bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppressive Antigen-Presenting Cells in Helminth Infection
Authors: MacDonald Andrew S. , Loke P’ng , Allen Judith E.
Published: April 2003

Infection with filarial nematodes is commonly associated with a failure of T cells to proliferate in response to parasite antigen. We have investigated the possibility that antigen-presenting cells recruited during filarial infection are responsible for impairment of T cell function. We have found that the human filarial parasite Brugia malayi, when implanted into the peritoneal cavity of mice, recruits a population of adherent cells that actively block the proliferation of T cells. Phenotypic analysis of the recruited cells reveals large numbers of both macrophages and eosinophils and cell sorting experiments demonstrate that these antiproliferative cells are Mac-1-positive. Studies in gene-deficient mice have demonstrated that proliferative suppression is dependent on the in vivo production of IL-4 but not IL-5 or IL-10, while suppression in vitro is not mediated by any known antiproliferative factor. Our results suggest that helminth infection can lead to the development and/or recruitment of an IL-4-dependent macrophage population that mediates suppression via a novel mechanism.
Changes in Brain Neurofilament and Beta-Tubulin Proteins after Cerebral Hypoxia-Ischemia in Rabbits
Authors: Mink Richard B. , Johnston Jill A.
Published: April 2003

Neurofilaments (NF) and tubulin are highly phosphorylated proteins that are important in neuronal structure and function. Changes in phosphorylation alter their antigenicity, and previous studies examining the effect of ischemia on these proteins failed to consider this factor. Using phosphate-independent antibodies and a quantitative immunoassay, we examined whether the amount of NF 68-kD (NF 68), NF 160-kD (NF 160), NF 200-kD (NF 200) and class III β-tubulin proteins in the brain are reduced after cerebral injury. Rabbits were subjected to 8 min of hypoxia and then to 8 min of ischemia. After 4 h of reperfusion, NF 68 decreased from an overall group mean (± SEM) of 17.5 ± 2.3 ng NF 68 μg/total protein in the noninjured controls (n = 8) to 12.9 ± 1.2 ng/μg total protein in the hypoxic-ischemic group (n = 9). Conversely, NF 200 increased from 31.6 ± 3.3 ng/μg in controls to 47.7 ± 3.2 ng/μg. The amount of NF 160 and β-tubulin was unchanged. The response of the NF proteins to brain injury is more complicated than described previously. Additional studies examining the regulation and metabolism of the NF are warranted, especially regarding the role of phosphorylation.
Immunopathological Factors for Vertical Transmission of HIV-1
Authors: Edgeworth Rebecca L. , Ugen Kenneth E.
Published: April 2003

With the global rise in human immunodeficiency virus-1 (HIV-1) infection in women of childbearing age, there has also been an alarming rise in the number of mother-to-child transmissions of HIV-1. Although drug therapies such as zidovudine as well as nevirapine have been demonstrated to significantly decrease the incidence of vertical transmission of HIV-1, these therapeutic regimens are still not widely available in some developing countries where maternal-to-child transmission of HIV-1 continues to occur at an alarming rate. Therefore, the continued studies of mechanisms and correlates of vertical transmission of HIV-1 are warranted. The current status of immunological and virological correlates of vertical transmission are summarized in this review. In addition, information concerning recent therapeutic agents for the prevention of HIV-1 vertical transmission is presented.
Direct Vasodepressor Effects of Pioglitazone in Spontaneously Hypertensive Rats
Authors: Verma Subodh , Bhanot Sanjay , Arikawa Emi , Yao Linfu , McNeill John H.
Published: April 2003

Effects of pioglitazone on plasma insulin levels, systolic blood pressure and arterial reactivity were studied in spontaneously hypertensive (SH) rats. Chronic treatment of SH rats with pioglitazone decreased plasma insulin levels and blood pressure. Direct effects of pioglitazone on vascular reactivity were also studied in aortae and superior mesenteric arteries from SH rats. Pioglitazone markedly inhibited arginine vasopressin (AVP) and norepinephrine (NE) responses without affecting responses to potassium chloride (KCl). These data suggest that (a) antihypertensive effects of pioglitazone in SH rats may be mediated via a direct vasodepressor effect, and (b) vasodilation may be coupled to insulin sensitivity in SH rats.
Cardiovascular Activity of A-74283, a 5-Hydroxytryptamine1A Agent, in the Spontaneously Hypertensive Rat
Authors: Lee Jang Yun , Hancock Arthur A. , Warner Robert B. , Brune Michael E. , Meyer Michael D. , DeBernardis John F.
Published: April 2003

A-74283, (+,-)trans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1H cyclobut [f] isoindol-1,3-dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydro-1H-benz[e]isoindol HCl, was studied in receptor binding assays and in the spontaneously hypertensive rat (SHR). In radioligand binding to rat cortex, A-74283 had high affinity (equipotent to 8-OH-DPAT) and high selectivity for 5HT1A receptors compared to 5HT1B sites. In conscious SHR, A-74283 lowered mean arterial pressure (MAP) in a dose-related fashion with a prolonged effect after oral administration of higher doses, but heart rate (HR) was not changed. In anesthetized SHR, i.v. administration of A-74283 decreased MAP and total peripheral resistance, but not cardiac output. Pretreatment of conscious SHR with the selective 5TH1A receptor antagonists spiroxatrine or BMY 7378 reduced the hypotensive effect of A-74283 significantly, but pretreatment with adrenergic antagonists phenoxybenzamine or idazoxan or the 5HT2 receptor blocker ketanserin did not alter the effect of A-74283. Intracisternal administration of A-74283 also decreased MAP; however, A-74283 had no effect on blood pressure in pithed SHR in which blood pressure was supported with vasopressin, in contrast to nitroprusside. These data demonstrate that A-74283 exerts a potent hypotensive effect in SHR via systemic vasodilation originating from a central 5HT1A receptor mechanism. A-74283 may be useful for studying 5HT1A receptors and cardiovascular function.
Evaluation of Intrinsic Sympathomimetic Activity of Bucindolol and Carvedilol in Rat Heart
Authors: Willette Robert N. , Mitchell Marcus P. , Ohlstein Eliot H. , Lukas Mary Ann , Ruffolo Jr. Robert R.
Published: April 2003

