bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitrocontractile and relaxant responses of human resistance placental stem villi arteries of healthy parturients: role of endothelium
Authors: Sabry S. , Mondon F. , Ferré F. , Dinh‐Xuan AT
Published: August 2009

Summary—As feto‐placental vessels in humans are not innervated, regulation of vascular tone in the fetal extracorporeal circulation most likely depends on either circulating hormones or local paracrine mechanisms. However, the latter have not yet been fully investigated. The aim of our study was to characterize vasomotor behaviour of resistance stem villi arteries when challenged with various constrictor and dilator agents, with special emphasis on the physiological importance of endothelium. The latter is poorly characterized in this particular vascular bed in humans. Villous stem arterial rings (internal diameter 182 ± 6 μm) were isolated under microscopy from term human placentae obtained after cesarean section. The vessels were mounted as ring preparations in an isometric myograph for tension measurements. Endothelium was removed from some of the rings by gentle insertion of a knotted human hair into the vascular lumen. Of the three vasoconstrictors tested, endothelin‐1 (ET‐1) showed the greatest potency, being 1,000 times more potent than serotonin and phenylephrine. The classical endothelium‐dependent vasodilators, acetylcholine, adenosine diphosphate (ADP) and histamine, caused dose‐dependent relaxation of the rings; an effect which was completely abolished by the removal of endothelium. Pre‐treatment with the nitric oxide (NO) synthase inhibitor, Nω‐nitro‐L‐arginine, also markedly reduced the endotheliumdependent relaxant responses to ADP. By contrast, the vasodilatory response to sodium nitroprusside was not affected by endothelial removal. We conclude that i) ET‐1 is a potent vasoconstrictor of the human placental vascular bed and ii) placental villous endothelial cells synthesize and release relaxing factor(s) which could possibly be NO.
Magnetic resonance imaging may be an asset to diagnose and classify fluoroquinolone‐associated Achilles tendinitis
Authors: Gillet P. , Blum A. , Hestin D. , Pourel J. , Pierfitte C. , Mainard D. , Kessler M. , Netter P.
Published: August 2009

Summary— The aim of this study was to document the accuracy of magnetic resonance imaging (MRI) during fluoroquinolone‐ associated Achilles tendinitis. Fourteen Achilles tendons were examined by MRI (T1 and T2 or T2*‐weighted sequences) in nine patients with typical tendinopathy (13 cases of tendinitis and 1 rupture) during fluoroquinolone therapy. Tendinous involvement was classified according to the prominence of intra‐ or peritendinous changes. The most typical feature was the presence of intratendinous changes, longitudinal or transversal, detected on T1 or T2‐weighted sequences. Peritendinitis was most visible in two cases and nodular involvement in three cases. It was concluded that MRI appears a helpful and accurate method in identifying and classifying such iatrogenic tendinitis. In addition, MRI indicates orthopedic management when detecting risk of rupture.
Regulation of beta3‐adrenoceptor expression in white fat cells*
Authors: Langin D. , Tavernier G. , Lafontan M.
Published: August 2009

Summary—Catecholamines (adrenaline and noradrenaline) stimulate adipocyte lipolysisviathree beta‐adrenoceptor subtypes β1, β2and β3. β3‐adrenoceptor‐mediated lipolysis varies according to the species. Rodent adipocytes exhibit the strongest response to β3agonists while human fat cells are poorly responsive. The species‐related differences can partly be explained by lower β3‐adrenoceptor mRNA levels in human adipocytes compared to rat adipocytes. Poor coupling efficiency of human adipocyte β3‐adrenoceptors cannot, however, be ruled out. The regulation of β3‐adrenoceptor gene expression has been studied in the adipocytes of the murine cell line 3T3‐F442A which express high levels of β3‐adrenoceptors. Insulin and glucocorticoids down‐regulate β3‐adrenoceptor expression through a trancriptional effect. The impairment of β3‐adrenoceptor gene expression in adipocytes of congenitally obeseob/obmice could be related to the higher glucocorticoid plasma levels when compared to lean littermates although the direct involvement of glucocorticoids remains to be demonstrated. In the rat and the rabbit, the β3‐adrenergic responsiveness varies according to the anatomical location of the fat pad. There is a marked decrease in β3‐adrenergic response in rabbit retroperitoneal fat cells during ageing. cAMP modulates the β3‐adrenergic response in white adipocytes at different levels. Human β3‐adrenoceptor expression seems to be up‐regulated by cAMP through an interaction with the promoter of the gene. It has been shown in cells transfected with cDNAs for the different β‐adrenoceptors that the β3‐adrenoceptor is less prone to desensitization than the β1and β2‐subtypes. This observation is in agreement with the absence of desensitization of the β3‐adrenoceptor response in isolated rat fat cells. Continuous infusion of noradrenaline for six days into hamsters does not lead to an alteration of the β‐adrenergic response. A similar treatment undertaken in the guinea pig, a species, unlike the hamster, devoid of β3‐adrenoceptor responsiveness, promoted strong desensitization of the β‐adrenergic response through down‐regulation of β1‐ and β2‐adrenoceptors. From these observations, it could be hypothesized that the β3‐adrenoceptor, that shows a low affinity for catecholamines, is the “emergency” β‐adrenoceptor which is essential under conditions of strong and sustained sympathetic nervous system activation.
Blockers of NMDA‐operated channels decrease glutamate and aspartate extracellular accumulation in striatum during forebrain ischaemia in rats
Authors: Ghribi O. , Callebert J. , Verrecchia C. , Plotkine M. , Boulu RG
Published: August 2009

