bluuebunny/crossref_metadata_2025 huggingface dataset:
Release of spermidine from the rat cortex following permanent middle cerebral artery occlusion
Authors: Carter C. , Poignet H. , Carboni S. , Fage D. , Voltz C. , Scatton B.
Published: August 2009

Summary—We have studied the effects of middle cerebral artery (MCA) occlusion in rats on polyamine efflux in the parietal cortex using the microdialysis technique. Dialysis probe implantation itself provoked a delayed, prolonged and vigorous release of spermidine and putrescine. Spermidine release returned to stable baseline levels within 48 hours. Putrescine release also returned to lower levels within this time period but putrescine levels in the dialysate fluctuated dramatically in individual animals. Because of the underlying effects of the dialysis probe (likely a reflection of traumatic cerebral damage and stimulation of polyamine metabolism and release within the immediate vicinity of the dialysis probe), MCA occlusion was performed 48 hours after probe implantation. MCA occlusion persistently (5/5 animals) resulted in a significant increase in cortical spermidine efflux, although the onset, magnitude and duration of this increased release was variable. Putrescine efflux was significantly increased in 2/5 animals with MCA occlusion but the increase in release was similar to the spontaneous fluctuations observed in control animals. Spermine was not detectable in cortical dialysates of control or MCA occluded groups. Spermidine, but not spermine or putrescine is consistently released from the parietal cortex following permanent focal ischaemia and may contribute to ischaemic neuropathology either through its effects at the N‐methyl‐D‐aspartate (NMDA) receptor orviadirect, and as yet uncharacterised, neurotoxic effects.
Pharmacological characteristics and species‐related variations of β3‐adrenergic receptors
Authors: Pietri‐Rouxel F. , Strosberg AD
Published: August 2009

Summary—Beta‐adrenergic receptors (β/‐AR) belong to the large multigenic family of receptors coupled to GTP‐binding proteins. Three subtypes have been identified: β1‐, β2‐ and β3‐AR. Much of the work delineating the precise pharmacological comparison of the three β‐ARs has come from investigations with stably transfected Chinese hamster ovary cells (CHO cells). This review discusses the structure and function of β3‐AR in various species and presents new findings on a number of β3‐AR ligands including carazolol, tertatolol and CL 316,243 which were found to be selective and potent β3‐AR agonists and ZD 2079 and salmeterol which appear to display full but non‐subtype selective agonistic activity. Species‐related variations of the β3‐AR pharmacology have been shown for propranolol and bupranolol. With the ongoing characterization of the β3‐AR at the molecular and cellular level, and with the advent of computer‐assisted molecular modelling to aid in the determination of the three‐dimensional structure of the receptor, it is thought that novel β3‐AR compounds will become available with improved selectivity and potency.
Beta3‐adrenoceptors in the cardiovascular system
Authors: Berlan M. , Galitzky J. , Montastruc JL
Published: August 2009

Summary—Behind the classic beta1, and beta2‐adrenoceptors, recent molecular and pharmacological studies have described a new receptor, called the beta3‐adrenoceptor, in various mammalian tissues (brown and white adipose tissue, digestive smooth muscle). Few authors have investigated the putative existence of the beta3‐adrenoceptor in the cardiovascular system. This paper reviews the available data.In vitrostudies show that beta3‐adrenoceptor agonists (BRL 37344, CGP 12177) induce a relaxation of fragments of rat carotid artery which is not antagonized by propranolol. In dogs, these drugs elicit a decrease in blood pressure due to peripheral vasodilation and an increase in heart rate which is of baroreflex origin. The vasodilating effects are mainly observed in cutaneous and adipose tissue vessels and cannot be explained by any known transductional mechanism. Activation of this vascular β3‐adrenoceptor requires higher doses of catecholamines than for β1‐ or β2‐adrenoceptors. In humans, the cardiovascular effects of beta3‐adrenoceptor agonists are explained by the activation of beta1‐ or beta2(and not beta3‐)‐adrenoceptors. These studies suggest the presence of vascular (but not cardiac) beta3‐adrenoceptors in dogs. In other species, including man, the presence of such cardiac β3‐adrenoceptors remains to be resolved. Their physiological relevance remains unknown.
Interest of modafinil, a new psychostimulant, during a sixty‐hour sleep deprivation experiment
Authors: Lagarde D. , Batejat D. , van Beers P. , Sarafian D. , Pradella S.
Published: August 2009

Summary— Modafinil, a new psychostimulant, was evaluated in eight healthy volunteers subjected to 60 hours of sleep deprivation. During continued wakefulness, vigilance was evaluated by self‐assessment questionnaires, analogue visual scales, multiple sleep latency tests (MSLT), sleep logs, and continuous ambulatory electroencephalographic recordings (EEG). Modafinil (200 mg) or a placebo was given every 8 hours for three days; the sessions were separated by a 15 day wash out period. Results indicated a satisfactory level of vigilance, both subjective and objective, after the administration of modafinil, characterised by the quasi total absence of microsleep episodes which gradually occurred under placebo conditions. The confirmed wakening potency of modafinil makes this substance suitable for therapeutic use in patients with sleep disorders such as Gelineau's syndrome and hypersomnia.
New developments in the conduct and management of multi‐center trials: an international review of clinical trial units
Authors: Gluud C. , Sørensen TIA
Published: August 2009