Many β-adrenoceptor antagonists are weak partial agonists, possessing significant intrinsic sympathomimetic activity (ISA). Under certain conditions, ISA may be deleterious through stimulation of β1- and/or β2-adrenoceptors in the heart. Drugs with ISA are particularly problematic in the treatment of congestive heart failure since agents that activate cardiac β-adrenoceptors, such as xamoterol, have been associated with increases in the incidence of arrhythmia and mortality. Carvedilol was recently approved for the treatment of congestive heart failure, and bucindolol is currently in large clinical trials for this indication. In the present study, the ISA of bucindolol and carvedilol was evaluated in a standard model used to investigate ISA, the pithed rat. Both compounds produced dose-dependent inhibition of the positive-chronotropic effects of the non-selective β-adrenoceptor agonist, isoproterenol, confirming that these drugs are β-adrenoceptor antagonists. However, cumulative administration of bucindolol (10–1,000 µg/kg i.v.) in the pithed rat produced a significant dose-related increase in heart rate. The maximal increase in heart rate produced by bucindolol was 44% of that obtained with isoproterenol (90 ± 6 vs. 205 ± 11 bpm, respectively). In marked contrast, cumulative administration of carvedilol (10–1,000 µg/kg i.v.) had no significant effect on resting heart rate in the pithed rat. The maximal increase in heart rate elicited by bucindolol (1,000 µg/kg i.v.) was inhibited by treatment with the competitive β-adrenoceptor antagonist, propranolol (99 ± 8.7 vs. 26 ± 2.6 bpm), confirming that the ISA observed with bucindolol was mediated through stimulation of myocardial β-adrenoceptors. Carvedilol, which had no ISA, antagonized the ISA of bucindolol, and was as effective as propranolol in blocking the ISA of bucindolol (99 ± 8.7 vs. 27 ± 2.3 bpm). In summary, bucindolol and carvedilol are both potent β-adrenoceptor antagonists in the pithed rat; however, only bucindolol possesses β-adrenoceptor-mediated ISA.
Differences in pH-Dependent Activation Rates of Substituted Benzimidazoles and Biological in vitro Correlates
Authors: Kromer W. , Krüger U. , Huber R. , Hartmann M. , Steinijans V.W.
Published: April 2003

Gastric proton pump inhibitors (PPIs) are substituted benzimidazole prodrugs that require an acid-induced activation. Its rate depends on the reactivity of the molecule relative to the environmental pH and determines the drug’s tissue selectivity. Factors affecting the exposure of moderately acidic tissues to the activated PPI are the area under the serum concentration-time curve (AUC), serum protein binding, the partition coefficient logP and the serum elimination half-life relative to the chemical activation half-life at a critical tissue pH of about 5. These parameters have therefore been determined in a comparative fashion in the present study. The data shows that pantoprazole is less likely to undergo unwanted activation at moderately acidic targets as opposed to the parietal cell, compared to omeprazole. Actually, although 40 mg pantoprazole (steady state) gave a slightly higher serum AUC of the total parent compound than 40 mg omeprazole (10.5 vs. 7.1 µmol × h × l–1), a higher serum protein binding of pantoprazole versus omeprazole (98 vs. 96%) reversed the AUC values for the free drug in favor of a lower value for pantoprazole (0.19 vs. 0.28 µmol × h × 1–1). It is the free parent compound that equilibrates across cell membranes to be activated in acidic tissue compartments. At pH 5.1, the activation half-life of pantoprazole was 4.7 versus 1.4 h for omeprazole, the latter being in the order of the common serum elimination half-life determined in an intraindividual comparison (1.24 vs. 1.25 h). Thus, pantoprazole is eliminated faster from blood than it is activated at a pH of about 5, while omeprazole is as quickly activated at this pH as it is eliminated from blood. Biological in vitro experiments confirmed that pantoprazole displays a lower liability to interfere with unwanted biological targets. This has been demonstrated in vitro for inhibition of both renal Na+/K+-ATPase, lysosomal acidification and the production of reactive oxygen species by neutrophils.
A Comparison of Cytochrome P450-Dependent Testosterone 2α-Hydroxylase in Rat (P450 2C11) and Mouse (P4502α)
Authors: Sharma Mahesh C. , Sharma Meena R. , Shapiro Bernard H.
Published: April 2003

Hepatic P450 2C11 in the rat and P4502α in the mouse are unique in being the only isoforms in their respective species with testosterone 2α-hydroxylase activity. Comparing gender differences, tissue distribution and physicochemical properties, we investigated whether this uncommon catalytic activity shared by the two isoforms is dependent upon a high degree of homology. Using additional substrates (e.g. androstenedione, hexobarbital), we observed that P4502α and P450 2C11 produced no metabolites in common. Moreover, concentrations of antisera prepared against purified P4502α that inhibited 95% of P4502α-dependent testosterone 2α-hydroxylase activity had only a minimal inhibitory effect (<20%) on P450 2C11-dependent testosterone 2α-hydroxylase and were similarly unreactive to the rat isoform isolated on Western blots. Comparison of the isoforms’ N-terminal amino acid residues and two internal peptide fragments indicated almost no sequence homology (<4%). Gender-dependent tissue expression levels of P4502α and P450 2C11 revealed additional dichotomies. Whereas hepatic P4502α was moderately female-predominant (M/F; 0.62), hepatic P450 2C11 was clearly male-specific (M/F; 32.9). Murine P4502α mRNA was equally and substantially expressed in liver, kidney and brain; by contrast earlier studies reported that rat P450 2C11 was exclusively expressed in liver. The present results indicate that the unique testosterone 2α-hydroxylase activities of P4502α and P450 2C11 are expressed by two very different proteins exhibiting minimal homology.
Protective Effect of Nifedipine against Carrageenan-Induced Inflammation
Authors: Sánchez Sílvia , Bartrons Ramon , Rodríguez Leocadio , González Pedro , Planas M. Eulàlia
Published: April 2003

