), morpholinosydnonimine (SIN-1) and the phospodiesterase V inhibitor zaprinast. In HUVEC, adrenomedullin concentration in the supernatant was measured by radioimmunoassay and mRNA expression was studied by Northern blot and competitive quantitative PCR. SNP, SIN-1, and zaprinast (100 µmol/l each) significantly increased adrenomedullin concentration in the supernatant of HUVEC twofold. The same concentrations increased adrenomedullin mRNA expression four- to tenfold. Similar results were obtained by both quantitative PCR and Northern blot. Thus, NO donor exposure in vitro increases both adrenomedullin secretion and mRNA expression in a dose-dependent manner.
Regulation of Endothelin-1 Production in Deoxycorticosterone Acetate- Salt-Treated Endothelial Cells
Authors: Yu Wen-Jen , Tomlinson Brian , Cheng Juei-Tang
Published: April 2003

The aim of this study was to investigate the direct effect of deoxycorticosterone acetate (DOCA) on the expression of endothelin-1 (ET-1) mRNA and production of ET-1 peptides in cultured bovine carotid endothelial cells (BCEC) and human umbilical vein endothelial cells (HUVEC). The mineralocorticoid, DOCA, was administered to BCEC and HUVEC with or without additional salt (200 mmol/l). The ET-1 mRNA was elevated to 150% and 180% after a 24-hour incubation with DOCA (5 µmol/l) in BCEC and HUVEC, respectively. Intracellular content of ET-1 peptides of BCEC and HUVEC was increased from 21.66 ± 0.3 to 23.64 ± 0.19 fmol/105 cells and from 8.38 ± 0.82 to 11.26 ± 0.91 fmol/105 cells, respectively, in the DOCA-conditioned medium. Also, DOCA treatment for 24 h increased the secretion of ET-1 peptide from 1.62 ± 0.17 to 5.33 ± 0.67 fmol/105 cells in BCEC and from 0.95 ± 0.08 to 3.56 ± 0.36 fmol/105 cells in HUVEC. In DOCA-salt-treated endothelium, regulation of ET-1 gene was similar to that with DOCA alone. The DOCA-induced increase in expression of ET-1 mRNA and the ET-1 peptide level were both diminished in dexamethasone (DEX, 10 nmol/l)- or mifepristone (RU486, 0.5 µmol/l)-treated endothelium. These results suggest that DOCA directly increased the ET-1 mRNA expression in endothelium and could be mediated in part by a glucocorticoid receptor pathway which was independent of salt and hyperosmolarity.
Acetylcholine-Induced Contractions in the Perforating Branch of the Human Internal Mammary Artery: Protective Role of the Vascular Endothelium
Authors: Pešić S. , Grbović L. , Jovanović A.
Published: April 2003

The effect of acetylcholine (ACh) on the isolated, nonprecontracted perforating branch of the human internal mammary artery (HIMA) was investigated. ACh induced concentration-dependent contractions of nonprecontracted rings with denuded endothelium (pEC50 = 6.72 ± 0.02, Emax = 88.8% of contractions induced by phenylephrine, 10–5 mol/l) and was without effect on arterial segments with intact endothelium. An inhibitor of nitric oxide synthase, NG-monomethyl-L-arginine (L-NMMA), or indometacin, a cyclooxygenase inhibitor, had no effect on acetylcholine-induced contractions of rings of the perforating branch of HIMA with denuded endothelium (pEC50 = 6.76 ± 0.03 and 6.62 ± 0.05, respectively). In the presence of indometacin, ACh did not evoke contractions of arterial segments with intact endothelium. In contrast, in the same type of preparations ACh induced contractions in the presence of L-NMMA (Emax = 34%). The muscarinic receptor antagonists atropine (no selectivity), pirenzepine (M1), methoctramine (M2), and p-fluoro-hexahydro-sila-difenidol (M1/M3) competitively antagonized the response to ACh. The pA2 values were 9.60 ± 0.10, 6.99 ± 0.02, 6.37 ± 0.17, and 8.02 ± 0.06, respectively. In conclusion, the results obtained indicate that secretion of nitric oxide from vascular endothelium may protect the perforating branch of HIMA against the contractile effects of ACh. On the basis of differential antagonist affinity, it can be suggested that the muscarinic receptors involved in the ACh-induced contractions of the isolated perforating branch of the HIMA are predominantly of the M3 subtype.
Effect of Captopril on Urinary Kallikrein, Blood Pressure and Myocardial Hypertrophy in Diabetic Spontaneously Hypertensive Rats
Authors: Sharma Jagdish N. , Kesavarao Uma
Published: April 2003