Summary— There is an urgent need for the performance of more, better designed, and better managed randomized clinical trials. After visits to 43 leading organizations and units involved in clinical trials in Europe and North America during 1993, the way of conducting randomized clinical trials was analyzed. By using a structured questionnaire, information on recent improvements in the way randomized clinical trials are performed was identified. These developments encompass human aspects (better information, collaboration, and communication) as well as non‐human aspects (press button phone randomization and data management systems). By employing such developments, randomized clinical trials can run much more efficiently. This facilitates faster and better answers to the questions addressed by randomized clinical trials, thereby also making them more ethical.
β3‐adrenoceptors and intestinal motility
Authors: Manara L. , Croci T. , Landi M.
Published: August 2009

Summary—Early substantial evidence of the low susceptibility to β‐adrenoceptor antagonists of non α‐adrenergic responses reducing gut motility and tone was reluctantly accepted as indicating a third β‐receptor subtype different from the β1and β2. This applied likewise to lipolysis until new selective “lipolytic” β‐agonists poorly effective at established β‐receptors were introduced. Shortly afterwards these “lipolytic” as well as certain newer and even more selective β‐adrenoceptor agonists were shown to be potent inhibitors of intestinal motility. The latter are the “gut‐specific” phenylethanolaminotetralins whose availability as pure isomers attested to the stringent stereochemical requirements for selectivity at non‐β1, non‐β2β‐adrenoceptors. Acceptance of the functionally based concept of a β3‐adrenoceptor was boosted on structural grounds by molecular biology studies. Sequence analysis indicated the existence in humans and rodents of genes coding for a third subtype of β‐receptor that, when expressed in transfected heterologous cells, had a pharmacological profile distinct from the previously established subtypes. Finally, aryloxypropanolaminotetralins have been prepared as the first selective antagonists of β3‐adrenoceptors, thus providing unambiguous conclusive evidence of the distinctive functional features of those abundant in the rat colon. The therapeutic potential in gastroenterology of the newer compounds targetable on the β3‐adrenoceptor is suggested by their potent intestinal actionin vivoin animal models without any of the cardiovascular or other unwanted effects of conventional β3‐adrenoceptor agonists and antagonists, and by the clinically confirmed importance of β‐adrenergic control of motor function throughout the alimentary canal. However, open questions include the incidence of species‐related differences in β3‐adrenoceptors, and as yet there are no data on gastrointestinal functions in humans under the influence of drugs designed to act selectively at these receptors.
Role of PAF in the late airway microvascular leakage induced by antigen in IgE‐sensitized rat
Authors: Kyriacopoulos F. , Boichot E. , Lagente V. , Mencia‐Huerta JM , Braquet P.
Published: August 2009

Summary—The effect of the antagonist of platelet‐activating factor (PAF), BN 50730, on PAF‐and antigen‐ induced increase in microvascular leakage, using Evans blue dye as an index of permeability, was investigated in rat pulmonary tissues. PAF (1 μg/kg, iv) induced a marked increase in Evans blue dye content in trachea, main bronchi and small bronchi, that was significantly reduced upon pretreatment of the rats with BN 50730 (25 mg/kg, orally) and by the serotonin antagonist, methysergide (1 mg/kg, iv), only in the small bronchi. Serotonin also induced an increase in microvascular leakage in the three tissues that was significantly inhibited when the animals were treated with methysergide but not by BN 50730. In contrast, histamine and lyso‐PAF did not induce significant increase in Evans blue dye content. Intravenous injection of antigen to IgE‐sensitized rats induced a biphasic increase in vascular permeability. An early increase in vascular permeability in trachea, main bronchi and small bronchi was observed 10 minutes after the injection of the antigen, and this phenomenon was significantly reduced upon treatment of the rats with methysergide, whereas, BN 50730 was ineffective. A late increase in vascular permeability was noted in the three tissues, with a maximum at 120 minutes and representing 30–40% of the magnitude of the first phase. Administration of BN 50730 (25 mg/kg) to the animals, evoked a significant inhibition of this increase in microvascular leakage, whereas, methysergide only significantly reduced the one induced by antigen in the trachea. These results demonstrate that the early (10 min) antigen‐induced microvascular leakage of the trachea, main bronchi and small bronchi in IgE‐sensitized rats is primarily due to the release of serotonin. However, the late increase (120 min) in vascular permeability involves PAF generation, as demonstrated by the marked inhibition of this process by the selective PAF antagonist BN 50730.
Cardiovascular variability after rilmenidine challenge: assessment of acute dosing effects by means of spectral analysis
Authors: Girard A. , Février B. , Elghozi JL
Published: August 2009

Summary— Short‐term fluctuations in blood pressure (BP) and heart rate (HR) were analysed in a group of twelve subjects with mild hypertension. Indirect finger BP was measured by a Finapres® device. The effects of an oral dose of rilmenidine (1 mg) were studied in a double‐blind cross‐over placebo‐controlled study. Compared with placebo, rilmenidine reduced the variability of standing BP after 2 hours as estimated from the standard deviation of systolic BP which diminished by 20%. Spectral analysis of fluctuations in BP showed this reduction predominated in the mid frequency (MF) region corresponding to 10‐second period oscillations, which depend on the activity of the autonomic nervous system. The average reduction in MF component for standing systolic BP was 24%. In addition the MF component for HR was reduced by 17%. This frequency domain analysis demonstrates a modified BP and HR variability profile with an acute dosing of rilmenidine. This effect being limited to the MF fluctuations in standing position orients towards an effect of the drug on the sympathetic cardiovascular control.
Is striatal dopaminergic receptor imbalance responsible for levodopa‐induced dyskinesia?
Authors: Blanchet PJ , Gomez‐Mancilla B. , Di Paolo T. , Bédard PJ
Published: August 2009