Administration of carrageenan (CA; 0.5 mg) to the plantar tissue of rats resulted in reversible inflammatory injury. The edema was monitored by changes in paw volume using a plethysmometer. Simultaneous administration of CA and nifedipine, intraperitoneally, at different doses (10, 20 and 50 mg/kg) prevented the inflammatory action, and the effect was dose- and time-dependent. In order to improve the nifedipine effects, we prepared liposomed nifedipine which, administered intraperitoneally, showed a greater anti-inflammatory action. In the presence of the L-type channel agonist Bay K 8644, the inflammation produced by CA increased and it was counteracted by free or liposomed nifedipine. The significance of these findings with respect to the mechanism of the anti-inflammatory action of nifedipine is discussed.
Comparative Analgesic Activity of Nimesulide and Diclofenac by Intramuscular Route: Correlation with Pharmacokinetic Profile of Nimesulide
Authors: Gupta S.K. , Velpandian T. , Mathur P. , Sengupta S.
Published: April 2003

Nimesulide, a selective cyclooxygenase-2-inhibiting nonsteroidal anti-inflammatory drug, has been found to be a potent anti-inflammatory and analgesic drug, when administered orally, rectally or topically. The aim of the present study was to evaluate the comparative efficacy of intramuscularly injected nimesulide with that of diclofenac and to elucidate the pharmacokinetic profile of this formulation. Swiss albino mice were used in the experiment. Analgesic activity was tested using the acetic acid writhing test and the tail-flick latency test. Plasma levels of nimesulide and its active metabolite, hydroxynimesulide, were determined by a HPLC method. A peak analgesic effect was observed between 60 and 120 min, while Cmax (10.6 ± 3.8 µg/ml) of nimesulide was reached at 60 min (Tmax). Analgesia was induced within 15 min of administration of nimesulide and was significantly higher than that of diclofenac at 90 and 120 min posttreatment in the writhing reflex and at 60 and 90 min in the tail-flick latency test. The results indicate that intramuscularly injected nimesulide may be an alternative mode of administration in uncooperative patients or when immediate analgesic effects are warranted.
Sn-mesoporphyrin Suppression of Hyperbilirubinemia in EHBR/Eis Rats, an Animal Model of Dubin-Johnson Syndrome
Authors: Drummond George S. , Kappas Attallah
Published: April 2003

Sn-mesoporphyrin (SnMP), a potent inhibitor of heme oxygenase (HO), controlled hyperbilirubinemia in rats of the mutant strain EHBR/Eis. This mutant strain displays pronounced conjugated hyperbilirubinuria and dark pigmentation of hepatocytes, characteristics of the Dubin-Johnson syndrome. SnMP administered at a dose of 10 µmol/kg body weight produced an immediate decrease in plasma bilirubin concentrations which could be maintained by weekly injections of this synthetic heme analogue. Marked inhibition of HO activity was demonstrated in liver, kidney and spleen but not in brain. These results demonstrate that SnMP can lower plasma bilirubin concentrations for extended periods in a new mutant rat model of Dubin-Johnson syndrome.
Heterogeneity of α1-Adrenoceptor Subtypes Mediating Noradrenaline-Induced Contractions of theRat Superior Mesenteric Artery
Authors: Yousif Mariam , Kadavil Elizabeth A. , Oriowo M.A.
Published: April 2003

The effects of subtype-selective α1-adrenoceptor antagonists on noradrenaline-induced contractions of ring segments of rat superior mesenteric artery were investigated to determine the subtype(s) of α1-adrenoceptors mediating contractions in this preparation. Noradrenaline-induced contractions of rat mesenteric artery ring segments were potently and surmountably antagonized by prazosin, WB 4101 and BMY 7378. Judging from the slopes of the Schild regression lines, which were significantly different from 1, WB 4101 and BMY 7378 behaved as noncompetitive antagonists. Spiperone and 5-methylurapidil were only effective at high concentrations. Chloroethylclonidine (CEC, 100 µmol/l) displaced the noradrenaline concentration-response curve to the right reducing its potency approximately 100-fold. Noradrenaline-induced contractions post-CEC were also antagonized by prazosin. However, prazosin was less potent against these contractions. A 61603, a selective α1A-adrenoceptor agonist, contracted ring segments of the mesenteric artery. These contractions were antagonized by prazosin, however with a low affinity, indicating interaction with a low-affinity receptor subtype. It was therefore concluded that α1D- and, possibly, α1L-adrenoceptor subtypes mediated noradrenaline- induced contractions of the rat superior mesenteric artery.
Inhibitory Effects of TRK-530 on Rat Adjuvant Arthritis
Authors: Tanahashi Masahiko , Funaba Yuriko , Itoh Masatoshi , Kawabe Norio , Nakadate-Matsushita Teruo
Published: April 2003