Summary—Brain microdialysis was used to study changes in the glutamate and aspartate extracellular concentrations in the striatum of conscious rats submitted to 30 minutes cerebral ischaemia, using the four‐vessel occlusion model. Perfusion of the N‐methyl‐D‐aspartate (NMDA) receptor channel blockers, dizocilpine (MK‐801; 75 μM) and Mg2+(2.5 mM), inhibited the ischaemia‐induced accumulation of glutamate and aspartate. The AMPA/kainate receptor antagonist, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamylbenzo (F) quinoxaline (NBQX; 15 μM and 450 μM) had no effect on glutamate and aspartate levels during ischaemia. On the other hand, omission of Ca2+from the perfusing solution did not alter the increases in glutamate and aspartate induced by ischaemia. These results suggest that the glutamate and aspartate accumulation in four‐vessel occlusion ischaemia is mediated by activation of NMDA receptors in a Ca2+independent manner.
Stress‐induced 5‐HT1Areceptor desensitization: protective effects ofGinkgo bilobaextract (EGb 761)
Authors: Bolaños‐Jiménez F. , de Castro R Manhães , Sarhan H. , Prudhomme N. , Drieu K. , Fillion G.
Published: August 2009

Summary—The effects of sub‐chronic cold stress on the functioning of hippocampal 5‐HT1Areceptors in old isolated rats and the possible protective effects ofGinkgo bilobaextract (EGb 761) were investigated. Cold exposure during five days, produced a significant reduction of the inhibitory effect of 8‐hydroxy‐2‐(di‐n‐propylamino)tetraline (8‐OH‐DPAT) on forskolin‐stimulated adenylyl cyclase activity. In contrast, neither the affinity nor the density of hippocampal [3H]8‐OH‐DPAT binding sites were affected indicating that the reduced sensitivity of 5‐HT1Areceptors induced by stress is probably due to a modification of their coupling mechanisms to adenylyl cyclase. The stress‐induced desensitization of 5‐HT1Areceptors was prevented by the administration of EGb 761 (50 mg/kgper os/14 days). These results clearly indicate that 5‐HT1Areceptors are desensitized by stress and point out the reduced capacity of old rats to cope with the adverse effects of a chronic stressor. EGb 761 appears to restore the age‐related decreased capacity to adapt to a chronic stressor.
Reduced β‐adrenergic sensitivity in healthy volunteers induced by hypoglycemia
Authors: Trovik TS , Jæger R. , Jorde R. , Sager G.
Published: August 2009

Summary— A single causative mechanism for development of hypoglycemia unawareness in insulin‐dependent diabetes mellitus (IDDM) is not yet apparent. Reduced adrenergic sensitivity may be part of the explanation. This study was carried out to investigate the effect of hypoglycemia on β‐adrenergic sensitivity. Ten healthy male subjects (age 19–23 years) gave informed consent to take part in the study. They were hospitalized overnight at the University Hospital of Tromsø, Department of Clinical Research, on two occasions. Isoprenaline and metoprolol sensitivity tests were performed the morning after hospitalization: once after an intravenous (iv) injection of placebo (0.9% NaCl), and once after an iv injection of insulin (0.15 IU insulin/kg body weight) to induce hypoglycemia. The dose of isoprenaline needed to increase heart rate (HR) by 25 beats per minute (bpm) (I25), and the dose of metoprolol (M–12.5) needed to inhibit I25 with 50% or 12.5 bpm, when injected simultaneously, were used as determinants of isoprenaline and metoprolol sensitivity. In this study, there was a significant (p < 0.05) increase both in I25 and M–12.5 after hypoglycemia. The dose‐response curve of isoprenaline/HR was significantly shifted to the right after hypoglycemia. This study shows that acute hypoglycemia induces a reduction in β‐adrenegic sensitivity, and it supports the hypothesis of reduced β‐adrenergic sensitivity as an important pathophysiological mechanism in hypoglycemia unawareness in IDDM.
Ambulatory blood pressure monitoring and cardiovascular function tests in multiple system atrophy
Authors: Frongillo D. , Stocchi F. , Buccolini P. , Stecconi P. , Viselli F. , Ruggieri S. , Cannata D.
Published: August 2009