Summary—Abnormal involuntary movements (dyskinesias) of variable intensity eventually emerge in the majority of Parkinson's disease patients chronically treated with standard oral levodopa. They create social and physical embarrassment and narrow the therapeutic options normally proposed to improve Parkinsonian symptoms. Thus far, indirect clinical and experimental evidence has implicated the potential role of dopamine D1receptor activation in the generation of dopa dyskinesia. In recent years, our group has tested several dopaminergic agonists of variable half‐life and selectivity in monkeys rendered Parkinsonian following toxic exposure to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). These monkeys readily develop dyskinesia when treated with levodopa and provide the best animal model to study this complication. Our results in “drug‐naive” and “dyskinesia‐primed” MPTP animals suggest that pathological sensitisation of D2receptor‐mediated striatal outflow is necessary and sufficient for the induction of dopa dyskinesia, with perhaps a synergistic contribution from D1receptors, and that repeated short‐lived stimulation is important in the sensitisation process. This model supports the hypothesis that more continuous forms of dopaminomimetic therapy represent the best therapeutic approach for Parkinson's disease and calls for the development of novel D1agonists for further clinical testing.
Role of the renin‐angiotensin system in systemic and regional vascular responses to orthostatic stress in healthy volunteers
Authors: Duranteau J. , Pussard E. , Berdeaux A. , Giudicelli JF
Published: August 2009

Summary—The effects of a single oral dose (5 mg) of the angiotensin‐converting enzyme (ACE) inhibitor, ramipril, on the systemic and regional vascular responses to simulated orthostatic stress by the lower body negative pressure (LBNP) technique were investigated in eight healthy volunteers, in a double‐blind, placebo‐controlled crossover study. Arterial blood pressure remained unchanged throughout the study. Ramipril increased significantly forearm (venous occlusion plethysmography, + 37% ± 4% from 1.98 ml±min−1±100 ml−1) and renal (PAH clearance, + 6 ± 2% from 1.20 1±min−1) blood flows and decreased corresponding vascular resistances, 150 minutes after its administration and before LBNP. It also significantly reduced calculated filtration fraction and inhibited by approximately 86% plasma ACE activity. Lower body negative pressure at −10 and −20 mmHg induced a progressive and significant decrease in central venous pressure and significant increases in forearm, splanchnic (indocyanine green clearance) and total peripheral vascular resistances which were of the same magnitude after ramipril and placebo administrations. Ramipril blunted the LBNP‐induced increase in renal vascular resistance observed at −20 mmHg after placebo but a similar increase in glomerular filtration rate (inulin clearance) was observed at LBNP‐10 and −20 mmHg after ramipril and placebo. Calculated filtration fraction increased after placebo (LBNP‐10 mmHg) and ramipril (LBNP‐20 mmHg). Finally, LBNP‐induced changes in biological parameters were similar after ramipril and placebo at all levels of LBNP. Thus, ramipril does not interfere with the adaptive forearm and splanchnic vascular responses and preserves renal hemodynamics during orthostatic stress simulated by LBNP in healthy volunteers.
The safety of nitrofurantoin during the first trimester of pregnancy: meta‐analysis
Authors: David S Ben , Einarson T. , David Y Ben , Nulman I. , Pastuszak A. , Koren G.
Published: August 2009

Summary— Asymptomatic bacteriuria is common during pregnancy and may adversely affect both the mother and her fetus. Nitrofurantoin (NF) has been long recognized as an effective agent in both nonpregnant and pregnant women suffering from urinary tract infections. This meta‐analysis was conducted in order to evaluate the safety of NF ingested during early pregnancy. Of twenty‐two studies, only four met the inclusion criteria and their analysis could not demonstrate any significant correlation between NF ingestion and fetal malformation. The pooled odds ratio was 1.29 with 95% confidence interval 0.25–6.57. Although the number and quality of the studies included are limited, we thought it important to present the existing data. More extensive controlled studies are urgently needed in order to increase the significance of our study.
Compared effects of ruthenium red and cis [Ru(NH3)4Cl2]Cl on the isolated ischaemic‐reperfused rat heart
Authors: Leperre A. , Millart H. , Prévost A. , Trenque T. , Kantelip JP , Keppler BK
Published: August 2009

Summary—The sequence ischaemia‐reperfusion is characterized by reperfusion damage. The calcium overload occurring at the beginning of reperfusion is one of the main mechanisms responsible for reperfusion damage. Ruthenium red, a blocker of the mitochondrial calcium uniport system, could prevent this damage by preserving the ATP synthesis in the mitochondria. We tested ruthenium red and another ruthenium compound, cis‐tetrammine dichlororuthenium (III) chloride in our experimental model of ischaemic‐reperfused rat hearts. After a 15 minute‐stabilization period, the hearts were submitted to a 30 minute global ischaemia period and then reperfused for 45 minutes with the standard perfusion solution or with ruthenium red or cis‐tetrammine dichlororuthenium (III) chloride at 1, 3 or 9 μM. Ruthenium red at 3 μM exerted a protective effect in our experimental conditions by showing a significant improvement of the contractility recovery at the end of reperfusion and a significant decrease of the malondialdehyde production, which reflects free radical production. The cis‐tetrammine dichlororuthenium (III) chloride (containing 1 Ru ion per molecule) at 9 μM was slighty less efficient than ruthenium red at 3 μM (containing 3 Ru ions per molecule). The heart ruthenium binding was better for the ruthenium red than for the cis‐tetrammine dichlororuthenium (III) chloride, suggesting a role of the ruthenium ion complexation in the crossing of the membrane, whereas the cardiac effect seemed to be linked to the ruthenium ion heart concentration, which was similar for the ruthenium red at 3 μM and for the cis‐tetrammine dichlororuthenium (III) chloride at 9 μM. One can hope that ruthenium compounds would limit reperfusion damage and infarct size after ischaemia inin vivomodels.
Effect of inhibition of the electrogenic Na+/K+pump on the mechanical activity in the rat uterus
Authors: Ausina P. , Savineau JP , Hernandez JS , D'Ocón MP , Martín JD , Candenas ML
Published: August 2009