TRK-530 is a novel bisphosphonate derivative. We examined the anti-inflammatory effects of TRK-530 on adjuvant arthritis (AA) rats. When TRK-530 at a dose of 2.5 mg/kg was administered for 2 weeks to AA rats, it inhibited destructive changes in arthritic joints such as paw edema, bone loss and joint degeneration. TRK-530 also inhibited splenomegaly and suppressed the increase in serum sialic acid which is measured as a systemic parameter of inflammation. To clarify the inhibitory mechanism of TRK-530, interleukin-1 (IL-1)-like activities of resident peritoneal macrophages in AA rats given TRK-530 were compared with those of control rats. We found that TRK-530 inhibited IL-1-like activity induced by bacterial lipopolysaccharide 6 weeks after administration when the IL-1-like activities of control rats were still at high levels. These findings suggest that TRK-530 exerts anti-inflammatory activities in AA rats.
Kinetic Properties of Nitric Oxide Synthase in Cerebral Cortex and Cerebellum of Morphine Tolerant Mice
Authors: Bhargava Hemendra N. , Kumar Shailendra , Barjavel Marc J.
Published: April 2003

The effects of chronic morphine administration on the kinetics of nitric oxide synthase (NOS) activity were determined in the mouse cerebral cortex and cerebellum. Male Swiss-Webster mice were implanted subcutaneously with morphine pellets each containing 25 mg of morphine base for 3 days. Mice implanted with placebo pellets served as controls. NOS activity was determined by measuring the rate of conversion of [3H]arginine to [3H]citrulline. Morphine pellet implantation increased NOS activity in the cerebral cortex and cerebellum. Analysis of the Eadie-Hofstee plot indicated that the Vmax of NOS in the cortex and cerebellum was 140 and 228 pmol [3H]citrulline formed/min/mg protein and the Km values were 9.3 and 10.1 µmol/l, respectively. Mice implanted with morphine pellets had higher Vmax values in both the cortex and cerebellum, but the Km values did not differ from those of control mice implanted with placebo pellets. It is concluded that chronic treatment with morphine increases NOS activity in the brain without modifying its substrate affinity.
Acute Natriuretic Effect of Fasidotrilat, a Mixed Inhibitor of Neutral Endopeptidase and Angiotensin I-Converting Enzyme, in Rats with Heart Failure
Authors: Marie Christine , Mossiat Claude , Lecomte Jeanne-Marie , Bralet Jean
Published: April 2003

The acute diuretic and natriuretic effects of fasidotrilat, a mixed inhibitor of neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) were evaluated in control and myocardial-infarcted rats. Fasidotrilat injection (10 mg/kg i.v.) had no significant effect on arterial blood pressure and led to significant elevations in urine volume (+57% in control rats and +114% in infarcted rats) and of urinary sodium excretion (+81% in control rats and +225% in infarcted rats). Comparison between control and infarcted rats showed that fasidotrilat-induced changes in diuresis and natriuresis were higher in infarcted rats (2.4-fold for diuresis and 4.7-fold for natriuresis, p < 0.05), despite a lower perfusion pressure (–10 mm Hg) in infarcted rats. These data show the potential therapeutic interest of mixed NEP/ACE inhibitors in congestive heart failure.
Inhibitors of Synaptosomal γ-Hydroxybutyrate Transport
Authors: McCormick S.J. , Tunnicliff G.
Published: April 2003

Synaptosomes prepared from mouse brain possess a Na+-dependent transport system for γ-hydroxybutyrate displaying saturation kinetics, the transport constant (Kt) for which was calculated as 31 ± 9 µmol/l. Several γ-hydroxybutyrate and γ-aminobutyric acid (GABA) structural analogues were tested as potential inhibitors of γ-hydroxybutyrate transport. The most effective inhibitor was harmaline (Ki = 94 ± 21 µmol/l), a known competitive inhibitor of Na+ binding to certain transport proteins. 2-Hydroxycinnamic acid, 3-(2-furyl)acrylic acid and citrazinic acid also inhibited transport and were competitive with respect to γ-hydroxybutyrate. The least effective γ-hydroxybutyrate analogues were 3-hydroxypropane sulfonic acid (Ki = 4.1 ± 0.8 mmol/l) 3,5-dihydroxybenzoic acid (Ki = 6.1 ± 2.8 mmol/l) and 3-hydroxybenzoic acid (Ki = 6.9 ± 3.3 mmol/l), although 2-hydroxypropane sulfonic acid and kynurenic acid had no measurable effects. Four inhibitors of GABA transport – nipecotic acid, guvacine, ketamine and β-alanine and GABA itself, were without effect on γ-hydroxybutyrate transport. These results show that certain drugs that structurally resemble γ-hydroxybutyrate have the capacity to compete with γ-hydroxybutyrate at its recognition site on the transporter. By examining the structure of such inhibitors, we can learn more about the properties of the substrate binding site on the carrier protein. Moreover, the absence of inhibition by GABA uptake inhibitors shows that γ-hydroxybutyrate transport is a separate entity from GABA transport.
N-Acetylheparin Pretreatment Reduces Infarct Size in the Rabbit
Authors: Park James L. , Kilgore Kenneth S. , Naylor Keith B. , Booth Erin A. , Murphy Kerri L. , Lucchesi Benedict R.
Published: April 2003