Summary— Cardiovascular tests (CT) of autonomic function and non‐invasive ambulatory blood pressure (BP) and heart rate (HR) monitoring were performed in 17 patients with multiple system atrophy (MSA) (mean age 61 ± 9 years) and in 12 healthy subjects matched for sex and age. CT showed severe autonomic dysfunction with orthostatic hypotension (OH) in eight patients with MSA (47%) (Group I). The remaining nine out of the 17 patients didn't show BP abnormalities during CT but an impaired HR reflex response was found (Group II). BP monitoring showed a reversed circadian BP rhythm in Group I with higher night‐time than day‐time values, a blunted circadian BP pattern in Group II and a normal day‐night BP reduction in controls. Day‐night HR reduction was poor in Group II and absent in Group I. Post‐prandial hypotension was evaluated after a standard meal. In Group I systolic/diastolic BP fell within 30 minutes after meal (from 135 ± 16/89 ± 13 to 118 ± 17/73 ± 12 mmHg; p < 0.05) and after two hours had not returned to basal levels. In Group II a reduction of only systolic BP was found within 45 minutes after meal and persisted for one hour. OH clinically identifies a subgroup of MSA patients with a more severe BP dysregulation characterized by severe post‐prandial hypotension and reversed circadian BP rhythm. CT and ambulatory BP monitoring are useful tools in identifying early stage of cardiovascular autonomic impairment.
Pharmacokinetic and bioavailability of diltiazem sustained‐release: influence of food and time of administration
Authors: Bianchetti G. , Bagheri H. , Houin G. , Dubruc C. , Thénot JP
Published: August 2009

Summary— Diltiazem is a calcium channel blocking agent known to be effective in the treatment of angina pectoris, hypertension and supraventricular arrhythmias. To improve the conditions of diltiazem administration in the treatment of hypertensive patients, a sustained‐release formulation (Mono‐Tildiem® LP 300 mg) allowing a single daily oral administration has been developed. The aim of the present study was to first evaluate the influence of food intake and second to evaluate those of the time of administration on the pharmacokinetic parameters and the bioavailability of this sustained‐release formulation. The influence of these factors was investigated over two different open, randomized, cross‐over studies in 12 healthy volunteers. Although a significant decrease in Tmax and an increase in Cmax occurred when diltiazem sustained‐release was administered with food intake, AUC0–48, and therefore the fraction absorbed, were not modified either by concurrent food intake or by different times of administration. The minor modifications of pharmacokinetic parameters of diltiazem sustained release observed were unlikely to induce any clinical consequence.
Endotoxins modify muscle fatigue characteristics
Authors: Goubel F. , Pigot A. , Allaf O. , Verleye M. , Gillardin JM
Published: August 2009

Summary— To test the hypothesis that endotoxins can directly modify muscle fatigue characteristics, in vitro experiments were performed on rat muscles 48 hours after injection of lipopolysaccharides (LPS) from Klebsiella pneumoniae. Resistance to fatigue was quantified by measuring tension production during repetitive electrical stimulation of the isolated epitrochlearis muscle. LPS treatment did not significantly modify initial force production whereas fatigability of the muscle was increased. This in vitro preparation should be used for testing antifatigue drugs.
Regulation of 5‐HT receptors by corticosteroids: where do we stand?
Authors: Chaouloff F.
Published: August 2009

Summary—Twenty five years ago, experimental procedures such as adrenalectomy and corticosteroid administration (to intact rats) allowed the recognition of direct and indirect controls of central 5‐HT synthesis rate by corticosteroids. These effects indicated that the activity of the hypothalamo‐pituitary‐adrenal (HPA) axis, whether under basal conditions or during stress, is endowed with a modulatory action upon serotonergic neurons. Nowadays,in situhybridisation,in vitroautoradiography, and radioligand binding on the one hand, and electrophysiological, behavioural, and neuroendocrinological responses on the other hand, are tools that allow the analysis of direct corticosteroid effects upon 5‐HT receptors. Among the dozen of 5‐HT receptors identified so far, four receptors (namely the 5‐HT1A, 5‐HT1B, 5‐HT2A, and 5‐HT2Creceptors) — and the 5‐HT uptake system — have been the focus of studies aimed at detecting corticosteroid modulatory effects. The results that are reviewed herein indicate that hippocampal 5‐HT1Areceptors are under the tonic inhibitory control of corticosterone. This control is directly exerted at the level of the 5‐HT1Areceptor gene, essentially through mineralocorticoid receptors; as well, electrophysiological findings bring support for an additional modulation of hippocampal 5‐HT1Areceptor‐mediated functions by indirect (ie5‐HT1Areceptor gene‐independent) genomic actions of corticosteroids. In keeping with the respective effects of stressful stimuli and psychotropic drugs upon the HPA axis and central serotonergic systems, it is likely that these corticosteroid‐5‐HT1Areceptor interactions in the hippocampus have consequences in the pathophysiology of mood disorders. However, because the data regarding a corticosteroid control of other 5‐HT receptors are either scarce and contradictory (eg5‐HT1B, 5‐HT2A, 5‐HT2Creceptors and 5‐HT uptake systems) or lacking, it is at the present time unknown whether corticosteroids exert other effects on 5‐HT receptor‐mediated functions, including those related to homeostasis.
Proarrhythmic effects of a quinidine analog in dogs with chronic A‐V block
Authors: Chézalviel‐Guilbert F. , Weissenburger J. , Davy JM , Guhennec C. , Poirier JM , Cheymol G.
Published: August 2009