We investigated the total urinary kallikrein levels, left-ventricular wall thickness and mean arterial blood pressure of nontreated and captopril-treated diabetic and nondiabetic spontaneously hypertensive rats. The mean arterial blood pressure was significantly elevated in diabetic spontaneously hypertensive rats as compared to nondiabetic spontaneously hypertensive rats. Captopril treatment caused a significant reduction in the arterial blood pressure of both nondiabetic and diabetic spontaneously hypertensive rats. The left-ventricular wall thickness was also significantly reduced in diabetic and nondiabetic spontaneously hypertensive treated with captopril as compared to nontreated diabetic and nondiabetic spontaneously hypertensive rats. The total urinary kallikrein levels were significantly raised in captopril-treated diabetic and nondiabetic spontaneously hypertensive rats against the values obtained from nontreated diabetic and nondiabetic spontaneously hypertensive rats. These results indicate that blood pressure reduction and left ventricular wall regression with captopril treatment might be due to enhanced renal kallikrein formation. The significance of these findings is discussed.
Influence of Estrogen and/or Progesterone on Isolated Ovariectomized Rat Uterus
Authors: Accorsi-Mendonça D. , Corrêa F.M.A. , Anselmo-Franci J.A. , de Oliveira A.M.
Published: April 2003

Steroids hormones can influence several functions of the uterus, including agonist-induced contractions. The aim of this work is to study the influence of hormonal replacement on angiotensin II (Ang II) and losartan responsiveness on the isolated rat uterus. The Ang II pD2 values are: 9.69 ± 0.07 for vehicle-treated animals, 8.85 ± 0.06 for estrogen-treated animals, 10.12 ± 0.03 for progesterone-treated animals and 8.90 ± 0.03 for estrogen-and-progesterone-treated animals. The losartan pD2’ values are: 8.43 ± 0.03 for vehicle-treated animals, 8.21 ± 0.03 for estrogen-treated animals, 7.83 ± 0.05 for progesterone-treated animals and 8.70 ± 0.09 for estrogen-and-progesterone-treated animals. There is not a correlation between Ang II pD2 and losartan pD2’ values, suggesting that the hormones affect Ang II and losartan binding by different mechanisms in rat uterus.
Role of GS Proteins in Hypoxic Constriction of Sheep Pulmonary Artery Rings
Authors: Uzun Özge , Demiryürek A. Tuncay , Kanzık İlker
Published: April 2003

The introduction of hypoxia is well known to cause contraction of pulmonary artery rings in vitro. Despite intensive studies, the cellular mechanisms of hypoxic pulmonary vasoconstriction are still not well defined. In this study, we aimed to determine the contribution of GS proteins in hypoxia-induced vasoconstriction in large-diameter sheep pulmonary arteries using cholera toxin (CT). Hypoxia caused further contractions in serotonin but not in NaF-precontracted pulmonary artery rings. However, hypoxic vasoconstriction due to lowering of pO2 from 97 to 5 mm Hg was totally abolished by preincubation with CT in serotonin-precontracted arteries. These preliminary results indicate that signal transduction mediated by Gs proteins may be an important mechanism in the hypoxic vasoconstriction of isolated pulmonary arteries of sheep.
Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties
Authors: Ioriya Katsuhisa , Noguchi Tsuyoshi , Muraoka Masami , Fujita Katsuya , Shimizu Hiroshi , Ohashi Naohito
Published: April 2003