The ability of the heparin derivative, N-acetylheparin (NHEP) to protect the heart from regional ischemia/reperfusion injury was examined in vivo. NHEP (2 mg/kg i.v.) or vehicle was administered 2 h before occlusion of the left circumflex coronary (LCX) artery. Open-chest, anesthetized rabbits were subjected to 30 min of regional myocardial ischemia followed by 5 h of reperfusion. Myocardial myeloperoxidase activity, membrane attack complex (MAC) deposition and IL-8 generation were assessed in supernatant samples from the area at risk. Infarct size in rabbits pretreated with NHEP (32.5 ± 3.8%, n = 10) decreased by 41% compared to infarct size in rabbits that received vehicle (55.3 ± 4.9%, n = 10; p = 0.002). Accumulation of neutrophils within the ischemic region, as assessed by myeloperoxidase activity, declined by 45% (p < 0.05) in AAR from NHEP-treated animals compared to AAR from vehicle-treated animals. Levels of MAC and IL-8 obtained from AAR were less in NHEP-pretreated animals compared to controls. These results suggest that NHEP may protect the myocardium by inhibiting complement activation and subsequent neutrophil infiltration.
Binding and Functional Potency of Neurokinin A Analogues in the Rat Fundus: A Structure-Activity Study
Authors: Matuszek M.A. , Comis A. , Burcher E.
Published: April 2003

Structure-activity relationships of neurokinin A (NKA) and the two analogues NKA(4-10) and [Nle10]NKA(4-10) were investigated at the rat fundus NK-2 receptor, using selected amino acid substitutions. Both radioligand binding with [125I][Lys5,Tyr(I2)7,MeLeu9, Nle10] NKA(4-10) and functional studies were performed and correlated. In membrane binding experiments loss of His1 and Lys2, or replacement of Lys2 with Ala did not substantially alter binding affinity of NKA. NKA(4-10) free acid was unable to compete with the radioligand. [Nle10]NKA(4-10) binding affinity to rat fundus membrane preparations was decreased when substituting Asp4 with Gln or Asn, or Val7 with either Tyr or Ile. Replacement of Ser5 with the negatively charged Glu also decreased the binding affinity, but substitution with the positively charged Lys substantially increased the affinity of [Nle10] NKA(4-10) for the NK-2 receptor. Lengthening NKA(4-10) or [Nle10]NKA(4-10) with Ala11 or Nle11, respectively, decreased the binding affinity of the peptide. In both binding and functional studies, replacement of any of the residues of NKA(4-10), except for Ser5, with alanine decreased the affinity of the peptide for the NK-2 receptor. Ala substitutions at positions 4, 6, and very obviously at 8, 9 and 10 of NKA(4-10) yielded peptides unable to achieve a maximum contractile response, although they did not demonstrate antagonist activity. These data confirm the importance of the NKA carboxyl terminus, and the requirement for Phe6, Val7, Gly8, Leu9 and Met10 integrity for interaction with the NK-2 receptor. They also suggest that Ser5 is a good site to target modifications leading to the design of new potential drugs.
Junctional Transmissions in Smooth Muscle of the Guinea Pig Duodenum and Their Modulation by the Prokinetic Agent DQ-2511
Authors: Takano Hiromichi , Suzuki Hikaru
Published: April 2003

Junctional transmissions and their modulation by DQ-2511, a novel prokinetic agent, were investigated in smooth muscle of the guinea pig duodenum. Transmural nerve stimulation evoked a cholinergic excitatory junction potential, a nonadrenergic, noncholinergic inhibitory junction potential, and a substance P mediated slow depolarization. DQ-2511 showed dual effects on the slow depolarization: a low concentration (10–9 mol/l) enhanced and high concentrations (>10–6 mol/l) tended to inhibit. The depolarization produced by exogenously applied substance P was enhanced by low concentrations of DQ-2511. The results suggest that the prokinetic actions of DQ-2511 involve an enhancement of transmission from substance P neurons due to an increase in sensitivity of postjunctional receptors to substance P.
Pharmacologic Effects of the Red Blood Cell Substitutes Cross-Linked and Non-Cross-Linked Hemoglobins on Hematopoiesis in Rabbits
Authors: Lutton J.D. , Jiang S. , Drummond G.S. , Abraham N.G. , Levere R.D. , Kappas A.
Published: April 2003

The red blood cell substitutes β-β cross-linked (DECA-Hb, XLBV-Hb) and non-cross-linked (HbA) hemoglobins (Hbs), were transfused into rabbits and their effects on hematopoiesis examined. All rabbits receiving DECA-Hb or XLBV-Hb tolerated the Hbs well, whereas 50% of the animals transfused with similar doses of non-cross-linked HbA died. Analysis of peripheral blood and bone marrow BFU-E and CFU-GM production revealed that there was no significant variation in the generation of BFU-E and CFU-GM numbers for each cross-linked Hb transfusion group, but there were significant reductions in the HbA group. In animals transfused with cross-linked Hbs, splenic heme oxygenase (HO) activity was similar to that of controls; liver HO activity was slightly elevated, whereas HO activity was significantly increased in kidneys. Transfusion with non-cross-linked HbA produced greater inductions of HO activity in the liver and kidneys. Hepatic δ-aminolevulinic acid synthase (ALAS) activity was significantly reduced in HbA-transfused animals, whereas transfusion with cross-linked Hbs produced only minor, statistically nonsignificant, reductions in ALAS activity.
Relative Efficacies of Gastric Proton Pump Inhibitors: Their Clinical and Pharmacological Basis
Authors: Kromer Wolfgang , Horbach Silke , Lühmann Reinhold
Published: April 2003

The present review will verify by intra-study rank orders, and their comparison between studies, that the different gastric proton pump inhibitors (PPIs) display similar dose-response relationships with similar potencies and efficacies on a milligram basis, i.e., at the same milligram doses. This is in line with their basic pharmacology which suggests that, primarily, the serum AUCs of the free pro-drugs and their chemical activation half lives at pH 1 relative to their serum elimination half lives determine the efficacies of PPIs. According to the literature, these drug characteristics are similar for all PPIs. Although PPIs have been introduced into the therapy of acute peptic ulcer disease at different daily, oral doses of 20 mg (omeprazole and rabeprazole), 30 mg (lansoprazole) and 40 mg (pantoprazole), the data suggest that the optimal dose of lansoprazole, omeprazole and pantoprazole, with respect to the acute treatment of peptic ulcers and moderate to severe gastroesophageal reflux disease (GERD), is about 30–40 mg daily. The data base of rabeprazole appears to be too small at present to make any definite statement. Lower daily doses of the PPIs of about 15–20 mg are sufficient in less severe cases of GERD and in maintenance therapy. It appears that different dose recommendations were based on different strategies to balance optimal drug dosage and safety, rather than on real differences in milligram-related efficacies.
Rabbit versus Rat Urinary Bladder: Effects of in vitro Hypoxia
Authors: Whitbeck Catherine , Barreto Mark , Horan Patrick , Levin Sheila S. , Levin Robert M.
Published: April 2003