Summary—The proarrhythmic effects of 3‐hydroxy‐hydroquinidine (3‐OH‐HQ) and quinidine were compared in a canine model of QT‐dependent ventricular arrhythmias. Eight hypokalemic ([K+] ≤ 3.2 mmol/l) dogs with AV block (around 45 bpm) were given either drug in a randomized order at 2‐day intervals. Each drug was given as two 1 hour doses, with a bolus (low dose: 5 mg/kg or high dose: 10 mg/kg) plus infusion (25 or 50 μg/kg/min) protocol. Propranolol infusion was combined with a third hour of the high dose infusion. Electrophysiologic measurements were performed at baseline and 30 minutes after the beginning of each dose and propranolol infusion, and proarrhythmic events were recorded 30 minutes before and during the experiment. Neither drugs altered the ventricular cycle length. Quinidine and 3‐OH‐HQ prolonged the QT interval similarly and significantly when paced at 60 bpm after the low dose (+ 39 ± 18 and + 28 ± 22 msec, respectively) and after the high dose (+ 51 ± 29 and + 50 ± 22 msec). Quinidine was more arrhythmogenic than 3‐OH‐HQ: 7/8 dogs (p ≤ 0.05) developed ventricular arrhythmias (isolated, repetitive ventricular beats, or polymorphic ventricular tachycardias) during quinidine infusion (low dose: 4 dogs) compared to 3/8 dogs (NS) during 3‐OH‐HQ infusion (low dose: 1 dog). Addition of propranolol‐induced bradycardia (around 30 bpm) caused torsades de pointes (wave burst arrhythmias) or polymorphic ventricular tachycardias after both drugs (in 3 dogs after quinidine and in 2 dogs after 3‐OH‐HQ). Thus 3‐OH‐HQ was slightly less arrhythmogenic than quinidine in this model of torsades de pointes, but the addition of an extra favouring factor (bradycardia) reduced that difference.
Colloid bismuth versus famotidine in the treatment and prevention of duodenal ulcer relapse: results of a double‐blind, double dummy randomized study
Authors: Masci E. , Colombo E. , Testoni PA , Fanti L. , Guslandi M. , Tittobello A.
Published: August 2009

Summary— Fifty‐three consecutive patients with active duodenal ulcer (DU) were randomly included in a double‐blind, double‐dummy study to test the healing and relapsing rate of two treatment regimens: famotidine 40 mg nocte for 4–8 weeks, followed by 20 mg for 12 months after healing of the ulcer and colloidal bismuth (CBS) (240 mg bid) for 4–8 weeks, followed by placebo maintenance treatment. The results of the short term period confirmed the efficacy of CBS in healing DU (24/25 in CBS group and 19/23 in famotidine group). However, the relapse rate in the CBS‐treated group was higher (77.8% at 12 months) than in the famotidine group (35.7%) (p = 0.041). Only 7 patients (41.2%) were cleared from Helicobacter pylori (HP) after CBS treatment. In conclusion, the high relapse rate observed in CBS treated patients may be related to the high percentage of patients with HP infection in the tested group and support the hypothesis that lack of efficacy of CBS in preventing DU recurrence is related to its poor eradication of HP.
How sympathetic tone maintains or alters arterial pressure
Authors: Julien C. , Zhang ZQ , Barrès C.
Published: August 2009

Summary— After chronic sympathectomy or sinoaortic denervation (SAD), arterial pressure (AP) becomes extremely unstable, especially because of movement‐related depressor episodes. The simultaneous measurement of AP and regional blood flows in sympathectomized and SAD rats indicates that these depressor episodes are accompanied by strong regional vasodilations, possibly involving an autoregulatory component. The sympathetic nervous system, mainly through baroreflex modulation of its activity, overrides these responses and thereby, considerably limits the AP variability. In the conscious unrestrained rat, AP fluctuates in a narrow range (variation coefficients calculated over 1‐hour beat‐to‐beat recordings are typically −5%). This variability of AP involves sympathetically‐mediated pressor episodes that are coupled to behavior and alerting environmental stimuli. Regarding the latter, studies in SAD rats point to an opposing interaction between centrally‐induced sympathoexcitation and baroreflex activation. Another component of normal AP variability appears as an oscillation centered around 0.4 Hz. Spectral analysis of AP and regional hemodynamic variables indicates that this oscillation is secondary to rhythmic fluctuations in the vasomotor sympathetic tone that are synchronized by the arterial baroreceptor reflex. It is concluded that both stability and normal variability of AP critically depend on the baroreflex control of the sympathetic vascular tone.
Evaluation of antiproliferative effects of the somatostatin analogue somatuline in a rabbit model of traction retinal detachment*
Authors: Baudouin C. , Imbert F. , Ettaiche M. , Gastaud P.
Published: August 2009

