bluuebunny/crossref_metadata_2025 huggingface dataset:
Levcromakalim decreases vascular tone, cytoplasmic Ca2+and Ca2+sensitivity in canine basilar artery
Authors: Sugai K , Yanagisawa T , Motohashi O , Suzuki M , Yoshimoto T
Published: August 2009

Summary—The involvement of large conductance Ca2+‐activated K+channels (BK) and ATP‐sensitive K+(KATP) channels in the regulation of canine basilar arterial tone was estimated in the presence of the agonist and blockers of these channels, by simultaneously measuring the changes in intracellular Ca2+concentration ([Ca2+]i) with the fura‐2 microfluorimetric method. In the resting condition, levcromakalim reduced [Ca2+]iand vascular tone. Levcromakalim suppressed the serotonin‐induced increases in [Ca2+]iand force of contraction, the maximum effects of which were much greater than those of nicardipine. The inhibitory effects of levcromakalim were blocked by glibenclamide but not by tetraethylammonium (TEA) or iberiotoxin (IbTX). In the presence of levcromakalim, the curve relating [Ca2+]iwith force in the presence of serotonin at different extracellular Ca2+concentration ([Ca2+]o) was shifted down‐ and right‐ward compared with that in the absence of levcromakalim, suggesting that levcromakalim may reduce the Ca2+‐sensitivity of the contractile proteins. Thus, levcromakalim may be a good candidate to suppress delayed cerebral vasospasm after subarachnoid hemorrhage.
In vitro effects of Uriage spring water on the apoptosis of human eosinophils
Authors: Beauvais F , Garcia‐Mace JL , Joly F
Published: August 2009

Summary— The influx of eosinophils in tissues plays a central role in the pathophysiology of allergic diseases such as allergic rhinitis, allergic asthma or atopic dermatitis. The death of eosinophils by apoptosis is an important factor for the resolution of hypereosinophilia. In the present study, we have shown that Uriage spring water induced in vitro the apoptosis of IL‐5‐primed eosinophils. This effect was dose‐dependent and was statistically significant at Uriage water concentrations above 20%. The induction of apoptosis was related to the Ca2+ content of Uriage water. Indeed, Ca2+ at the same concentration as in Uriage water mimicked the apoptotic effect of the spring water. Furthermore, EGTA reversed the apoptotic effect of Uriage water. These results suggest that topically applied, Uriage water could contribute to the resolution of eosinophilic inflammation.
Acute effects of bisoprolol on respiratory sinus arrhythmia
Authors: Wargon M , Laude D , Girard A , Elghozi JL
Published: August 2009

Summary— Respiratory sinus arrhythmia (RSA) is often quantified by computing the spectra of heart period (HP) or of its reciprocal heart rate (HR) at the respiratory frequency. This study was undertaken to describe the effect of an acute beta‐blockade achieved with bisoprolol on RSA, obtained during a calibrated breathing (breathing frequency 0.25 Hz, tidal volume VT 500 or 700 mL) in 15 normal volunteers, using a double‐blind, placebo‐controlled, cross‐over method. The two heart signals were computed and the RSA values were compared to the individual estimates of vagal tone obtained using an additional atropine injection. The difference between the HP (or HR) value obtained after beta‐blockade and the HP (or HR) value observed following the double blockade (bisoprolol plus atropine) was taken as an index of cardiac vagal tone. Bisoprolol administration resulted in a significant reduction in HR reaching 60.3 ± 1.4 bpm at VT of 500 mL (compared to 70.5 ± 1.8 bpm with placebo, P < 0.001). Changes in HP were also significant with an increase in HP reaching 1004.5 ± 22.2 msec at this controlled VT (compared to 860.3 ± 21.5 msec with placebo, P < 0.001). Similar changes were observed at a VT of 700 mL. The relationship between RSA in bpm and vagal tone was not significant for HR while a significant positive relationship was observed between RSA in msec and vagal tone for the two respiratory patterns (r = 0.65 for a tidal volume of 500 mL, P < 0.01, and r = 0.62 for 700 mL, P < 0.05). This demonstrates that the detection of the variability effect highly depends upon the unit. The parallelism between vagal tone and RSA supports the view that the HF component of HRV in msec quantifies the vagal tone. The increased RSA during beta‐blockade could well reflect this vagotonic effect of this class of drugs.
Effect of bromazepam versus placebo on inhibition and waiting capacity in young women with traits of anxiety
Authors: Schuck S , Allain H , Gandon J‐M , Patat A , Millet V , Le Coz F
Published: August 2009

Summary—The effect of 3 dosages of bromazepam administered as single oral doses (1.5, 3 and 6 mg) on anxious inhibition phenomena was studied in a population of 16 young women (18–30 years) with anxiety‐traits, selected on the criteria of Cattell's anxiety scale supported by two personality inventory (Eysenck's, MMPI). A double‐blind, placebo study design was chosen. The main assessment criteria were based on the go/no‐go test (Logan's procedure), slow response rate (SRR) and a task of forced or unforced decision (use of the CFF). Attentional processes and declarative memory were analyzed as secondary criteria. None of the three dosages modified inhibition or acting‐out. Sustained attention was reduced with 1.5 mg and 6 mg, as was memory performance with 3 and 6 mg, 3.5 h after drug administration. In contradistinction with studies carried out in healthy volunteers or with other benzodiazepine compounds, bromazepam at single low dosages does not modify inhibition capacity in these subjects with traits of anxiety, in this particular procedure.
Serotonin syndrome: history and risk
Authors: Gillman PK
Published: August 2009