Purpose: Studies indicate that bladder hypoxia may be an etiological factor for lower urinary tract dysfunction. Rat and rabbit are two species of experimental animals used frequently to study lower urinary tract function and dysfunction. The objective of this study was to compare directly effects of in vitro hypoxia on contractile responses of rat and rabbit urinary bladder to different forms of stimulation. Methods: Sexually mature male New Zealand White rabbits and Sprague-Dawley rats were compared. Each bladder was excised while the animal was anesthetized, and longitudinal bladder strips were cut, then mounted in organ baths. A tension of 2 g was placed on all strips. Effects of 1, 2, 3 and 4 h hypoxia followed by 1 h of reoxygenation on contractile responses of bladder strips to field stimulation (FS), carbachol (100 μmol/l), ATP (1 mmol/l) and KCl (120 mmol/l) were determined. Results: Contractility, per unit tissue mass, of rat bladder strips was significantly greater than that of rabbit bladder strips in response to FS (all frequencies), carbachol, KCl and ATP. Hypoxia (followed by reoxygenation) resulted in time-dependent progressive reduction in contractile responses of bladder strips to all stimuli. Rat bladder was significantly more sensitive to hypoxia than rabbit bladder in response to FS and carbachol. Hypoxia induced similar effects on rat and rabbit bladder responses to ATP and KCl. Conclusion: Rat bladder neurogenic and cholinergic responses are significantly more sensitive to hypoxia than are those of rabbit bladder, which may be due to the rat bladder’s greater contractile force generation and previously reported higher Ca2+-ATPase activity.
Stereoselective Inhibition of Ethanol- Induced Gastric Lesions in the Rat by the H3-Receptor Agonist (R)-α-Methylhistamine and Its (S)-Configured Isomer
Authors: Morini Giuseppina , Grandi Daniela , Bertaccini Giulio , Leschke Christian , Schunack Walter
Published: April 2003

The histamine H3 receptor shows high degree of stereoselectivity for histamine analogues branched in the side chain. The hypothesis that gastroprotection by (R)-α-methylhistamine could be H3 receptor-mediated was tested by comparing the effect of (R)-α-methylhistamine and of (S)-α-methylhistamine on ethanol-induced histologic lesions in the rat gastric mucosa. Extensive damage was caused by 60 min exposure to absolute ethanol, 91% of the mucosa examined being damaged. Conversely only 23% of the mucosa was damaged after pretreatment with (R)-α-methylhistamine (100 mg/kg i.g.). In the groups pretreated with (S)-α-methylhistamine (55.44 and 166.3 mg/kg i.g.) total damage ranged from 77 to 79%, though it was confined to the upper portion of the mucosa. Morphometric analysis of stained intraepithelial mucosubstances revealed that (R)-α-methylhistamine pretreatment resulted in an increase in number and volume of surface mucous cells, not evident after (S)-α-methylhistamine pretreatment. Scanning electron microscopy confirmed light microscopy evaluations. The two isomers of α-methylhistamine differently affect the response of rat gastric mucosa to absolute ethanol and they appear to differ in their influence on surface mucous cells. A basis for interpreting the effects of the two isomers of α-methylhistamine rests on the high degree of stereoselectivity of H3 receptors and on the different affinities of the two isomers for these receptors.
Potential of Calcitonin Gene-Related Peptide in Coronary Heart Disease
Authors: Franco-Cereceda Anders , Liska Jan
Published: April 2003

A subpopulation of capsaicin-sensitive cardiac C-fibre afferents co-store calcitonin gene-related peptide (CGRP), substance P and neurokinin A. CGRP exerts positive inotropic and chronotropic effects and is one of the most potent endogenous vasodilators yet discovered. A number of endogenous agents and conditions cause activation of cardiac C-fibre afferents with subsequent local release of CGRP. In myocardial ischaemia with its clinical manifestations angina pectoris and infarction, C-fibre afferents not only convey the sensation of pain, but there is also a local ‘efferent’ release of CGRP in the heart. After being released, CGRP causes coronary vasodilatation and attenuates the development of myocardial infarction. CGRP may thus represent an endogenous local myocardial protective substance with interesting clinical implications.
Ca2+ Influx Mediates Apoptosis Induced by 4-Aminopyridine, a K+ Channel Blocker, in HepG2 Human Hepatoblastoma Cells
Authors: Kim Jung-Ae , Kang Young Shin , Jung Mi-Wha , Kang Ga-Hwa , Lee Sun Hee , Lee Yong Soo
Published: April 2003