Summary— As growth hormone (GH) and insulin‐like growth factor type I (IGF‐I) have been suggested to be involved in the development of some proliferative ocular disorders, we investigated the eventual antiproliferative properties of a long acting somatostatin analogue, somatuline or BIM23014 (IPSEN Biotech, France), in an original model of experimental proliferative vitreoretinopathy. Two studies were separately done to investigate respective effects of subcutaneously‐ and intravitreally administered somatuline. Injections of 107 human platelets freshly prepared from a unique normal donor were injected into the vitreous, cavity of pigmented rabbits. The first experiment consisted of evaluating vitreoretinal proliferation in 17 eyes from rabbits receiving subcutaneous injections of 25 μg/kg of BIM23014, given twice a day, from the day after injection for one month. A group of 14 eyes served as non treated controls. The second experiment was conducted in 33 eyes: 10 received intravitreally 1 μg of somatuline given once a week for one month, 10 eyes similarly received 5 μg/week of somatuline, the remaining 13 eyes serving as controls with intravitreal injections of sterile saline. All animals were examined ophthalmoscopically twice a week for one month in a masked manner, and sacrificed at the end of the experiment for histological and immunohistological analyses. In all but two eyes from the subcutaneously treated group, intravitreal and preretinal membranes formed, five to eight days after platelet injection. Intravitreal proliferation progressively increased, resulting in various degrees of vitreoretinal retraction and retinal detachment. Finally, comparison between eyes from animals receiving subcutaneous BIM23014 and non treated control eyes showed significantly fewer retinal detachments in the treated ones (7/17 vs 11/14, p < 0.05) and significantly lower proliferation scores at the end of the experiment (3.79 ± 1.25 vs 2.24 ± 1.78, p = 0.01). In contrast, comparisons between intravitreally treated and untreated control eyes showed no difference, nor protective effect of intraocular somatuline. Histological examination revealed similarly in all groups intravitreal lymphocytes and proliferation of keratin‐ or vimentin‐positive cells forming various patterns of preretinal membranes and retinal retraction. BIM23014 thus showed a significant reduction of vitreoretinal proliferation, but only when given systemically. These results suggest a therapeutic interest in proliferative retinopathies, but additional studies will be necessary to better understand the role of GH, IGF‐I and somatostatin in these disorders.
Characterization of lymphocyte β‐adrenoceptor activity and Gs‐protein in patients with rheumatic heart valvular disease
Authors: Dzimiri N. , Hussain S. , Moorji A. , Prabhakar G. , Bakr S. , Kumar M. , Almotrefi AA , Halees Z.
Published: August 2009

Summary— In order to test whether the β‐adrenoceptor activity in rheumatic heart valvular disease depends on the ventricular load conditions, we determined their density and binding affinity to [125I]‐iodocyanopindolol in lymphocytes, as well as plasma catecholamine and cAMP levels in 69 patients with regurgitant and stenotic lesions of the aortic and mitral valves. The patients were classified as having left ventricular pressure overload (LVP), left ventricular volume overload (LVV), mixed lesions (MOL) or right ventricular pressure overload (RVP). The β‐adrenoceptor activity was determined by radioligand binding methods, catecholamines by high performance liquid chromatography using an electrochemical detector and cAMP by radioimmunoassay. The mean β‐adrenoceptor density (Bmax) of the control group was 60.1 ± 9.5 /mol (n = 29) per 106 lymphocytes. In the study population, the density was decreased by 83% in LVP, 78% in LVV, 87% in MOL and 86% in RVP. Plasma norepinephrine was elevated by 89% in LVP and 60% in MOL, epinephrine by 43% in LVP, 50% in VOL, 115% in MOL and 20% in RVP, while dopamine was not significantly changed, and cAMP was slightly elevated in all four groups. Screening for activating mutational changes in the Gsα‐protein gave negative results, possibly dissociating the elevation in plasma cAMP from stimulatory effects of such abnormalities in the Gs‐protein signaling. These results show a significant attenuation in lymphocyte β‐adrenoceptor density of patients with rheumatic heart valvular disease, irrespective of the type of the prevailing ventricular load conditions. The reduction in receptor density is accompanied by a significant increase in plasma norepinephrine levels in patients with a left ventricular pressure overload and epinephrine in those with volume overload.
Neuropharmacological profile of non‐peptide neurotensin antagonists
Authors: Gully D. , Jeanjean F. , Poncelet M. , Steinberg R. , Soubrié P. , Fur G Le , Maffrand JP
Published: August 2009

Summary—Neurotensin, an endogenous peptide widely distributed throughout the brain, fulfils neurotransmitter criteria. When administered centrally, neurotensin induces various effects and modulates the activity of the mesolimbic dopamine system. It antagonizes the behavioural action of dopamine in a manner similar, but not identical, to antipsychotic drugs. Neurotensin is even considered to be an endogenous neuroleptic. In fact, microinjection of neurotensin elicits different effects depending on both the dose and the cerebral structures into which the injection is made. Our work on the development of orally‐active neurotensin antagonists has led to the identification of SR 48692, the first non‐peptide antagonist of the neurotensin receptor, and some analogues. This small molecule reveals a surprising neuropharmacological profile. It antagonizes turning behaviour induced in mice and rats (after striatal or ventral tegmental area administration of neurotensin, respectively), hypolocomotion induced by intracerebroventricular injection of neurotensin in rats, and reverses the inhibitory effect of neurotensin (nucleus accumbens injection) on amphetamine‐induced hyperlocomotion in rats. However, SR 48692 cannot reverse either dopamine release in the nucleus accumbens evoked by neurotensin injection in ventral tegmental area, or hypothermia and analgesia induced by intracerebroventricular injection of neurotensin. As direct and indirect dopamine agonists have been reported to promote neurotensin release in the cortex, behavioural studies were performed using injection of apomorphine. In these experiments, SR 48692 inhibited only turning and yawning. It did not antagonize other apomorphine‐dependent effects such as climbing, hypothermia, hypo‐ or hyperlocomotion, penile erection and stereotypies. All together, these data raise the question of the existence of neurotensin receptor subtypes and confirm that the nature of neurotensin and dopamine interactions depends on the brain structures considered.
Mast cell activation involves plasma membrane potential‐ and thapsigargin‐sensitive intracellular calcium pools
Authors: Kassel O. , Amrani Y. , Landry Y. , Bronner C.
Published: August 2009