Summary—The effects of ouabain and K+‐free solution were studied in estrogen‐primed rat uterine strips under resting tone or repeatedly stimulated with KCl, acetylcholine or oxytocin applied for 20 minutes at 60 minute intervals. These effects were compared with those of the K+channel opener cromakalim. In preparations under resting tone, ouabain (0.1 mM and 0.3 mM) induced rhythmic contractions which disappeared after 20–30 minutes whereas at a higher concentration (1 mM) it evoked a rapid, phasic response followed by a small tonic contraction. Exposure of the strip to a K+‐free solution induced either rhythmic waves, which ceased after 8–10 minutes, or a single phasic contraction which was followed by a small and slow increase in the resting tone (54 ± 10 mg after 180 min exposure). Nifedipine (0.3 μM) abolished the rhythmic or phasic component of these responses but failed to modify the late small tonic contraction induced by ouabain 1 mM or by K+‐free solution. Ouabain (0.1–1 mM) or K+‐free‐evoked responses disappeared after short (4 min) or prolonged (60 min) exposure to a Ca2+‐free, 3 mM EGTA‐containing solution. Cromakalim (10 nM −0.1 mM) did not induce any variation in the resting tone either in the presence or in the absence of Ca2+in the medium. In strips repeatedly stimulated with acetylcholine (0.1 mM) or oxytocin (1 μM), ouabain (0.3 mM), K+‐free‐solution and cromakalim (10 μM) reduced the amplitude of the initial, phasic response and progressively decreased the oscillatory component of the response to these agonists. Conversely, the successive responses evoked by KCl 60 mM in similar experimental conditions were not affected by ouabain or cromakalim. Ouabain (0.3 mM), K+‐free solution and cromakalim (10 μM) decreased the Ca2+‐independent, maintained contractions induced by acetylcholine or oxytocin after prolonged exposure to a Ca2+‐free, EGTA‐containing medium. These inhibitory effects were partially or completely reversed in the presence of the non‐selective potassium channel blocker tetraethylammonium (10 mM) or in a Ca2+‐free solution containing 60 mM K+. In conclusion, these results suggest that the response induced by ouabain or K+‐free solution in estrogen‐primed rat myometrium involves Ca2+influx through potential‐operated calcium channels but not Ca2+release from intracellular stores. In addition, our results show that prolonged exposure to ouabain or K+‐free medium decreases membrane receptor‐mediated responses in rat uterus. This inhibitory effect seems to be the result, at least in part, of a decrease in the cytosolic level of K+, due to the inhibition of the electrogenic Na+pump.
Preclinical assessment of a new transdermal delivery system for clonidine (M‐5041T)
Authors: Naruse T. , Ishida T. , Ishii R. , Tagawa T.
Published: August 2009

Summary—The effects of a new transdermal delivery system for clonidine (M‐5041T) on hypotensive effect, urine volume, plasma renin activity (PRA) and antidiuretic hormone (ADH) in spontaneously hypertensive rats (SHRs) were compared to the effects of the continuous infusion of clonidine. Both M‐5041T (1.5 and 4.5 mg/kg) and the continuous infusion of clonidine (250 μg/kg/24 h) elicited hypotensive effects persisting for 12 hours or more. These effects were based on consistent plasma concentrations of clonidine. These two treatments produced diuresis followed by antidiuresis, which was remarkably observed by continuous infusion of clonidine. Single subcutaneous injection of clonidine (50 μg/kg) produced diuresis accompanied by increases in electrolytes corresponding to plasma levels of clonidine. M‐5041T at 1.5 mg/kg did not affect PRA until 12 h, and produced an increase in PRA at 24 h. M‐5041T at 4.5 mg/kg and the continuous infusion of clonidine resulted in a decrease in PRA at 2 and 1 h followed by an increase at 12 and 24 h, respectively. M‐5041T at 1.5 mg/kg did not affect plasma levels of ADH. Plasma ADH did increase at 2 and 4 h accompanied by diuresis following M‐5041T at 4.5 mg/kg or the continuous infusion of clonidine, respectively. Clonidine‐induced diuresis was not at least due to the inhibition of ADH release. The decrease in urine volume observed by continuous infusion of clonidine may be due to decrease in renal blood flow based on stimulation of peripheral adorenoceptors of clonidine. These findings suggest that the increases in ADH and PRA are due to the compensatory effects related to both diuresis and the long‐lasting hypotensive effect induced by high plasma concentrations of clonidine. Thus, it can be expected that M‐5041T at 1.5 mg/kg showing the minimum effective plasma concentration of clonidine will not result in tolerance to the hypotensive effect of clonidine associated with the retention of sodium in SHRs.
Antipyretic efficacy of tiaprofenic acid in febrile children
Authors: Vauzelle‐Kervroédan F. , Revzani Y. , Pons G. , Consten L. , Pariente‐Khayat A. , D'Athis P. , Olive G.
Published: August 2009