Apoptosis appears to be implicated in the pathogenesis and therapeutic applications of cancer. In this study we investigated the induction of apoptosis by 4-aminopyridine (4-AP), a K+ channel blocker, and its mechanism in HepG2 human hepatoblastoma cells. 4-AP reduced cell viability and induced DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. In addition, 4-AP induced a sustained increase in intracellular Ca2+ concentration, which was completely inhibited by the extracellular Ca2+ chelation with EGTA. 4-AP also induced Mn2+ influx, indicating that the 4-AP-induced increased intracellular Ca2+ levels were due to activation of Ca2+ influx pathway. 4-AP also depolarized membrane potential that was measured by using di-O-C5(3), a voltage-sensitive fluorescent dye. 4-AP-induced Ca2+ influx was significantly inhibited not by voltage-operative Ca2+ channel blockers (nifedipine or verapamil), but by flufenamic acid (FA), a known nonselective cation channel blocker. Quantitative analysis of apoptosis by the flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca2+ chelator, significantly inhibited the 4-AP-induced apoptosis. Taken together, these results suggest that the observed 4-AP-induced apoptosis in the HepG2 cells may result from Ca2+ influx through the activation of voltage-sensitive Ca2+-permeable non-selective cation channels. These results further suggest that membrane potential change by modulation of K+ channel activity may be involved in the mechanism of apoptosis in human hepatoma cells.
2-Oxo-2H-Pyrimido[2,1-b]Benzothiazoles Inhibit Brain Benzodiazepine Receptor Binding in vitro
Authors: Ai Jinglu , Wang Xiaomei , Wahe Helen , Fomum Zacharias Tanee , Sterner Olov , Nielsen Mogens , Witt Michael-Robin
Published: April 2003

2-Oxo-2H-pyrimido[2,1-b]benzothiazole derivatives were found to inhibit the in vitro binding of 3H-Ro 15-1788 (3H-flumazenil) to rat cortical benzodiazepine receptors with IC50 values in the range of 0.7–13 μmol/l. The most potent compound, 2-oxo-4-phenyl-2H-pyrimido[2,1-b]- benzothiazole showed a similar potency to inhibit 3H-Ro 15-1788 binding to membrane preparations of rat brain cortex, cerebellum and hippocampus as well as to various subunit combinations of recombinant human γ-aminobutyric acidA/benzodiazepine receptors. Scatchard plot analysis showed that 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole is a competitive inhibitor of 3H-Ro 15-1788 binding to rat brain cortical membrane preparations.
Pharmacological Analysis of Neurogenic, Sympathetic Responses Mediated through Alpha-1-, Alpha-2-Adrenergic and Purinergic Receptors in the Dog Saphenous Vein
Authors: Hiraoka Yasuko , Taniguchi Takanobu , Oshita Masafumi , Muramatsu Ikunobu
Published: April 2003

Electrical transmural stimulation evoked a sympathetic contraction in the isolated dog saphenous vein. This contraction consisted of three components (α1-adrenergic, α2-adrenergic and purinergic), which were separately observed under combined treatments either with yohimbine (blockade of α2-adrenoceptor) and α,β-methylene ATP (desensitization of P2X-purinoceptors), with prazosin (blockade of α1-adrenoceptor) and α,β-methylene ATP, or with prazosin and yohimbine, respectively. The α1-adrenergic and purinergic contractions immediately developed after the start of stimulation and reached a peak rapidly. In contrast, the α2-adrenergic contraction developed slowly, thus the time to peak contraction was longer than the other two components. The relationship between the peak amplitudes of contraction and stimulus frequencies were similar between α1- and α2-adrenergic components, but the purinergic contraction was smaller than the other components at all frequencies (0.1–30 Hz). Cocaine, a neuronal uptake inhibitor of noradrenaline, significantly potentiated α1- and α2-adrenergic components and prolonged their duration with a relatively greater effect on the α2-adrenergic component. In contrast, the purinergic component was not affected by cocaine. Exogenous noradrenaline produced concentration-dependent contraction, which was inhibited more effectively after combined treatment with combination of prazosin and yohimbine than either blocker given alone. Cocaine potentiated the attenuated contractile response to noradrenaline in the presence of prazosin, resulting in the recovery of response to the control level. Exogenous ATP produced a transient contraction, which was abolished under conditions where postjunctional P2X-purinoceptors were desensitized with α,β-methylene ATP. Cocaine did not affect the ATP-induced contraction. These results suggest that sympathetic contraction of the dog saphenous vein is caused through three distinct routes (α1- and α2-adrenoceptors and P2X-purinoceptors).
Assessment of Affinities of Propranolol and Bopindolol to Membranes from COS-7 Cell Transiently Transfected with Beta-1- and Beta-2-Adrenoceptors Using a Radioligand-Binding Assay Method
Authors: Nakamura Takashi , Suzuki Ayako , Ohnuki Toshio , Hattori Kaoru , Watanabe Kenichi , Kurose Hitoshi , Nagao Taku , Nagatomo Takafumi
Published: April 2003

This study was performed to assess the affinities of propranolol, bopindolol, its two metabolites (18-502, 20-785), pindolol, metoprolol, and atenolol to β1- and β2-adrenoceptor (β1- and β2-AR) subtypes using the membranes of COS-7 cells transiently expressing β1- and β2-AR subtypes. Radioligand-binding assays were performed and the results were compared with those (pKi or pA2 values) obtained from the membrane-enriched fractions from the rat heart, cerebral cortex, bovine heart, tracheal smooth muscle or guinea-pig heart muscle. The pKi values of propranolol, bopindolol, its two metabolites, atenolol, pindolol and metoprolol to β1-AR subtypes obtained from COS-7 cell membranes were 9.02 ± 0.04, 7.44 ± 0.12, 9.38 ± 0.31, 6.65 ± 0.16, 5.55 ± 0.14, 8.17 ± 0.15 and 5.99 ± 0.13, respectively. The rank order of pKi values for these agents to β-2-ARs in COS-7 cell membranes was the same as that of β1-ARs. In addition, good correlations were observed between pKi values of homogenates from various tissues and those of transfected COS-7 cell membranes to β1- and β2-ARs. Although good correlations were also observed between pA2 values obtained from tracheal smooth muscle (β2-ARs) and pKi values obtained from transfected COS-7 cell membranes to β2-ARs, low correlation coefficient values to β1-ARs were observed, however. In conclusion, these results suggested that binding characteristics of 3H-CGP-12177 to β-AR subtypes in these membranes from transfected COS-7 cells are similar to those from membrane fractions of various tissues.
Effect of a Novel Anti-Allergic Agent, HSR-609, on Antigen-Induced Airway Hyperresponsiveness in Mice
Authors: Musoh Keiichi , Maeda Yoshizou , Tanaka Hiroyuki , Inagaki Naoki , Nagai Hiroichi
Published: April 2003