We investigated the effects of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activities in the liver and intestine, and in macrophages. We measured its effects on the serum cholesterol levels and hepatic cholesterol content in mice, rabbits and hamsters. SMP-500 inhibited ACAT activities in rabbit liver and small intestine microsomes with IC50 values of 72 and 84 nmol/l, respectively, and acted as a competitive inhibitor of rabbit liver ACAT. SMP-500 potently inhibited cholesterol esterification in rat peritoneal macrophages (IC50 = 15 nmol/l). In high-fat and high-cholesterol diet-fed mice and in high-cholesterol diet-fed rabbits, SMP-500 reduced the serum cholesterol levels and the hepatic cholesterol content. SMP-500 also reduced the serum and hepatic cholesterol in normal chow-fed hamsters in a dose-dependent manner. In all the animal models, SMP-500 reduced the hepatic free cholesterol content as well as the total and esterified cholesterol. Administered orally, SMP-500 had a direct inhibitory effect on hepatic ACAT activity. These results indicate that SMP-500 is a potent and competitive ACAT inhibitor and may have a therapeutic potential for treating hypercholesterolemia and atherosclerosis.
Desensitization of α2-Adrenoceptors which Regulate Noradrenaline Synthesis and Release after Chronic Treatment with Clorgyline in the Rat Brain
Authors: Prieto Mónica , Giralt M. Teresa
Published: April 2003

The sensitivity of α2-adrenoceptors which regulate synthesis and release of noradrenaline was investigated in hippocampus, parietal cortex, and hypothalamus of rats treated with clorgyline. After administering a DOPA decarboxylase inhibitor, the in vivo tyrosine hydroxylase activity and the noradrenaline content were evaluated. Acute and chronic treatment with clorgyline led to both increases of noradrenaline levels and decreases of tyrosine hydroxylase activity, determined as the accumulation of DOPA. Whereas the α2-adrenoceptor agonist clonidine induced a similar reduction in tyrosine hydroxylase activity in the group subjected to the acute treatment and in the control group, it failed to do so after chronic clorgyline treatment. In hippocampal and cortical synaptosomes, a reduction in the sensitivity of α2-adrenoceptors which regulate [3H]noradrenaline release, reflected by the shift to the right of the concentration-effect curves for oxymetazoline, was also found after the repeated treatment. These results indicate a desensitization of α2-adrenoceptors after chronic treatment with clorgyline.
Effects of Nipradilol on Alpha-Adrenoceptor Function in Ocular Arteries
Authors: Okamura Tomio , Fujioka Hideyuki , Ayajiki Kazuhide
Published: April 2003

The effects of nipradilol, a drug used in the treatment of glaucoma, on the contractions induced by noradrenaline and phenylephrine in isolated dog central retinal, external and internal ophthalmic arteries and pig ciliary arteries were investigated. In dog ocular arteries treated with oxyhemoglobin (1.6 × 10–5 mol/l) to adsorb nitric oxide, noradrenaline (2 × 10–8 to 10–5 mol/l) produced a concentration-related contraction which was markedly inhibited by prazosin but not by yohimbine. Nipradilol (10–9 to 10–7 mol/l) slightly but significantly inhibited the noradrenaline-induced contraction in a concentration-related manner, but the inhibitory potency and efficacy were much less than those of prazosin. However, nipradilol inhibited the phenylephrine-induced contraction with a similar PA2 value of prazosin. In pig ciliary arteries treated with oxyhemoglobin, noradrenaline-induced contraction was slightly inhibited by prazosin but markedly inhibited by yohimbine. Nipradilol, similarly to timolol, did not inhibit, but rather tended to potentiate, the contraction elicited by noradrenaline. The contraction induced by phenylephrine was significantly inhibited by prazosin and nipradilol. It is concluded that nipradilol acts as an α1-adrenoceptor antagonist (but not as an α2-adrenoceptor antagonist) in the ocular arteries, which may partially explain its ocular-pressure-lowering mechanism. Taken together with the results of our previous studies, the potencies of the nipradilol-induced vascular actions in ocular arteries are found to be in the following order: β-adrenoceptor inhibition > α1-adrenoceptor inhibition ≒ direct vasodilation via a release of nitric oxide.
An X-Ray Investigation of Pharyngeal Constriction in American English Schwa
Authors: Gick Bryan
Published: April 2003