Summary— In children, tiaprofenic acid (TA), a non steroidal antiinflammatory drug, propionic‐acid derivative, has been proven effective in the treatment of symptoms of tonsillitis and pharyngitis but not yet in the symptomatic treatment of fever. This doubleblind, parallel group, placebo (PI) controlled study was designed in order to demonstrate the antipyretic activity of TA. The coprescription of other antipyretic medications in children may therefore be avoided. Two groups of children, 29 (TA group) and 26 (PI group), were included and received either 4.2 ± 0.5 mg/kg of TA given orally in a single dose or a PI match. Rectal temperature was recorded just before and 1, 2, 4 and 6 hours after dosing. The maximum temperature decrease was significantly greater in the TA group (– 1.3 °C ± 0.7 °C) than in the PI group (– 0.4 °C ± 0.8 °C). The percentage of children who needed a rescue treatment during the study was 35% (10/29) and 62% (16/26) in the TA and PI group, respectively. The rescue treatment was composed of a single oral acetaminophen dose in case of fever above 39.5 °C or if the temperature decrease was not at least equal to 0.6 °C four hours after dosing. No major side effect was reported by the parents during the study period. In conclusion, TA at a single mean 4.2 mg/kg oral dose, is an effective antipyretic drug in febrile children. The duration of the antipyretic effect was estimated as at least four hours.
Two faces of cholecystokinin: anxiety and schizophrenia
Authors: Bourin M. , Malinge M. , Vasar E. , Bradwejn J.
Published: August 2009

Summary—It has been suggested that cholecystokinin (CCK), a gut‐brain peptide found in high concentrations in the mammalian brain, might be implicated in the neurobiology of anxiety and panic disorder. The administration of CCK tetrapeptide induced panic attacks analogous to spontaneous ones in patients suffering from panic disorder and to a lesser degree in healthy volunteers. In animal models of anxiety, the pretreatment with CCK agonists and antagonists produced, respectively, anxiogenic‐ and anxiolytic‐like action on the exploratory paradigms. On the other hand, CCK could also play a role in the pathophysiology of schizophrenia. The administration of CCK agonists (caerulein, CCK‐8s) to rodents results in behavioural effects analogous to those of antipsychotic drugs. However, CCK agonists lack any activity in rodent behavioural models to reveal antipsychotic drugs. A significant reduction of CCK concentration and CCK receptors has been shown in cortical and limbic structures of patients suffering from schizophrenia. Nevertheless, administration of CCK agonists to these patients does not effect their symptoms. Two major conclusions should be drawn: first, CCK is involved in the neurobiology of anxiety; second, changes in the CCK system in schizophrenia could be linked to a cortical neurodegeneration related to this disease.
Which drug for which orthostatic hypotension?
Authors: Senard JM , Montastruc JL
Published: August 2009

Summary— This review focuses on the actual limits of the clinical pharmacology of drugs used for the treatment of orthostatic hypotension. The evidences for heterogeneity of the pathophysiological mechanisms of primary orthostatic hypotension and autonomic failure are discussed. The available data on the efficacy of some drugs used in orthostatic hypotension are also discussed.
Role of endothelial cells in restenosis after coronary angioplasty
Authors: Meurice T. , Vallet B. , Bauters C. , Dupuis B. , Lablanche JM , Bertrand ME
Published: August 2009

Summary— Percutaneous transluminal coronary angioplasty (PTCA) is today a procedure of choice in many patients with atherosclerotic coronary artery disease. Despite high rates of initial success, restenosis, occurring in 30 to 40 percent of patients within the first six months, remains the major problem limiting the long‐term efficacy of the procedure. Animal models have enhanced our knowledge in the understanding of the mechanisms involved in the restenotic process after experimental angioplasty. In fact, the two known determinants of restenosis are the proliferative and migrative response of underlying smooth muscle cells with production of extracellular matrix and the recently highlighted vascular remodeling. Endothelium, which regenerates from the leading edge of the de‐endothelialized area within the weeks following arterial injury, is of particular interest in the modulation of the healing process after the procedure. Endothelial dysfunction, as an imbalance between relaxing and contracting factors, between anti‐ and procoagulant mediators or growth‐inhibiting and growth‐promoting factors, occurs at sites of regenerating endothelium. Experimental studies, using drugs that enhance endothelium‐derived relaxing factors release or drugs that diminish endothelium‐derived contracting factors production, have often been shown to be effective in the restenosis prevention. Thus, impairment in endothelial cell function may be considered as one of the major regulatory element in the restenotic process. This review discusses the interactions between endothelial and smooth muscle cells and has for aim to point out the major role of endothelial cells in the development of neointimal thickening and arterial remodeling.
Influence of indomethacin on the haemodynamic effects of lipopolysaccharide in rats
Authors: Fatehi‐Hassanabad Z. , Muller B. , Andriantsitohaina R. , Furman BL , Parratt JR , Stoclet JC
Published: August 2009