The effects of a newly synthesized anti-allergic agent, HSR-609, on allergic airway hyperresponsiveness and airway inflammation have been studied in sensitized mice. The effects were compared with those of two histamine H1 receptor antagonists, cetirizine and terfenadine, and prednisolone. Three inhalations of antigen caused an increase in leukocytes (including eosinophils) with increases in IL-5 in BALF and airway hyperresponsiveness to acetylcholine in BALB/c mice. All drugs were orally administered once a day for 10 days from the day before the first inhalation of antigen. HSR-609 (10 mg/kg) and prednisolone (5 mg/kg) significantly inhibited the antigen-induced airway hyperresponsiveness, whereas cetirizine (10 mg/kg) or terfenadine (100 mg/kg) did not affect this airway response. At the same time HSR-609 inhibited the antigen-induced eosinophilia and IL-5 production in BALF. Prednisolone also showed an inhibitory effect on the airway eosinophilia and IL-5 production but not cetirizine and terfenadine in the same experiments. In addition, HSR-609 (p.o.) dose-dependently suppressed the accumulation of eosinophils elicited by antigen-stimulated D10G4.1 cells, a murine Th2 clone, in peritoneal cavity lavage fluid in AKR/J mice. These results suggest that HSR-609 inhibits allergic airway hyperresponsiveness to acetylcholine probably because of the inhibition of Th2-dependent eosinophilia caused by IL-5. In addition, effects of HSR-609 were different from those of cetirizine and terfenadine concerning the inhibition of antigen-induced airway hyperresponsiveness in mice.
The CYP2C19 Enzyme Polymorphism
Authors: Wedlund Peter J.
Published: April 2003

The genetic test is gradually replacing probe drugs as the primary tool for screening populations for the CYP2C19 polymorphism. A full appreciation for the clinical and toxicological relevance of this genetic variation is presently limited. Further research is needed in several areas. The development and use of 3-D models of the CYP2C19 enzyme to automate and increase the rate at which CYP2C19 substrates are identified could reap great benefits. Meanwhile, clinical research should begin to determine whether the CYP2C19 polymorphism affects therapeutic outcomes and toxicity of drugs in actual patient settings. Combining research efforts in molecular modeling, genetic testing, clinical and epidemiological research will be required if better appreciation of this genetic variation and its importance in the population at large is to emerge.
A Longitudinal Study of the Development of Temporal Properties of Speech Production: Data from 4 Children
Authors: Smith Bruce L. , Kenney Mary Kay
Published: April 2003

A general conclusion that has emerged from the collective results of a number of studies regarding acoustic characteristics of children’s speech production development is that both the duration and temporal variability of segments, words, and phrases tend to decrease as one considers increasingly older groups of children. While this conclusion is largely appropriate when considering averages for groups of children studied across intervals of several years, the limited amount of longitudinal data that exists suggests that similar patterns may not routinely be observed in the development of individual children, especially when shorter time periods are involved. Cross-sectional, acoustic studies have provided important general descriptions of speech production development, but additional longitudinal investigations are also needed to address issues that cannot be effectively evaluated utilizing cross-sectional data. For example, it was hypothesized in the present study that decreases in duration and variability would be greater when children were younger and that progressively smaller decreases would occur as they became older. Despite general tendencies for decreases in duration and variability to occur with increased age, it was also hypothesized that not all segments and words would be affected to the same extent in this regard. To consider these and related questions, the speech of 4 children was recorded approximately every 7–10 months for periods ranging from 4 to 6 years. There was some support for the notion that duration/variability decreases were greater when children were younger, but often this was not observed. It was also found that whereas some sounds/words decreased in duration across time, others remained relatively constant. Also, within the same word, certain segments became shorter across time, while others remained unchanged. These observations provide a perspective concerning speech production development that represents an important supplement to more general conclusions that have been obtained from group-oriented studies.
Mancunian Intonation and Intonational Representation
Authors: Cruttenden Alan
Published: April 2003

There has been little systematic description of the intonation of English accents other than RP and General American. In the first part of this article the characteristics of the tones of Mancunian intonation are described together with a functional categorisation of these tones, in which a dichotomy is proposed between Open and Closed varieties. In the second part the description is related to the current model of intonation known as ToBI and the inadequacies of a representation of Mancunian tones in a standard and a modified form of ToBI are revealed. A more radical modification of the ToBI approach based on tonal features is proposed.
Laparoscopic Surgery in a Patient with a Ventriculoperitoneal Shunt: A New Technique
Authors: Gaskill Sarah J. , Cossman Ronald M. , Hickman Mark S. , Marlin Arthur E.
Published: April 2003

With advances in the treatment of hydrocephalus, patients with ventriculoperitoneal shunts (VPS) often have normal life expectancies. They are therfore more commonly requiring abdominal surgery. Laparoscopic surgery has become the favored technique for performing many of these operations. However, the presence of a VPS has been considered a contraindication or hazard in performing many of these laparoscopic operations. We present a case report of a laparoscopic Toupet fundoplication in a patient with a VPS and describe a technique for the successful management of the VPS throughout the procedure with no adverse sequelae.