Summary— The regulation and role of the intracellular Ca2+ pools were studied in rat peritoneal mast cells. Cytosolic free calcium concentration ([Ca2+]i) was monitored in fura‐2 loaded mast cells. In the presence of Ca2+ and K+, compound 48/80 induced a biphasic increase in [Ca2+]i composed of a fast transient phase and an apparent sustained phase. The sustained phase was partially inhibited by the addition of Mn2+. DTPA, a cell‐impermeant chelator of Mn2+, reversed this inhibition, suggesting that a quenching of fura‐2 fluorescence occurs in the extracellular medium. In the absence of extracellular Ca2+, the transient phase, but not the sustained one, could be preserved, provided that mast cells were depolarized. The transient phase was completely abolished by thapsigargin, a microsomal Ca2+‐ATPase inhibitor. Maximum histamine release induced by either compound 48/80 or antigen was obtained in the absence of added Ca2+ only when mast cells were depolarized. These histamine releases were inhibited by low doses (< 30 nM) of thapsigargin. Thapsigargin at higher doses induced histamine release which was unaffected by changing the plasma membrane potential, but was completely dependent on extracellular Ca2+, showing that a Ca2+ influx is required for thapsigargin‐induced exocytosis. Together, these results suggest that the mobilization of Ca2+ from thapsigargin sensitive‐intracellular pools induced by compound 48/80 or antigen is sufficient to trigger histamine release. The modulation of these pools by the plasma membrane potential suggest their localization is close to the plasma membrane.
Lack of efficacy of 5‐HT2A receptor antagonists to reduce brain damage after 3 minutes of transient global cerebral ischaemia in gerbils
Authors: Piera MJ , Beaughard M. , Michelin MT , Winslow E. , Massingham R.
Published: August 2009

Summary— Stimulation of the 5‐HT2A receptors by serotonin has been reported to exert an excitatory effect on neocortical neurons in rats and mice, to facilitate ischaemia‐induced release of excitatory amino acids and to mediate the vasomotor constrictor component of the response of blood vessels to 5‐HT. 5‐HT2A receptor antagonists have, therefore, been proposed as potential protectants against the effects of cerebral ischaemia. The aim of this study was to evaluate the effects of two relatively selective 5‐HT2A receptor antagonists, ketanserin and ritanserin, on delayed hyperactivity and the ensuing neuronal degeneration induced by 3 minutes of bilateral carotid artery ligation in Mongolian gerbils. Effects were compared to that of flunarizine, which blocks calcium overload and served as a positive control in this paradigm. Temporal and/or rectal temperatures were measured and strictly controlled during the ischaemia and the early reperfusion phase. Locomotor activity was measured one day after the ischaemia and neuronal degeneration quantified 7 days later using an image analysis system (Quantimet 570, Leica). Global ischaemia in gerbils elicits hyperactivity associated with a delayed neuronal degeneration predominantly in the CA1 zone of the hippocampus. Ketanserin and ritanserin (3 and 10 mg/kg ip, twice daily for 3 days, pre‐ and postischaemia) did not protect the CA1 neurons against ischaemic damage. The postischaemic hyperactivity was inhibited only with the higher dose of ketanserin. As previously reported, flunarizine (30 mg/kg po) markedly reduced neuronal degeneration (‐44.2%, p < 0.01) and totally abolished the ischaemia‐induced hyperactivity. These data demonstrate that ketanserin and ritanserin are not effective protectants of the gerbil hippocampus against ischaemic damage when the body temperature of the animals is controlled, thus suggesting that 5‐HT2A receptors are not directly implicated in the pathogenesis of global cerebral ischaemia in this model.
Human adipocytes express α2‐adrenergic receptor of the α2A‐subtype only: pharmacological and genetic evidence
Authors: Castan I. , Devedjian JC , Valet P. , Paris H. , Lafontan M.
Published: August 2009

Summary— In the present study we have reinvestigated the subtype of α2‐adrenoceptors expressed in human adipocytes (from subcutaneous and internal fat deposits) by means of radioligand binding using subtype‐selective antagonists, and RNase mapping using a set of specific probes prepared from human α2‐adrenoceptors genes (α2C2, α2C4 and α2C10). Comparison of the pharmacological properties of the human adipocyte α2‐adrenoceptors with those of the different human adrenoceptors expressed in COS‐7 cells demonstrated that: i) human adipocyte α2‐adrenoceptors displays a KD for [3H]RX821002 and [3H]MK912 identical to that found in COS‐7 cells transfected with the α2C10 gene; ii) yohimbine and oxymetazoline is 1,000‐fold more potent than prazosin to inhibit [3H]antagonist binding. RNase protection assays on cellular RNA prepared from the three fat deposits showed the presence of substantial amounts of α2C10 transcripts: in contrast, mRNAs from α2C2 and α2C4 genes were undetectable. Altogether these results definitively establish that human adipocytes express only one α2‐adrenoceptor which is of the α2A‐subtype and encoded by the α2C10 gene.
Similia similibus obscurantur: the pharmacological clinical activity bias I. A prototype model to correct a disease‐drug interaction leading to misestimations of drug‐attributable side effects
Authors: Bernheim JL , Vrana I.
Published: August 2009