Summary—This study was undertaken to evaluate the influence of the cyclooxygenase inhibitor indomethacin on the time course of the haemodynamic effects of lipopolysaccharide (LPS) intravenous infusion (10 mg·kg−1·h−1) in anaesthetized rats. LPS infusion produced a rapid (within 10 min) and prolonged (over the 90 min observation period) fall in mean arterial blood pressure (MABP) and a decrease in the pressor responses to noradrenaline (NA, 0.1, 0.3 and 1 μg·kg−1, intravenously [iv]) elicited 60 and 90 min after the onset of LPS infusion. Indomethacin (7 mg·kg−1iv 30 min prior to the onset of saline or LPS infusion), which by itself did not affect basal MABP nor reactivity to NA in control rats, significantly attenuated the fall in MABP observed within 20 min after the onset of LPS infusion (but did not significantly modify the hypotension observed between 30 and 90 min). Indomethacin also completely prevented the hyporeactivity to NA observed 60 min after the onset of LPS infusion, but it did so only partially at 90 min. Aortic rings removed from LPS or LPS + indomethacin‐treated rats showed an identical profile of contractile reactivity (hyporesponsiveness to NA, relaxation to L‐arginine, and restoration of the contractile response by methylene blue). These results suggest that in this model, cyclooxygenase products are involved in the early haemodynamic effects of LPS. However, they do not seem to play an obligatory role in the onset of longer term haemodynamic changes.
Lack of pharmacodynamic interaction between trimetazidine and cyclosporin A in human lymphoproliferative and mouse delayed hypersensitivity response models
Authors: Albengres E. , Tillement JP , D'Athis P. , Salducci D. , Chauvet‐Monges AM , Crevat A.
Published: August 2009

Summary— The hypothesis of an interaction between trimetazidine and the immunosuppressive effect of cyclosporin A was investigated in two models: a) ex vivo, the lymphoproliferative response of normal human lymphocytes to phytohemagglutinin and a murine monoclonal antibody against the CD3 T‐lymphocyte membrane complex; b) in vivo, the delayed hypersensitivity response model in mouse. The uptake of methyl‐3H‐thymidine was measured in both models. For the lymphoproliferative response, statistical analysis showed that there was a significant inhibitory effect of cyclosporin A on cell proliferation (P < 0.001) and confidence intervals obtained by ANOVA showed the equivalence of the results when trimetazidine was combined with cyclosporin A (all CI95% ≤ 10). In the delayed hypersensitivity model, cyclosporin A was also found to be very effective in inhibiting the immune response (P < 0.001), while trimetazidine did not interfere with cyclosporin A's effect. It was concluded that trimetazidine exerted neither an immunostimulatory nor an immunosuppressive effect in the two models, suggesting of the absence of interaction between trimetazidine and cyclosporin A's effectiveness when both drugs are given in combination.
Pharmacological evidence that NK‐2 tachykinin receptors mediate hypotension in the guinea pig but not in the rat
Authors: Floch A. , Thiry C. , Cavero I.
Published: August 2009

Summary—Vascular NK‐1 and NK‐2 tachykinin receptors in the rat and the guinea pig were characterized pharmacologically by using available agonists and antagonists exhibiting varying degrees of selectivity for these receptors. Because the anesthetized guinea pig has unusually low blood pressure, these animals were pithed and vagotomized and infused, throughout the experimental procedure, with norepinephrine (6 μg/kg/min). This treatment raised their blood pressure to a level appropriate for the determination of dose‐hypotensive response curves. The NK‐1 receptor agonists substance P (SP) and septide (0.004 to 1 μg/kg iv) decreased carotid artery blood pressure in a dose‐dependent manner in both species, but they were more potent (13‐ and 33‐fold, respectively) in guinea pigs than in rats. The NK‐2 receptor agonist [βAla8]‐NKA(4–10)(0.06 to 1 μg/kg) also dose‐dependently lowered blood pressure in the pithed guinea pig with noradrenaline‐supported blood pressure, although it failed to do so in the same rat preparation. RP 67580, a selective NK‐1 antagonist, antagonized the SP‐ or septide‐induced hypotensive response in rats, but not in guinea pigs. Conversely, RPR 100893, a novel NK‐1 receptor antagonist chemically related to RP 67580, dose‐dependently inhibited hypotension induced by SP, and even more, that induced by septide only in guinea pigs. In the latter species, neither RP 67580 nor RPR 100893 affected decreases in blood pressure induced by [βAla8]‐NKA(4–10). These decreases were, however, inhibited by the NK‐2 receptor antagonist SR 48968. The selectivity of this compound for the latter receptor was confirmed by its failure to affect SP‐ or septide‐induced hypotension in either guinea pigs or rats. These results confirm that the hypotensive responses to SP and septide are mediated by NK‐1 receptors in the two species studied. However, functional NK‐2 receptors appear to be present in the vascular bed of the guinea pig but not that of the rat, since in the former species the hypotensive responses induced [βAla8]‐NKA(4–10)were inhibited by SR 48968 but not by the NK‐1 receptor antagonists studied. This conclusion is, to our knowledge, drawn here for the first time from clear‐cut pharmacological results.
Effects of SCA40 on human bronchi and on guinea pig main bronchi in vitro. Comparison with cromakalim
Authors: Naline E. , Cui YY , Michel A. , Bonnet PA , Bakdach H. , Advenier C.
Published: August 2009