Summary—This review focuses on the history of investigations into the behavioural reaction resulting from excess stimulation of postsynaptic 5‐hydroxytryptamine receptors and the relative risk of this occurring with different combinations of drugs. Other aspects, particularly treatment with 5‐hydroxytryptamine receptor antagonists, are reviewed in a recent separate paper [44]. The first human case was in 1955 and animal work had defined the characteristic features by 1958, and established they were lessened by chlorpromazine. Substantial evidence of a ‘dose‐effect’ relationship existed by 1984. The relative risk with different drug combinations is assessed from available evidence and argued to be strongly associated with the degree of elevation of 5‐hydroxytryptamine, which is greatest following combinations of irreversible inhibitors of monoamine oxidase A and B with potent serotonin reuptake inhibitors. The various serotonergic drugs that may be implicated in serotonin syndrome are tabulated and discussed in relation to the relative risk. It is suggested that the proposed ‘diagnostic criteria’ for serotonin syndrome are inappropriate since there is a continuous spectrum from side effects to toxicity. The term ‘serotonin syndrome’ may encourage the presumption that it is an idiosyncratic response, as neuroleptic malignant syndrome is usually considered to be. The terms ‘toxic serotomimetic reaction’ or ‘toxic serotonin syndrome’ may be preferable alternatives. The differences between serotonin syndrome and neuroleptic malignant syndrome are highlighted with examples from difficult or questionable cases in the recent literature. It is proposed that more systematic national collection of toxicity data is essential in order to quantify the relative risk of serotonin syndrome with various combinations of serotonergic drugs.
Studies by electron paramagnetic resonance of the importance of iron in the hydroxyl scavenging properties of ascorbic acid in plasma: Effects of iron chelators
Authors: Benderitter M , Maupoil V , Vergely C , Dalloz F , Briot F , Rochette L
Published: August 2009

Summary— Ascorbic acid is considered to be the most important antioxidant of plasma. Its oxidation leads to the ascorbyl free radical (AFR), detected by electron paramagnetic resonance (EPR) spectroscopy. The purpose of this study was to investigate by EPR the interaction of plasma AFR levels in different situations of oxidative stress. Our results showed that plasma AFR remains constant after rat feeding with vitamin C (5 mg or 50 mg per 100 g body weight). We also demonstrated that: (1) the ascorbyl free radical (AFR) level was increased after direct addition of iron Fe3+/EDTA to plasma, the optimal level was reached after addition of 8 μM Fe3+/EDTA (1:2); (2) this AFR production was associated with the formation of hydroxyl radicals. Iron chelators (deferrioxamine, a synthetic iron chelator and apotransferrine, a biological iron chelator) added just before the Fe3+/EDTA complex inhibited the increase of AFR signal induced by this complex. The scavenging effect of plasma was significantly correlated with the AFR production. Therefore, AFR, which is naturally present in plasma, could be used as an index of oxidative stress in which free radicals or adverse iron mobilisation are implicated.
Anticonvulsant action of a NMDA receptor antagonist CGP 40116 varies only quantitatively during ontogeny in rats
Authors: Haugvicová R , Mareš P
Published: August 2009

Summary— Anticonvulsant action of CGP 40116, a competitive antagonist of N‐methyl‐D‐aspartate type of excitatory amino acid receptors, was studied in rats during development (7, 12, 18, 25 and 90 days old). Two types of motor seizures were elicited by a subcutaneous injection of pentylenetetrazol. Pretreatment with CGP 40116 did not influence minimal, predominantly clonic seizures in any age group. Generalized tonic‐clonic seizures were at first modified — their tonic phase was restricted to forelimbs, then selectively suppressed — and with increasing dosage the clonic phase was blocked too. This effect exhibited only minor quantitative changes during development.
Dextromethorphan and dextrorphan in rats: Common antitussives — Different behavioural profiles
Authors: Dematteis M , Lallement G , Mallaret M
Published: August 2009

Summary—Dextromethorphan (DM), a widely used and well‐tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)‐like side‐effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP‐like non‐competitive antagonist at the N‐methyl‐D‐aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose‐dependent decrease in both locomotion and stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30,40 mg/kg) induced a dose‐dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20–40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in the cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long‐lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10–30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10–30 mg/kg) and DX (5–15 mg/kg) did not impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP‐like effects for DX. However, PCP‐like side‐effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.
Effects of nerve growth factor on brain glutathione‐related enzymes from aged rats
Authors: Cruz‐Aguado R , Fernández‐Verdecia CI , Díaz‐Suárez CM , González‐Monzón O , Antúnez‐Potashkina I , Bergado‐Rosado J
Published: August 2009

Summary—Neurotrophins, like the nerve growth factor (NGF), trigger a variety of biological effects in their targets. Stimulating effects on antioxidant defenses have been postulated to underlie neurotrophic influence on neuron survival and maintenance. To test whether NGF is capable of inducing changes in glutathione‐related enzymes in the aged cognitively impaired brain, glutathione reductase (GRD), glutathione S‐transferase (GST) and total glutathione peroxidase (GPX) activities were measured in the striatum, septum, hippocampus and frontal cortex of four Sprague‐Dawley rat groups: young (2 months old), aged (20 months old) untreated, aged cytochrome c‐treated, and aged NGF‐treated (icv delivery, 34 4mUg during 28 days). All the aged rats utilized in the study were memory impaired according to their performance in the Morris water maze test. These aged rats showed increases in the activities of septal and hippocampal GST, as well as, in the hippocampal, striatal and cortical GPX. These increases could be interpreted as compensatory responses to cope with the oxidative damage that has been accumulated by the aged brain. The increases in hippocampal and cortical GPX activity were attenuated by NGF treatment, whereas the neurotrophin induced an increase in GRD activity in the striatum of aged rats. These results point out GRD and GPX as possible targets of the neurotrophic effects.
α1D‐Adrenoceptors contribute to the neurogenic vasopressor response in pithed rats
Authors: Castillo EF , López RM , Rodríguez‐Silverio J , Bobadilla RA , Castillo C
Published: August 2009