Summary— Drugs have side effects that manifest as signs or symptoms which are sometimes undistinguishable from signs or symptoms of active disease. The conventional approximation of the rate of side effects of drugs is by subtracting the rate of signs and symptoms in the placebo group from that in the drug group. This measures net side effects and is adequate in studies with healthy volunteers, in which no interaction between drug and disease exists. For ethical and practical reasons, however, volunteer studies cannot be large and the frequency of non‐rare side effects must be estimated in large‐scale clinical trials. In the latter, biasing drug disease interactions may occur. We report on such a hitherto undescribed interaction: the pharmacological clinical activity bias. If one is interested in estimating not the net, but the direct or intrinsic, ie, drug‐attributable side effects, the conventional approximation is biased whenever, in clinical trials, both of two conditions apply. The first is that the variable on the scale of which a sign or symptom is recorded as a putative side effect, is also in the absence of drug affected by uncontrolled disease. The second is that the drug has pharmacological clinical activity (A) on that sign or symptom, thus reducing the contribution of disease (D) to what is measured. In this case the drug affects the variable under study both directly, through its intrinsic side effect, and indirectly, through its clinical activity, and the rate of attributable side effects differs from the rate of net side effects as calculated by the conventional approximation. We present a simple deterministic model, which assumes that disease remains stable if untreated, additivity of the relative contributions of drug, placebo and disease to the total rate of the sign or symptom, and no other interaction between intrinsic properties of the drug and active disease than pharmacological clinical activity. This theoretical model quantifies the bias as D0(Ad ‐ Ap), in which D0 is the baseline frequency of the sign or symptom in the studied patients, and Ad and Ap are the intrinsic clinical activities of drug and placebo, respectively, on the sign or symptom under study. The model confirms that the conventional approximation of drug side effects is unbiased only in healthy volunteers or with drugs devoid of clinical activity. Without correction by such a model, any clinical activity of the drug or manifestation of active disease will cause the conventional approximation of side effects to be biased. This may manifest as artifacts such as attribution of a side effect when there is none, and as under‐ or overestimation, pseudo‐ tachyphylaxis, or pseudo‐delayedness of attributable side effects.
Endothelin‐1 does not modulate O2· release and [Ca2+]i variations in resting or differentiated HL‐60 cells
Authors: Gallois A. , Bueb JL , Tschirhart E.
Published: August 2009

Summary— Endothelin‐1 (ET‐1) by itself was not an effective stimulus for inducing superoxide (O2*) generation in human resting or DMSO‐differentiated neutrophil‐like HL‐60 cells. ET‐1 (0.01 – 100 nM) was not able to modulate O2* generation stimulated by the chemotactic peptide N‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine (fMLP, EC50 = 4.24 ± 1.63 nM in the absence and 3.16 ± 1.95 nM in the presence of ET‐1). Neither did ET‐1 (0.01 – 100 nM) promote the mobilization of intracellular calcium ions or modulate fMLP‐induced [Ca2+]i increase in this model of human neutrophils. Phosphoramidon, a neutral endopeptidase inhibitor, was not able to reveal any biological (O2*) or biochemical ([Ca2+]i) response to ET‐1 in the absence or in the presence of fMLP in these cells. These results indicate that DMSO‐differentiated neutrophil‐like HL‐60 cells are not sensitive to ET‐1 in terms of O2* generation or [Ca2+]i variations.
Effect of serotonin and calcium in normal and sensitized guinea pig isolated trachea
Authors: Perpiña M. , de Diego A. , Compte L. , Bertó L. , Cortijo J. , Morcillo EJ
Published: August 2009

Summary— Tracheal strips from normal and actively sensitized guinea pigs were studied to determine the responses to serotonin (5‐hydroxytryptamine, 5‐HT; 1 nM – 0.1 mM) and ouabain (0.1 μM – 0.1 mM), and the effects of increasing the extracellular calcium (Cao) concentration on tonic contractions elicited by 5‐HT. Sensitized trachea exhibited an increased responsiveness and sensitivity to 5‐HT and ouabain. Increases in Cao to achieve final concentrations of 5, 10 and 20 mM caused concentration‐related relaxations of normal and sensitized tissues contracted to a similar plateau level with 5‐HT. Inhibition of the Na+/K+‐ATPase by ouabain (10 μM) reversed the effects of Cao from relaxation to contraction in normal and sensitized tissues contracted with 5HT. Sensitized preparations showed reduced relaxations in response to Cao (10–20 mM), and sensitized, ouabain‐treated, trachea showed augmented contractions to Cao (10–20 mM) when compared to normal tissues. These results demonstrate a decreased membrane‐stabilizing effect of Cao in sensitized trachea and the implication of the Na+/K+‐ATPase in the regulation of membrane stability by Cao, suggesting a possible relevance to those mechanisms underlying airway hyperreactivity.
Effects of nitric oxide and sodium nitroprusside on the intrinsic elastic properties of pressurized rat coronary artery
Authors: Pourageaud F. , Freslon JL
Published: August 2009