Summary—The aim of this study was to examine the activity of SCA40, a novel charybdotoxin‐sensitive potassium channel opener, against a variety of spasmogens or against electrical field stimulation in guinea pig isolated main bronchi and in human isolated bronchi; the effects of SCA40 were compared with those of cromakalim. Like cromakalim, SCA40 reduced the contractility of guinea pig and human isolated bronchi precontracted with acetylcholine 10−6M or neurokinin A 10−6M, SCA40 being more efficient and more potent than cromakalim. Moreover, on guinea pig isolated main bronchi, SCA40 can exert a preventive effect on contractions induced by acetylcholine, neurokinin A or capsaicin, that is, it shifts to the right the concentration‐effect curves of these substances, whereas cromakalim has no such effect. The effects of cromakalim were antagonized by glibenclamide 10−5M, whereas the effects of SCA40 were inhibited by tetraethylammonium (TEA 10−2M) and charybdotoxin (3 × 10−8M), but this inhibitory effect of TEA was reversed by nifedipine (10−6M). Electrical field stimulation of guinea pig isolated main bronchi induced two successive contractile responses. Both contractions were significantly reduced by SCA40 (10−6and 10−5M) and cromakalim (10−5M). Since cromakalim was unable to inhibit the effects of acetylcholine or neurokinin A, it might be suggested that for this latter compound the inhibition seems to take place prejunctionally and to affect the release of neuromediators produced by electrical field stimulation. In contrast, in the case of SCA40, a postjunctional effect seems to be likely, owing to its preventive effects, although a prejunctional effect cannot be excluded. Finally, on guinea pig isolated main bronchi, SCA40 (10−8‐10−6M) did not potentiate the relaxant effect of isoprenaline or sodium nitroprusside, suggesting a lack of functional manifestation of inhibition of phosphodiesterase for these concentrations. In conclusion, these results demonstrate that SCA40 is a potent and efficient relaxant of guinea pig and human airway smooth muscle, and is able to inhibit, in the guinea pig isolated main bronchi, the contractions induced by electrical field stimulation. It has an effect on TEA‐sensitive K+ channels, but this effect is probably not involved in its relaxant effect which does not also rest on an inhibitory effect of phosphodiesterase.
In vitro pharmacological effects of S 12370 (2‐[4‐benzhydryloxypiperidinoethyl]isoxindole; an antibronchoconstrictor agent) in normal and sensitized tissue
Authors: Martin CAE , Félétou M. , Lonchampt M. , Dacquet C. , Dhainaut A. , Canet E.
Published: August 2009

Summary—The effects of S 12370 (2‐[4‐benzhydryloxypiperidinoethyl]isoxindole), were studied in vitro. In guinea pig isolated tracheal rings, S 12370 induced a similar competitive inhibition of the contractile responses produced by acetylcholine, histamine and serotonin. However, it did not affect the contractions induced by leukotriene D4(LTD4), substance P and U 46619, a stable analogue of thromboxane A2. S 12370 induced a concentration‐dependent inhibition of the cholinergic component of the contraction induced by electrical field stimulation, whereas it did not influence the sustained nonadrenergic noncholinergic (NANC) excitatory response observed in guinea pig isolated bronchi. S 12370 did not influence the relaxations induced by prostaglandin E2, isoprenaline and salbutamol, and did not modify the nonadrenergic noncholinergic inhibitory response induced by electrical field stimulation. In isolated left atria, the negative inotropic effect of acetylcholine was competitively inhibited by S 12370. In binding experiments, S 12370 exhibited similar affinity for M1, M2, M3, M4muscarinic receptors and also recognized 5‐HT2serotonin and H1histamine receptor subtypes. In ovalbumin‐sensitized animals, the contractile response of isolated tracheal rings produced by exposure to the allergen was not influenced by S 12370. Tracheal rings from sensitized animals preexposed in vitro to the allergen developed a hyporesponsiveness to β‐adrenoceptor stimulation. S 12370 prevented the inhibitory effect caused by ovalbumin immune sensitization in the relaxation to isoprenaline. In rat polymorphonuclear neutrophil (PMN) cells, S 12370 up to 10−5M did not inhibit the arachidonic acid metabolism. These results suggest that in guinea pig tracheal smooth muscle, S 12370 is a competitive inhibitor of muscarinic, serotonin and histamine receptors and can modulate the β‐adrenergic dysfunction induced by immune sensitization. S 12370 may present some therapeutic interest in inflammatory airway diseases.
Interruption of prolonged ramipril treatment in hypertensive patients: effects on the renin‐angiotensin system
Authors: Stephan D. , Grima M. , Welsch M. , Barthelmebs M. , Vasmant D. , Imbs J.
Published: August 2009

Summary— The increase in renin secretion and the induction of the converting enzyme (ACE) observed during treatment by ACE inhibitors (CEIs) could result in increased angiotensin II (ang II) synthesis when the treatment is stopped. The object of this study was to compare changes in the components of the renin‐angiotensin system with changes in arterial pressure in hypertensives, following the cessation of long‐term ramipril treatment. Twenty hypertensives, treated for at least three months with ramipril, in monotherapy for the last three weeks, were randomly allocated to two parallel groups and received for fifteen days, on a double‐bind basis, either a placebo (withdrawal group W, n = 12) or ramipril at the previous doses (treated group T, n = 8). Blood pressure was measured using four different techniques. The active renin (AR), angiotensinogen, angiotensin I (ang I), angiotensin II (ang II) and aldosterone plasma concentrations were measured, as was plasma angiotensin I converting enzyme (ACE) activity in vitro (colorimetric and fluorimetric method) and in vivo (the ang II/ang I ratio). The biological effects of cessation of long‐term ramipril treatment in hypertensives were a decline in AR and angiotensin I concentrations, an increase in ACE activity and no significant changes in angiotensinogen, angiotensin II and aldosterone levels. Fifteen days after withdrawal, the different parameters of the renin‐angiotensin system appear to have returned to basal value. A slow rise in blood pressure was also observed but no rebound increase was noted during the 15 days neither in angiotensin II levels nor in blood pressure. Following the cessation of prolonged ramipril treatment, in vivo converting enzyme inhibition disappears slowly, probably on account of the slow tight binding inhibitor properties of ramiprilat, the active metabolite of this CEI. The gradual decline in AR plasma levels, together with the prolonged ACE inhibition as measured in vivo by the ang II/ang I ratio, explains the absence of a rise in ang II synthesis.
Noninterchangeability of specific radioimmunoassay and monoclonal antibody fluorescent polarization immunoassay in cyclosporine measurements
Authors: Pape D. , Vernillet L. , Bellissant E. , Bentue‐Ferrer D. , Allain H.
Published: August 2009