Summary—The aim of the present study was to assess the role of vascular α1D‐adrenoceptors in the sympathetic vasopressor response in vivo. Specifically, we evaluated the effect of a selective α1D‐adrenoceptor antagonist, BMY 7378 (8‐(2‐(4‐(2‐methoxyphenyl)‐1‐piperazinyl)ethyl)‐8‐azaspiro(4,5)decane‐7,9‐dione 2HCI), on the vasopressor response induced by preganglionic (T7‐T9) sympathetic stimulation in the pithed rat. The vasopressor response was dose‐dependently sensitive to inhibition by intravenous BMY 7378 (0.1, 0.31, 1 and 3.1 mg/kg), doses of 1 and 3.1 mg/kg being equally effective. Like BMY 7378, 5‐methylurapidil (0.1, 0.31, 1 and 3.1 mg/kg) antagonized the vasopressor response to spinal stimulation; doses of 1 and 3.1 mg/kg were also equally effective. In combination experiments, BMY 7378 (1 mg/kg, iv) and the α1A‐adrenoceptor antagonist, 5‐methylurapidil (1 mg/kg, iv), showed an additive effect. The present results demonstrate that the α1D‐adrenoceptor subtype plays an important role in the pressor response to sympathetic nerve stimulation in the pithed rat, and confirm the participation of the α1A‐adrenoceptor subtype in the same response.
Pharmacokinetic and pharmacodynamic variations of acenocoumarol orally administrated either once or twice daily in patients with deep venous thrombosis
Authors: Mismetti P , Reynaud J , Laporte‐Simitsidis S , Thijssen H , Tardy‐Poncet B , Tardy B , Buchmuller A , Decousus H
Published: August 2009

Summary— The literature suggests that variations in anticoagulant effect occur when acenocoumarol is administrated in a daily dose. We assessed the anticoagulant effects of acenocoumarol with INR, factors VII and X and protein C in 12 randomly selected hospitalised patients with deep‐vein thrombosis, six of them receiving a daily dose of acenocoumarol, the other six receiving twice‐daily doses. When the drug effect had been at a steady‐state for at least 72 h, five blood samples were drawn per patient over a period of 24 h. No nycthemeral significant variations were noted for INR, factor X and protein C in the two groups (P > 0.10). Nycthemeral significant variation in factor VII when acenocoumarol was administered once daily was noted (P = 0.02), but the clinical relevance of factor VII variation at steady‐state is uncertain. In spite of the short pharmacokinetic half‐life of acenocoumarol, a stable nycthemeral pharmacodynamic activity was observed after once daily administration; twice‐daily administration of acenocoumarol does not appear to be justified.
Ethics and clinical trials1
Authors: Chassany Olivier , Duracinský Martin
Published: August 2009

Abstract— The current reference guideline about ethics in clinical trials is the Declaration of Helsinki of human rights in medical research. Three major principles are emphasised: respect of the patient to accept or not to participate in a trial, the constraints and the presumed risks must be acceptable for patients included in a study, and vulnerable subjects should not participate in studies. The investigator is responsible for obtaining a free and well‐informed consent from patients before their inclusion in a study. Where possible, a new drug should always first be compared to placebo in order to prove its superiority. Else, a small‐sized trial comparing a new drug versus a reference treatment can lead to an erroneous conclusion of absence of difference. Moreover, good results or improvement are obtained in at least 30% of cases with placebo, whatever the disease. The use of placebo is unethical in life‐threatening diseases and when an effective proved drug exists. The use of placebo is ethical in severe diseases with no efficient drug, in some severe diseases even when an active reference treatment is available, and in all moderate and functional diseases. In order to detect flawed studies, most journals now ask for any manuscript submitted and reporting results of a randomised clinical trial to join a checklist in order to verify the quality of the trial. Finally, it remains the responsibility of the doctor to decide whether or not a protocol is ethical, to participate or not and to include patients or not.
Endothelin, but not angiotensin II, contributes to the hypoxic contractile response of large isolated pulmonary arteries in the rat
Authors: Pape Danielle , Goineau Sonia , Guillo Pascal , Durand‐Castel Xavier , Bellissant Eric
Published: August 2009

Abstract— The aims of this study were to investigate whether angiotensin II and/or endothelin could contribute to the hypoxic contractile response of isolated rat pulmonary artery. Experiments were performed for 1 h on noradrenaline precontracted arterial rings in hypoxic conditions (95% N2 and 5% CO2). Nicardipine, lisinopril, losartan, phosphoramidon, FR139317 and bosentan were used to block Ca2+ channels, angiotensin I‐converting enzyme, AT1 receptors, endothelin‐converting enzyme, ETA receptors, and ETA/ETB receptors, respectively. The profile of the hypoxic contractile response was biphasic, displaying, after a short relaxation, a weak and transient contraction (from 2–4 min) and then, before complete relaxation, a slowly developed but sustained contraction (from 14–60 min). Endothelium removal abolished the transient contraction and reduced (–59%) the sustained contraction. Nicardipine did not modify the transient contraction, but concentration‐dependently decreased (from –35% to –100%) the sustained contraction (P = 0.024). Lisinopril and losartan did not affect the response (P = 0.418 and P = 0.973, respectively). Bosentan did not modify the transient contraction, but concentration‐dependently decreased (from –14% to –71%) the sustained contraction (P = 0.016), whereas phosphoramidon and FR139317 did not affect the response (P = 0.830 and P = 0.806, respectively). Conclusions: in rat, (i) both phases of the hypoxic contractile response are endothelium‐dependent and independent of angiotensin II; (ii) the transient contraction does not depend on endothelin; (iii) the sustained contraction, which involves calcium influx, appears partly dependent on mature endothelin released from storage granules by stimulating ETB receptors.
Soman‐induced hypertension in conscious rats is mediated by prolonged central muscarinic stimulation
Authors: Létienne Robert , Julien Claude , Barrès Christian , Lallement Guy , Baubichon Dominique , Bataillard Alain
Published: August 2009