A study of early X-ray footage of 4 subjects was conducted to test the prediction that there may be a midpharyngeal constriction in American English schwa. Results show a significant constriction during schwa relative to lingual rest position for all 4 speakers. This evidence contradicts views of American English schwa as having no articulatory target or place features, as well as those which have suggested a neutral target throughout the vocal tract. These findings, however, support claims connecting English schwa with reduced /r/. In addition to the basic effect 1 subject showed a bimodal pattern in schwa, which may indicate that this subject has distinct schwas in lexical vs. functional words, a property that has also been observed with respect to /r/ in r-vocalizing dialects.
Management of Major Depression in the Primary Care Setting
Authors: Mischoulon David , McColl-Vuolo Rachel , Howarth Shauna , Lagomasino Isabel T. , Alpert Jonathan E. , Nierenberg Andrew A. , Fava Maurizio
Published: April 2003

Background: Patients treated in community clinics, particularly those of minority status, may rely more heavily on primary care physicians (PCPs) for the diagnosis and management of depression. We wished to determine how PCPs in a community clinic setting initially manage patients newly diagnosed with major depression. Methods: 698 patients were screened for major depression by the Structural Clinical Interview for DSM-III-R in a community-based primary care health center. Forty outpatients (29 Hispanic) were found to suffer from major depression. A letter explaining positive findings was sent to the patients’ PCPs. Medical record charts were reviewed 3 months later to determine the PCP’s management following the diagnosis. Results: Of the 38 patients who remained in the study at 3 months, 20 (53%) received no intervention from the PCP by the end of 3 months after diagnosis, and of these, 14 were Hispanic. Five (13%) were prescribed an antidepressant by the PCP. Nine (24%) were referred to mental health services for medication, psychotherapy or combination treatment. Four (11%) were prescribed an antidepressant and then referred to mental health services. Differences between management of Hispanic and non-Hispanic patients were not statistically significant. Conclusions: Independent screening by psychiatrists in primary care settings may not be adequate enough to ensure appropriate management of depression by PCPs. Possible explanations may include time constraints during primary care visits, patient and/or physician reticence, and insufficient education of PCPs about depression.
Association of Serum Nitric Oxide Levels with Depressive Symptoms: A Study with End-Stage Renal Failure Patients
Authors: Papageorgiou C. , Grapsa E. , Christodoulou N.G. , Zerefos N. , Stamatelopoulos S. , Christodoulou G.N.
Published: April 2003

Background: Nitric oxide (NO) is a soluble gas produced by the activity of an enzyme found in neurons. It has been implicated in a great number of normal physiological functions (such as noradrenaline and dopamine release, memory and learning, regulation of the cerebrovascular system, modulation of wakefulness, modulation of nociception, olfaction, food intake and drinking) as well as pathologies (Alzheimer’s, Huntington’s disease, cerebral ischemia, stroke). Two reports have addressed the involvement of NO in depression. Methods: The objective of the study was to examine the association between NO and specific depressive symptoms. For this purpose, in a sample of 28 end-stage renal failure patients (who have increased NO levels), we tested the hypothesis that the subgroup of patients with these specific depressive symptoms was differentiated from the patients without these symptoms with regard to serum levels of NO metabolites. The depressive symptoms were assessed using the Zung self-rating scale. Results: Our study revealed an association of NO with the following depressive symptoms: sexual dysfunction, weight loss, psychomotor retardation, indecisiveness and irritability. Conclusion: The association between NO system and symptoms of depression does not necessarily imply a pathogenetic association between NO and depressive disorder. Further research is needed to verify these findings and study their possible pathogenetic implications.
Low Psychopathology Scores in the Prognosis of Breast Cancer
Authors: Trikas Panayotis , Vlachonikolis Ioannis , Samonis George , Askoxilakis Ioannis , Tsiftsis Dimitris , Koutsoubi Katerina , Paritsis Nicholas
Published: April 2003