Summary—This study compares cyclosporine (CsA) concentrations in whole blood from patients receiving bone marrow (n= 10), renal (n= 48), heart (n= 50) or liver (n= 50) transplants, as measured by monoclonal antibody flurorescence polarization immunoassay (FPIA) and specific125I‐radioimmunoassay (RIA). The FPIA overestimated CsA by an average of 25%. Results were higher for all indications: FPIA/RIA ratios were 1.17 for bone marrow, 1.23 for renal and 1.27 for both heart and liver transplants, and these values were significantly different from 1.0. The percentage of overestimation was higher at low CsA concentrations (≤ 100 μg/L) than at high CsA concentrations (≥ 400 μg/L). In all indications, results by both methods correlated well (r> 0.96) but slopes and intercepts were different from 1.0 and 0.0, respectively, and these parameters varied greatly between the grafted populations. These findings obtained with the two methods could not be attributed to matrix effect because the mean FPIA/RIA ratio for spiked control samples was 1.0. The discrepancy between the FPIA and RIA could be explained by the lower specificity of the monoclonal antibody contained in the FPIA kit. These results suggest that FPIA is not as accurate as RIA and that the two methods are not interchangeable in CsA level measurement.
Effects of graded hemorrhage on short‐term variability of blood pressure in conscious rats
Authors: Baujard C. , Ponchon P. , Elghozi JL
Published: August 2009

Summary— A controlled graded bleeding was performed in conscious rats with 15 min intervals between two withdrawals, in order to induce a 25% blood loss without hypotension. Heart rate (HR) was unaffected as well. The spectral profiles of systolic blood pressure (SBP) analyzed on 51.2 s segments exhibited increases in the high frequency (HF, respiratory) component. This increase paralleled the blood loss with a rise ranging from 20% for a 1 mL/kg hemorrhage to 90% for a 11 mL/kg removal. These changes were associated with increases in the mid‐frequency (MF, Mayer waves) component of SBP variability. These latter rises were between 30 and 40% of the control value. Breathing frequency (BF) and blood gases were unaltered following hemorrhage. A shift of fluid occurred during the 3 h session as reflected by the significant hemodilution. Rats were also bled after pretreatment with prazosin (1 mg/kg) or with an association of prazosin (1 mg/kg) and losartan (10 mg/kg). These treatments increased HR. A marked fall in SBP occurred with the double blockade. Hemorrhage determined a relative bradycardia together with the SBP decrease (reversible shock) after prazosin and losartan treatment. Prazosin determined opposite changes in MF (‐33%) and HF (+58%) SBP components. A further decrease in the MF SBP component was observed following the double blockade. Spectral profiles following hemorrhage were unchanged compared to the prehemorrhage blocked levels. Therefore graded nonhypotensive, ie, normotensive hemorrhage in rats, was associated with progressive increases in the respiratory SBP variations, estimated from the SBP spectrum. This sensitive index could reflect the low preload state due to hypovolemia. The hemorrhage‐induced MF SBP component increase could reflect an increased sympathetic vasomotor drive, prevented with prazosin, as a reflex adjustment to hypovolemia. Renin activation could also contribute to the genesis of MF waves and its role in maintaining BP following hemorrhage was examplified with α1‐adrenoceptor blockade.
Aerosolized tachykinin antagonists inhibit pentamidine‐induced bronchoconstriction in guinea pigs
Authors: Jarreau PH , Harf A. , Boyer V. , Macquin‐Mavier I.
Published: August 2009

Summary—To investigate the role of tachykinins in pentamidine‐induced bronchoconstriction and airway microvascular leakage in the guinea pig, we examined the effects on bronchoconstriction and microvascular leakage of the nonpeptide antagonists of NK1and NK2tachykinin‐receptors, respectively, CP‐96,345 and SR 48968. Respiratory system resistance was measured by the occlusion method in anaesthetized, tracheotomized and mechanically ventilated guinea pigs. Airway microvascular permeability was evaluated by measuring the quantity of Evans blue dye in the trachea and main bronchi. Aerosolized CP‐96,345 or SR 48968 partially abolished pentamidine‐induced bronchoconstriction (at 5 to 30 mg/mL pentamidine; 60 breaths) whereas the combination of the two prevented it. In contrast, CP‐96,345 and SR 48968 did not prevent the increase in airway microvascular permeability induced by pentamidine (50 mg/mL; 90 breaths) whether they were administered separately or together, by aerosol or intravenously. These results demonstrate that in the guinea pig, pentamidine‐induced bronchoconstriction is mediated through both NK1and NK2tachykinin‐receptor activation and that when directly administered into the airways, tachykinin antagonists effectively prevent pentamidine‐induced bronchoconstriction.