Abstract— The acetylcholinesterase inhibitor, soman, induces marked and sustained hypertension and tachycardia associated with a convulsive syndrome in rats. The aims of the present study were to distinguish between the cardiovascular and convulsant effects of soman and to determine whether the maintenance of the soman‐induced hypertension and tachycardia depends solely on a central muscarinic effect. To this end, using a computerised analysis of blood pressure (BP) in conscious freely moving rats, we examined the consequences on the increase in mean BP (MBP) and heart rate (HR) induced by soman (60 μg/kg, i.v.) of 1) a pre‐treatment with the anticonvulsant drug diazepam (3 mg/kg, i.v.) and 2) atropine sulphate (10 mg/kg, i.v.) administered 10 or 60 min after the intoxication. Pretreatment with diazepam prevented the convulsions, assessed by electroencephalogram (EEG) recording, but modified neither the magnitude nor the kinetics of the pressor and tachycardic effects of soman (Δ MBP = 74 ± 2 and 73 ± 5 mmHg, Δ HR = 69 ± 10 and 79 ± 7 bpm, maximum MBP = 186 ± 3 and 182 ± 6 mmHg, maximum HR = 545 ± 9 and 522 ± 16 bpm in solvent‐ (n = 8) and diazepam‐ (n = 8) pre‐treated rats, respectively). Whatever its time of administration, atropine sulphate fully and immediately reversed the rise in BP induced by soman. The soman‐induced tachycardia was also suppressed by atropine administered 10 min after soman whereas it persisted when atropine was injected 60 min after the intoxication. These results show that the cardiovascular effects of soman can occur independently of the convulsive syndrome and that the maintenance of the soman‐induced hypertension depends entirely on a permanent central muscarinic stimulation.
Functional, endogenously expressed corticotropin‐releasing factor receptor type 1 (CRF1) and CRF1receptor mRNA expression in human neuroblastoma SH‐SY5Y cells
Authors: Schoeffter Philippe , Feuerbach Dominik , Bobimac Ionel , Gazi Lucien , Longato Rémy
Published: August 2009

Abstract—Corticotropin‐releasing factor (CRF) is a hypothalamic 41‐amino acid peptide which stimulates corticotropin (ACTH) release from the anterior pituitary and is also involved in the body response to stress. CRF, receptors represent a potential target for novel antidepressant/anxiolytic drugs. The aim of the present study was to search for a human cell line expressing native, functional CRF, receptors as a starting material for screening purposes. We identified CRF, receptors functionally coupled to cAMP formation in human neuroblastoma SH‐SY5Y cells. CRF induced concentration‐dependent increases in cAMP accumulation in SH‐SY5Y cells (maximal increase 6.9 ± 0.9 fold over basal values,n= 14). This effect was mimicked by related peptides with similar potencies: (mean pEC50value) human/rat CRF (8.63), rat urocortin (9.32), sauvagine (8.97), urotensin I (8.93), ovine CRF (8.81). The efficacies of these agonists were nearly the same, with the exception of ovine CRF which was slightly less efficacious (75% the Emaxof CRF). The responses to CRF were competitively antagonised by the following peptide fragments (mean pKBvalue): α‐helical‐CRF (9–41) (7.54), [D‐Phe12, Nle21,38, CαMeLeu37]CRF (12–41) (8.36) and [D‐Tyr12]astressin (9.49) and by the selective, non‐peptidic CRF, receptor antagonists, CP‐154,526 (7.76) and antalarmin (9.19). Estimation of receptor density by [125I]Tyr0‐ovine CRF saturation binding yielded a modest number of binding sites (Bmax12 fmol/mg protein, KD0.2 nM). Analysis of mRNA by reverse transcription‐polymerase chain reaction clearly revealed the presence of mRNA for CRF1receptors in SH‐SY5Y cells. A slight signal for CRF2receptor mRNA was also observed. We conclude that neuroblastoma SH‐SY5Y cells are endowed with native CRF1receptors positively coupled to cAMP formation. They therefore constitute a useful functional model for the search of CRF1selective compounds with potential anxiolytic/antidepressant activity.
Effect of povidone‐iodine on wound healing in control, diabetic and steroid depressed rats
Authors: Margaret Isukapalli , Praveen Bhoopathi , Jamil Kaiser
Published: August 2009

Abstract— A comparative study was made on the effect of povidone‐iodine on wound healing in normal, diabetic and steroid depressed states in the excision wound model in rats. Healing was assessed by the rate of contraction of wounds and epithelialization after three weeks of topical application. Normal and diabetic groups were comparable (P <0.02) concerning the above‐mentioned parameters as well as collagen formation. The steroid group showed significant retardation in healing time (P <0.001), epithelialization (P <0.001) and collagen formation (P <0.001) showing that povidone‐iodine did not overcome the steroid effect.
Effects of cigarette smoking on short‐term variability of blood pressure in smoking and non smoking healthy volunteers
Authors: Ragueneau Isabelle , Michaud Pierre , Démolis Jean‐Louis , Moryusef Angèle , Jaillon Patrice , Funck‐Brentano Christian
Published: August 2009