Background: Research findings regarding the influence of psychopathology on cancer progression are not yet clear. This preliminary report investigates the severity of psychopathology assessed before biopsy in patients with invasive breast carcinoma (IBC) and its association with two follow-up outcomes: disease-free (to first recurrence) and survival periods. Method: The psychiatric assessment of 80 patients under 70 years old was established by means of an interview before biopsy. The DSM-IV criteria were used to establish the past and current psychiatric diagnoses. The Present State Examination (PSE)-Index of Definition (ID)-computer program (CATEGO) was used to define total PSE score, clusters of psychiatric symptoms (psychiatric syndromes) and current clinical severity (ID). The independent influence of biological prognostic factors and psychiatric variables on first recurrence or survival period was tested using Cox’s proportional hazards regression model. Results: After biopsy, 38 IBC patients were followed up for 3–81/3 years. During this period, 8 patients died from IBC and 7 were alive with metastatic disease. Cox’s proportional hazards regression analyses showed that tumor diameter and low ID were independent significant predictors of early recurrence, whereas tumor diameter, negative estrogen receptors and low ID were independent significant predictors of survival. Conclusions: A low prebiopsy psychopathology score in IBC is a predictor of early recurrence and short survival.
Incidence of Malignant Pleural Mesothelioma due to Environmental Asbestos Fiber Exposure in the Southeast of Turkey
Authors: Şenyiğit A. , Babayiğit C. , Gökirmak M. , Topçu F. , Asan E. , Coşkunsel M. , Işık R. , Ertem M.
Published: April 2003

Background: Inhabitants of the southeast of Turkey (ST) have been exposed since childhood to inhalation of asbestos, from a material containing tremolite, used for whitewashing. This has resulted in an increased incidence of malignant pleural mesothelioma (MPM). Objectives: To review the epidemiological features of MPM cases in ST; to calculate and compare the incidence with the previously reported ones. Subjects and Methods: The study included 176 MPM cases from different places in ST. The incidence of MPM was calculated for those places according to the distribution of the cases. Results: In the previously identified regions of asbestos (region 1) where the population had been informed of the danger with the soil some decades ago, the MPM incidence was decreased, as compared to the previous reports. The annual incidence of MPM in these places was found to be 42.9 per million in this study while it had been reported to be 105.5 per million in the previous studies. In contrast, the incidence that was reported previously to be 2.75 per million in the regions where asbestos exposure had not been identified before (region 2) was found to be 8.6 per million in this study. In region 2 the incidence of MPM increased even in the second half of the last decade (5.9 versus 11.9 per million). Conclusions: Use of asbestos-containing soil continues in different places in ST. Even if the use of this soil is abandoned today, MPM will be an important health problem in this region till the third or fourth decades of this century. Informing the villagers of the danger and preventing the use of this soil may result in a considerable decrease in the incidence of MPM.
Comparison of the Effectiveness of Some Pleural Sclerosing Agents Used for Control of Effusions in Malignant Pleural Mesothelioma: A Review of 117 Cases
Authors: Şenyiğit Abdurrahman , Bayram Hasan , Babayiğit Cenk , Topçu Füsun , Balci Akın E. , Satici Ömer
Published: April 2003