Abstract— The present trial was planned to study the effects of smoking on short‐term variability of blood pressure and on haemodynamic parameters after an overnight cessation and after one day of repeated smoking in healthy cigarette smoking volunteers, compared to a control group of non‐smokers who were not asked to smoke. 40 healthy male volunteers, 20 smokers and 20 non‐smokers, participated in an open study with two periods of measurements over a single day (morning and afternoon). Blood pressure and heart rate were measured using standard and finger recordings over 6 min before and 10 min after smoking one cigarette (in smokers only). During the two periods, smokers were asked to smoke 4 cm of a cigarette containing 1 mg of nicotine in 2 min, and a blood sample was taken for a plasma nicotine assay. In the smoking group, smoking the first cigarette of the day caused a significant increase of systolic blood pressure (+7%), diastolic blood pressure (+10%) and heart rate (+25%). The blood pressure variability in the frequency range of the Mayer waves (66–129 mHz) was increased after an overnight cessation of smoking in the smoking group in comparison to the non‐smokers, and decreased significantly after the first cigarette of the day (7.1 ± 4.0 to 3.2 ± 1.8 mmHg2; P <0.01). The changes observed in the afternoon after continuous smoking were significantly less important (3.8 ± 1.9 to 3.2 ± 1.9 mmHg2; NS). In the non‐smoking group, the different parameters remained stable between the different measurements. These results suggest that an overnight cessation of smoking in smoking subjects is associated with an increase in sympathetic activity to the vascular system in the morning, which is released by smoking the first cigarette. This effect of smoking is reduced in the afternoon after a continuous nicotinic impregnation.
Nicorandil, its denitrated metabolite, SG‐86 and naturally occurring vasodilators synergistically interact on adenosine‐induced vasodepression in rats: special reference to adrenomedullin
Authors: Sakai Kazushige , Saito Keiji
Published: August 2009

Abstract—To investigate synergistic effects among nicorandil, its main metabolite, SG‐86 and endogenous vasodilators such as adrenomedullin (ADM), vasoactive intestinal polypeptide (VIP) and calcitonin gene‐related peptide (CGRP), the effects of ADM, VIP and CGRP as well as nicorandil and SG‐86 alone, and their low‐dose combination were examined on adenosine‐induced vasodepression in anesthetized rats. Single bolus i.v. injections of adenosine (3–100 μg/kg) caused a dose‐dependent reduction of arterial blood pressure, accompanied by slight decreases (except for 100 μg/kg) in heart rate. I.v. infusion of nicorandil (10 μ/kg/min), SG‐86 (100 μ/kg/min), ADM (1 ng/kg/min), VIP (30 ng/kg/min) or CGRP (1 ng/kg/min) alone, or the low‐dose combination of either nicorandil (1 μg/kg/min) and SG‐86 (10 μg/kg/min) or either nicorandil or SG‐86 and endogenous vasodilators, significantly potentiated the vasodepression produced by bolus i.v. adenosine, but not that by bolus i.v. acetylcholine (0.1 μg/kg). The observed enhancement did not occur in the presence of glibenclamide (20 mg/kg i.v.). The present results indicate that nicorandil, SG‐86 and endogenous vasodilators reciprocally interact, partly in link with KATPchannels in vascular smooth muscle.
A study on the effects of endogenous nitric oxide on coronary blood flow, myocardial oxygen extraction and cardiac contractility
Authors: Okubo Tomoyuki , Suto Naoyuki , Kudo Shigeaki , Hanada Hiroyuki , Mikuniya Atsushi , Okumura Ken
Published: August 2009

Abstract— The purpose of the present study was to clarify how endogenous nitric oxide (NO) affects cardiac contractility and myocardial oxygen consumption (MVO2) in vivo. α‐Chloralose‐anesthetized dogs (n = 18) were instrumented to perform continuous and simultaneous measurements of coronary blood flow (CBF), anterior interventricular vein oxygen saturation (with the use of a fiberoptic catheter), aortic pressure, left ventricular pressure, and left ventricular volume. CBF, myocardial oxygen extraction (O2‐extract), MVO2, the relationship between CBF and O2‐extract during direct vasodilation induced by intracoronary papaverine (0.1, 0.2, 0.4 mg/kg), and cardiac contractility (Emax) were examined at control, after intracoronary infusion of NG‐monomethyl‐L‐arginine (L‐NMMA, 2 mg/kg) and after antagonization of NO by L‐arginine (20 mg/kg). L‐NMMA decreased CBF from 62.0 ± 1.7 to 59.7 ± 2.4 (mL/min/100 g, P < 0.05) and increased O2‐extract from 68.2 ± 1.7 to 79.0 ± 1.7% (P < 0.05). Emax was increased after L‐NMMA from 3.2 ± 0.2 to 3.7 ± 0.1 (mmHg/mL/100 g, P < 0.05). These effects of L‐NMMA were antagonized by L‐arginine (P < 0.05 vs. after L‐NMMA, P = NS vs. before L‐NMMA). L‐NMMA shifted CBF and O2‐extract relationship determined by papaverine injection upward and L‐arginine antagonized it to its baseline level. Endogenous NO reduces cardiac contractility and decreases MVO2, while increasing CBF.
Role of the calcium/calmodulin‐dependent protein kinase II in the regulation of the renal basolateral PAH and dicarboxylate transporters1
Authors: Gabriëls G. , Krämer C. , Stärk U. , Greven J.
Published: August 2009

Abstract—The aim of the present study was to investigate whether the activities of the renal basolateral organic anion transporter (PAH transporter) and the sodium‐dependent dicarboxylate transporter are modulated by the calcium/calmodulin‐dependent multifunctional protein kinase II (CaM kinase II). The studies were performed on isolated S2segments of proximal tubules microdissected from rabbit kidneys without the use of enzymatic agents.3H‐PAH was used as marker substance of the anion transporter, and14C‐glutarate as a marker of the sodium/dicarboxylate cotransporter. Because the tubules were not perfused, and hence were collapsed, the tubular uptake of the marker substances reflects transport across the basolateral cell membrane. To obtain uptake rates most closely related to initial transport rates, 30 s tubular uptake measurements were performed. The results show that a selective inhibitor of CaM kinase II, KN93, inhibited tubular PAH uptake. The smallest effective dose was 10−7M. An inactive analogue of KN93, KN92, was without effect, even at the high concentration of 105M. In contrast to PAH transport, tubular14C‐glutarate uptake was not affected by KN93 (10−5M). PAH transport was also inhibited after elevation of intracellular Ca2+by the Ca2+‐ionophore A 23187 and by the polycationic antibiotic neomycin, but not by the intracellular Ca2+modulators thapsigargin and ryanodine. The effect of the Ca2+‐ionophore could be abolished by KN93, but not by Rp‐cAMPs, an inhibitor of protein kinase A, indicating that this event was mediated by CaM kinase II, but not by PKA. The results provide the first evidence that, in addition to the protein kinases A and C (previous studies from this lab), CaM kinase II has a role in the regulation of the renal basolateral PAH transporter, whereas the renal basolateral dicarboxylate transporter does not depend on CaM kinase II activity.
In vitro and in vivo effects of the new nonpeptide bradykinin B2receptor antagonist, LF 16‐0335C, on guinea‐pig and rat kinin receptors
Authors: Pruneau Didier , Luccarini Jean‐Michel , Fouchet Chantal , Defrêne Evelyne , Franck Rose‐Marie , Loillier Bruno , Duclos Hervé , Robert Claude , Cremers Béatrice , Bélichard Pierre , Paquet Jean‐Luc
Published: August 2009

Abstract—Activation of the kinin‐kallikrein system and stimulation of bradykinin (BK) B2receptors are thought to play an important role in the pathophysiology of inflammation and pain. In the present study, we report the pharmacological properties of a novel nonpeptide bradykinin B2receptor antagonist, LF 16‐0335C, (1‐[[3‐[(2,4‐dimethylquinolin‐8‐yl)oxymethyl]‐2,4‐dichloro‐phenyl]sulfonyl]‐2(S)‐[[4‐[4‐(aminoiminomethyl)‐phenylcarbonyl]piperazin‐1‐yl]carbonyl]pyrrolidine, 2HC1). In binding studies, LF 16‐0335C competed with [3H]bradykinin givingKivalues of 1.65 ± 0.36 nM and 2.20 ± 0.30 nM in membrane preparations from rat uterus (RU) and guinea‐pig ileum (GPI), respectively. In functional experiments, LF 16‐0335C inhibited in a competitive manner BK‐induced contractions of both isolated RU and GPI, leading to calculated pA2values of 7.70 ± 0.70 and 8.30 ± 0.30, respectively. The inhibitory effect of LF 16‐0335C was fully reversible by washing in the guinea‐pig ileum. In vivo, LF 16‐0335C given intravenously inhibited in a dose‐dependent manner BK‐induced hypotension in both animal species, although it was more potent in the guinea‐pig than in the rat (ED50, 2.5 ± 1.6 μg/kg versus 22.6 ± 2.3 μg/kg). BK is a potent constrictor of guinea‐pig airways and this effect was markedly attenuated by LF 16‐0335C. In contrast, LF 16‐0335C did not affect histamine‐ and acetylcholine‐induced hypotensive response in the rat. We conclude that LF 16‐0335C is a potent and selective nonpeptide B2receptor antagonist which equally binds to the rat and guinea‐pig receptor but displays a different in vivo potency in the two species. Therefore, this drug represents a useful tool to better assess the role of bradykinin in pathophysiological conditions.
Effects of cinnarizine on different experimentally induced oedemas
Authors: Blazsó Gábor , Rázga Zsolt , Gábor Miklós
Published: August 2009

Abstract—Experiments with male mice (28–32 g) of the CFLP strain showed that cinnarizine in doses of 2.5, 5.0 or 10.0 mg kg−1significantly inhibited the extent of ear oedema induced by croton oil, capsaicin or dithranol, in a dose‐dependent manner. In rats of the Wistar strain, oedema was induced in the hind paw by subplantar injection of carrageenin, and simultaneously by the application of croton oil to the inner surface of the ear. Preliminary cinnarizine treatment (5, 10 or 20 mg kg−1) inhibited the development of both types of oedema, to a statistically significant extent, in a dose‐dependent manner.
Effects of interleukin‐10 and modulators of cyclic AMP formation on endotoxin‐induced inflammation in rat lung
Authors: Escofier Nicolas , Boichot Elisabeth , Germain Noëlla , Silva Patricia M.R.e , Martins Marco A. , Lagente Vincent
Published: August 2009

Abstract—The aim of this study was to investigate the effects of IL‐10, a cell permeable analogue of cyclic AMP, dibutyryl‐cAMP (db‐cAMP), modulators of intracellular cyclic AMP such as phosphodiesterase (PDE) inhibitors and a β2‐adrenoceptor agonist, salmeterol, on pulmonary inflammation following acute lung injury induced by endotoxin exposure in rats. Pulmonary inflammation was induced in adult Wistar rats by a 60‐min exposure to endotoxin (lipopolysaccharide, LPS, 100 μg/mL). 4 h later bronchoalveolar lavage (BAL) was performed. The PDE inhibitors, rolipram (3 and 5 mg/kg) and theophylline (30 and 100 mg/kg) inhibited neutrophil recruitment, TNF‐α release and cellular activation in BAL. Salmeterol (0.5 mg/mL) and IL‐10 (0.1 μg) only inhibit TNF‐α increase in the BAL fluid and db‐AMPc (2.5 μg/rat) was ineffective. The present data show that the selective PDE4 inhibitor, rolipram, and the non‐selective PDE inhibitor, theophylline, markedly reduced the pulmonary inflammation associated with acute lung injury in the rat. These effects may be mediated in part by IL‐10 rather than by cyclic AMP, as demonstrated by the potent inhibitory activity of exogenous IL‐10 on the increase in TNF‐α release in BAL fluid of rats exposed to LPS.
The effect of chlorambucil upon lysozyme activity
Authors: Brecher Arthur S. , Rasmusson Erin , Riley Cheryl , VanDenBerghe Sharon
Published: August 2009