Background and Objectives: Management of malignant pleural mesothelioma (MPM) has been an important clinical issue regardless of the treatment modality employed. We aimed to investigate the efficacy of oxytetracycline (OT), Corynebacterium parvum (CP), and nitrogen mustard (NM) in the management of pleural effusion associated with MPM. Methods: One hundred and seventeen patients who had stage-2 MPM or over according to the Butchart staging system and unilateral or bilateral pleural effusion took part in the study. The patients received either OT (35 mg/kg), CP (7 mg), or NM (0.4 mg/kg) through a chest tube for pleurodesis. The association between several clinical parameters and patient survival was also investigated. Results: OT was applied to 59, CP to 29 and NM to 29 cases. A statistical analysis of the results obtained by these agents have demonstrated that OT (30 days, 81%; 90 days, 76.2%) and CP (30 days, 86.2%; 90 days, 79.3%) led to a significantly higher rate of successful pleurodesis as compared to NM (30 days, 48.2%; 90 days, 41.3%; p <0.05). Although the procedure was generally well tolerated by the patients, the NM-treated group experienced significantly more nausea-vomiting (46.1%) and hypotension (35.8%) compared to patients who received OT (nausea-vomiting and hypotension 4.3%; p < 0.001) and CP (nausea-vomiting and hypotension 5.1%; p < 0.001). Furthermore, we found that thrombocytosis, chest pain and weight loss were significantly associated with poor prognosis, whereas epithelial type had a positive effect on survival. Conclusion: These results suggest that OT and CP may be used as effective sclerosing agents for pleurodesis in the control of pleural effusions associated with MPM, without major side effects.
Distorted Trachea in Patients with Chronic Obstructive Pulmonary Disease
Authors: Muro Shigeo , Nakano Yasutaka , Sakai Hiroaki , Takubo Yasutaka , Oku Yoshitaka , Chin Kazuo , Nishimura Koichi , Hirai Toyohiro , Kawakami Kenzo , Nakamura Takashi , Mishima Michiaki
Published: April 2003

Background and Objectives: We evaluated the size and configuration of the trachea in patients with chronic obstructive pulmonary disease (COPD; n = 35) on high-resolution computed tomography (HRCT) images and compared them with those of healthy volunteers (n = 24). Methods: Using a newly developed computed method for analyzing the digital data of HRCT, the size and configuration of the trachea were automatically evaluated. Results: The size of the trachea of the COPD subjects was the same as that of the control subjects; however, the configuration was more distorted in the COPD patients. There was no difference in the tracheal index (TI), which is the ratio of the coronal to the sagittal length, between these two groups; however, the ratio of the short to the long radius (SR/LR) was significantly smaller in the COPD group than in the control group. There was a significant correlation between SR/LR and airflow limitation as assessed by pulmonary function tests in the COPD group. Conclusions: The SR/LR is a better index of tracheal deformity than the classical TI. This deformity is not a consequence secondary to hyperinflation or emphysematous change of the lung, because the low attenuation area of the lung was not correlated with SR/LR.
Exhaled Nitric Oxide – Is It Really a Good Marker of Airway Inflammation in Bronchial Asthma?
Authors: Tsujino Ichizo , Nishimura Masaharu , Kamachi Atsuko , Makita Hironi , Munakata Mitsuru , Miyamoto Kenji , Kawakami Yoshikazu
Published: April 2003

Background: The concentration of exhaled nitric oxide ([NO]) has been reported to reflect the inflammatory process of airways in patients with bronchial asthma, particularly when they are steroid naive. However, it is not fully understood whether it equally reflects the degree of airway inflammation in patients receiving inhaled corticosteroids, but whose symptoms are not necessarily well controlled. Objective: To examine whether the exhaled [NO] really reflects airway inflammation in patients with bronchial asthma, regardless of treatment with inhaled steroids. Methods: Exhaled [NO] was measured in patients with bronchial asthma (43 steroid treated and 32 steroid naive), chronic obstructive pulmonary disease (COPD) (n = 36), bronchiectasis (n = 10) and in control subjects (n = 26). We examined in each asthmatic group whether the exhaled [NO] correlated with parameters reflecting airway inflammation. Results: Exhaled [NO] was significantly correlated with symptom score, clinical severity, circulating eosinophil count, and the percentage of eosinophils in induced sputum in the steroid-naive asthmatics, but not in the steroid-treated asthmatics, although airway inflammation in this group was not well controlled, as evidenced by clinical symptoms and the higher percentage of eosinophils in induced sputum. Exhaled [NO] from the patients with COPD (6.2 ± 0.7 ppb) or bronchiectasis (5.4 ± 1.3 ppb) was not significantly increased compared with the controls (6.0 ± 1.0 ppb), and was significantly lower than in the asthmatic patients as a whole (19.0 ± 2.0 ppb). Conclusions: Although exhaled [NO] is a useful marker of airway inflammation for differential diagnosis and evaluation of severity in steroid-naive patients with bronchial asthma, it may not be as useful in steroid-treated patients.