Abstract— Chicken egg white lysozyme is progressively inhibited by diazoacetyl‐DL‐norleucine methyl ester (DANME) and by chlorambucil at concentrations of 3.4 × 10−3 M and 5 × 10−3 M respectively over a three‐hour time period. DANME inhibits lysozyme activity to the extent of 87%, and chlorambucil inhibits the enzyme to the extent of 93%. N,N',N'‐triacetylchitotriose [(NAG)3], which binds to subsites A, B and C of the enzyme protects lysozyme from DANME inhibition to the extent of 40% of the total activity when added to the enzyme at a concentration of 3.6 × 10−3 M prior to the addition of DANME. (NAG)3 protects the enzyme from inhibition by chlorambucil to the extent of 14% of the total activity when added to the enzyme at a concentration of 5.6 × 10−3 M prior to the addition of chlorambucil. Since DANME reacts exclusively with carboxyl groups, and since aspartic acid 101 is required for binding the carbohydrate substrate at site A, it is suggested that (NAG)3 may bind reversibly to the active site of the enzyme, thereby protecting aspartic acid 101 from esterification by DANME and subsequent inactivation. Chlorambucil, which may react with carboxyl, amino, imidazole and thiol groups, more likely acts upon a larger number of susceptible sites, thereby causing irreversible alkylation and conformation changes. As a Afunctional alkylating agent, it may also cross‐link with two available nucleophiles. The Km for lysozyme with M. lysodeikticus as a substrate in wholly aqueous medium was determined to be 0.05 mg/mL. The inhibitor exhibits a partially uncompetitive inhibition upon pre‐incubation with the enzyme, and a mixed inhibition between competititve and noncompetitive when pre‐incubated with the substrate.
Comparative oxidation of loxapine and clozapine by human neutrophils
Authors: Jegouzo Anne , Grassier Bernard , Frimat Bruno , Brunet Claude , Dine Thierry , Luyckx Michel , Kouach Mostapha , Cazin Micheline , Cazin Jean‐Claude
Published: August 2009

Abstract—The clozapine‐induced agranulocytosis could be due to the formation of a reactive intermediate formed in polymorphonuclear neutrophils and granulocyte precursors with the myeloperoxidase‐hydrogen peroxide system. On the contrary, no case of agranulocytosis has been described for loxapine, an other neuroleptic drug with a very close structural analogy. We have compared the clozapine and loxapine interaction with the oxidative burst and particularly with this enzymatic complex. On the one hand, the assay of the oxidative species demonstrated a different impact for the two neuroleptics. The 50% inhibitory concentration was 92 μM for hydrogen peroxide and 40 μM for hypochlorous acid for loxapine. The loxapine target is located before the myeloperoxidase‐hydrogen peroxide system in the oxidative stream, whereas clozapine diverts the chlorination pathway of the enzyme. On the other hand, the in vitro metabolism of drugs by the myeloperoxidase‐hydrogen peroxide system has been investigated by mass spectrometry. Loxapine remains inert but clozapine undergoes the oxidation. The glutathione or ascorbate addition in the medium leads to a removal of the oxidation. Glutathione is able to trap the toxic intermediate and could avoid its formation.
Histamine H3receptor‐mediated inhibition of noradrenaline release in the human brain
Authors: Schlicker Eberhard , Werthwein Sven , Zentner Josef
Published: August 2009

Abstract—Stimulation‐evoked3H‐noradrenaline release in human cerebrocortical slices was inhibited by histamine (in a manner sensitive to clobenpropit) and by imetit, suggesting H3receptor‐mediated inhibition of noradrenaline release in human brain.
The pharmacological basis and pathophysiological significance of the heart rate‐lowering property of diltiazem
Authors: O'Connor Stephen E. , Grosset Alain , Janiak Philip
Published: August 2009

Abstract—The calcium channel blocker diltiazem lowers heart rate in man and this property probably contributes to its clinical effectiveness in ischaemic heart disease and hypertension. This review examines the pharmacological basis of diltiazem's heart rate‐lowering activity and considers its pathophysiological significance. The points discussed include the potent direct inhibitory effect of diltiazem on the sinus node and the frequency‐dependence of this action. In addition, the well‐balanced tissue selectivity profile of diltiazem and its ability to modulate cardiac reflex responsiveness contribute by counteracting the potential for reflex tachycardia.
Functional characterization of β‐adrenoceptors mediating relaxation in sheep gallbladder
Authors: Oriowo Mabayoje A. , Thulesius Olav
Published: August 2009

Abstract— The purpose of this study was to characterize β‐adrenoceptor subtype(s) mediating relaxation in smooth muscle strips of the sheep gallbladder. Experiments were performed on isolated smooth muscle strips suspended in tissue baths containing Krebs' solution. Isoprenaline (10−8 M‐10−5 M) and salbutamol (10−7 M‐10−4 M) produced concentration‐dependent relaxation of carbachol (10−7 M‐3 × 10−7 M) contracted smooth muscles of the sheep gall bladder. Isoprenaline‐induced relaxation was significantly antagonized by propranolol with ‐logKB values of 7.81 ± 0.11 (n = 7) and 7.73 ± 0.12 (n = 6) in the fundic and ductal strips respectively. Atenolol (10−5 M), a selective β1‐ adrenoceptor antagonist, also significantly antagonized isoprenaline‐induced relaxation with ‐logKB values of 5.82 ± 0.11 and 6.09 ± 0.09 in the fundic and ductal strips respectively. However, ICI 118551, a selective β2‐adrenoceptor antagonist, at concentrations up to 10−6 M had little or no effect on isoprenaline‐induced relaxation in either of these preparations. BRL 37344A, a selective β3‐adrenoceptor agonist produced concentration‐dependent relaxation of carbachol‐precontracted fundic and ductal strips. BRL 37344 was approximately 9‐fold more potent in the ductal than fundic strips. In both preparations, BRL 37344‐induced relaxation was not significantly (p > 0.05) antagonized by propranolol (3 × 10−7 M). This would confirm that the response was mediated via β3‐adrenoceptors. It was concluded that β1‐ and β3‐adrenoceptors coexist in the sheep gallbladder and mediate smooth muscle relaxation.
The influence of the wall tension on the contractile responses of arteries
Authors: Nunes José P.L. , Guimarães Serafim
Published: August 2009

Abstract—The present study aimed at determining the influence of tension on the responses of arterial smooth muscle to noradrenaline, phenylephrine and angiotensin II. Concentration‐response curves to these agonists were obtained in the rat aorta, at two levels of tension: 3 g (29.4 mN) and 0.5 g (4.9 mN). The results obtained show that the maximal responses to the agonists used (in percent of the maximal response to noradrenaline) were significantly larger (P< 0.05) at 3 g than at 0.5 g: 113% versus 66%, respectively, for noradrenaline; 95% versus 59%, respectively, for phenylephrine; 60% versus 24%, respectively, for angiotensin II. In the presence of gadolinium (100 μmol/L) ‐ a mechanogated ion channel blocker ‐ the responses to noradrenaline at 3 g were still significantly larger than responses at 0.5 g: 103% versus 67%, respectively. The compound H‐7 (20 μmol/L) ‐ a protein kinase C inhibitor ‐ caused a marked decrease in the maximal responses to noradrenaline at both levels of tension, the responses being reduced to 44% at 3 g and to 20% at 0.5 g. Isradipine (1 μmol/L) ‐ a calcium channel blocker ‐ caused a slight decrease in the responses to noradrenaline at both levels of tension, the responses being reduced to 86% (3 g) and to 50% (0.5 g). In endothelium‐free arterial rings, the responses to noradrenaline at 3 g and 0.5 g were also significantly different: 118% versus 80%, respectively. It is concluded that the tension of the arterial wall is a major factor influencing the effects of vasoconstrictor agents; however the mechanisms underlying this supersensitivity at higher tension remain unknown.
Endothelin‐1 and relaxation of the rat aorta during pregnancy in nitroarginine‐induced hypertension
Authors: Dieye Amadou Moctar , Van Overloop Bruno , Gairard Alexis
Published: August 2009

Abstract— In pregnant rats during hypertension induced by NO synthase inhibition, endothelin (ET) plasma levels are increased as in some preeclamptic women. Previously, the enhanced vasodepressor effect of endothelin‐1 (ET‐1) has been observed in this model, thus we decided to study the relaxation induced by ET‐I on the aorta. Non‐pregnant or pregnant Wistar rats (n = 7 by group) were fed for 7 days (day 13‐day 20) on a nitroarginine‐enriched diet (L‐NNA, 0.063% i.e. 30 mg/kg/day) or a control diet. Systolic blood pressure, measured by the tail cuff method on conscious rats at day 20 of gestation, was raised by the chronic L‐NNA treatment (mean ± s.e.m., mmHg, p < 0.001: pregnant L‐NNA treated, 145 ± 1.84 vs. pregnant control, 101 ± 2.00 and non‐pregnant L‐NNA treated, 148 ± 3.11 vs. non‐pregnant control, 119 ± 1.80). On day 20 ex vivo aortic ring relaxation was produced by ET‐1 in vessels previously precontracted with norepinephrine only when endothelium was present. In control rats, ET‐1 (10−8 to 5 × 10−8 M) produced a short but significant relaxation (mean value between 4 to 19%) followed by a long‐lasting contracting phase, and a higher ET‐1 concentration (10−7 M) only produced contraction. Chronic L‐NNA treatment decreased the level of relaxation (at least p < 0.05, in non‐pregnant and pregnant rats) and with a 30 min L‐NAME (10−4 M) preincubation, relaxation was completely inhibited in non‐pregnant and pregnant rats. BQ‐123, an ETA receptor antagonist, did not produce any effect on ET‐1 induced relaxation. BQ‐788, an ETB receptor antagonist, significantly decreased it. In conclusion, in female rats, as in male rats, ET‐1 induces a transient relaxation in the preconstricted aorta which involves endothelial ETB receptors. Despite a decrease in the systemic vascular reactivity during late gestation, the vasodilating and vasoconstricting properties of ET‐1 on the aorta are not changed.
Mibefradil, a potent CYP3A inhibitor, does not alter pravastatin pharmacokinetics
Authors: Becquemont Laurent , Funck‐Brentano Christian , Jaillon Patrice
Published: August 2009

Abstract— Dramatic drug‐drug interactions have been observed between several HMG‐CoA reductase inhibitors and cytochrome P450 3A (CYP3A) inhibitors. The aim of the present study was to investigate the effects of mibefradil, a potent CYP3A inhibitor, on pravastatin pharmacokinetics. 12 healthy volunteers were included in this open‐label one‐period study. Pravastatin pharmacokinetics (following a single oral dose of 40 mg) was studied in the absence of mibefradil (day 1) and after repeated doses (100 mg/day) of mibefradil (day 8). Pravastatin pharmacokinetics after repeated doses of 40 mg/day was also studied in association with repeated doses (100 mg/day) of mibefradil (day 16). Pravastatin area under the plasma concentration vs. time curve (AUC0‐∞,) and Cmax in the absence of mibefradil on day 1 (170 [117 to 395] ng h/mL and 91 [72 to 200] ng/mL respectively, geometric mean [95% confidence intervals]) were not significantly altered in the presence of mibefradil on day 8 (224 [174 to 381] ng h/mL and 124 [72 to 200] ng/mL) and on day 16 (200 [137 to 555] ng h/mL and 91 [74 to 184] ng/mL). Tmax of pravastatin in the absence of mibefradil (0.9 ± 0.1 h, arithmetic mean ± SD) was slightly delayed in the presence of mibefradil on day 8 and 16 (1.1 ± 0.3 and 1.2 ± 0.3 h respectively, p < 0.01 for both comparisons). The results of the present study confirm the lack of pharmacokinetic interactions between mibefradil and pravastatin and indicate that pravastatin may be safely prescribed in the presence of potent CYP3A inhibitors.