Summary— The study was designed to assess the influence of either nitric oxide (NO) or sodium nitroprusside and the absence of endothelium on the intrinsic elastic properties of coronary arteries from WKY rats. For this purpose, segments of the right interventricular coronary were mounted in an arteriograph where wall thickness and internal diameter were continuously monitored while intraluminal pressure was controlled in the absence of flow. To study the passive properties, pressure‐diameter relationships were determined by measuring the corresponding internal diameter for each stepwise increase in intraluminal pressure. Thus, wall stress, strain and incremental elastic modulus (Einc) were assessed in the following experimental conditions: control, incubation with nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) or L‐NAME + L‐arginine (L‐arg, 100 μM), incubation with sodium nitroprusside (SNP, 100 μM), endothelium removal (CHAPS). The Einc‐stress relationship was not significantly different in the different experimental conditions, but values of Einc plotted as function of strain were significantly decreased after L‐NAME incubation and partly reversed after L‐arg addition. The same effect was observed after endothelium destruction but to a lesser extent. After SNP incubation, values of Einc were significantly decreased for small values of strain and increased for high values of this parameter. These results show that NO synthase inhibition induced, for a given strain, a decrease of elastic modulus in coronary arteries. It can be speculated that functional antagonism exerted by NO against spontaneous contractile tone was reduced. Thus, the smooth muscle cells were in a greater state of activation and probably more strongly involved in the intrinsic elastic properties of this preparation. However, an unexplained effect of NO on wall stiffness cannot be excluded. Conversely, SNP increased the initial diameter and induced an initial decrease in stiffness followed by a subsequent increase. After endothelium destruction, stiffness was significantly decreased compared to control conditions. It can be concluded that NO modulates the intrinsic elastic properties of the coronary arteries through smooth muscle cell relaxation. Furthermore, results with SNP support the hypothesis that the lower the state of activation of the smooth muscle cells, the higher the elastic modulus of the arterial wall in this coronary artery preparation.
Effect on gastric secretion, gastrin and histamine release during and after long‐term treatment by pirenzepine in dogs
Authors: Vatier J. , Riquet W. , Célice‐Pingaud C. , Olivier A. , Mignon M. , Farinotti R.
Published: August 2009

Summary— We assessed the effects of pirenzepine (2 mg/kg per os) on gastric secretion and gastrin and histamine release in response to food and histamine dihydrochloride infusion in four dogs during 24 weeks of treatment and for 15 weeks after the end of treatment. The results were compared to those obtained in the same animals in control experiments, before treatment, and in four untreated dogs. Pirenzepine absorption was checked by measuring plasma concentrations. Pirenzepine led to a significant reduction in acid and pepsin secretion in response to histamine. In response to food, the reduction in secretion was concomitant with a reduction in gastrin and histamine release. Baseline concentrations of gastrin were reduced, while those of histamine were unchanged. No side effects were observed. After treatment, a long time lapse (about 15 weeks) was required for acid and pepsin secretion and gastrinemia to return to control levels, while histamine release in response to food normalized rapidly. Pirenzepine fixes selectively to M1 muscarinic receptors of the synaptic ganglion, thus inhibiting the effect of vagal stimulation, especially on pepsin secretion. Our data suggest that it might also fix to M1 receptors located on ECL cells, thereby reducing histamine release. In addition, pirenzepine probably fixes to other muscarinic receptors inhibiting gastrin release and resulting in a G and secretory cell mass reduction, probably by increasing somatostatin release.
The arterial wall: a new pharmacological and therapeutic target*
Authors: Laurent S. , Vanhoutte P. , Cavero I. , Chabrier PE , Dupuis B. , Elghozi JL , Hamon G. , Janiak P. , Juillet Y. , Kher A. , Koen R. , Madonna O. , Maffrand JP , Pruneau D. , Thuillez C.
Published: August 2009

Summary— In recent years, two key concepts having numerous interrelationships were advanced for the understanding of various cardiovascular diseases: the “endothelial dysfunction” and the “arterial remodelling”. Both endothelial dysfunction and arterial remodelling occur in various pathologies including essential hypertension, heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extra‐cellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates‐NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extra‐cellular matrix.
Smooth muscle relaxant activity of A1‐ and A2‐selective adenosine receptor agonists in guinea pig trachea: involvement of potassium channels
Authors: Hadjkaddour K. , Michel A. , Laurent F. , Boucard M.
Published: August 2009

Summary—The relaxant activities of N6‐cyclopentyladenosine (CPA), an A1‐selective agonist, and of 5′‐(N‐cyclopropyl)‐carboxamidoadenosine (CPCA), a potent A2‐receptor agonist, in the carbachol‐contracted guinea pig isolated trachea have been evaluated. Both CPA and CPCA induced concentration‐dependent relaxations of the guinea pig trachea, CPCA demonstrating a more potent but less efficient activity. 8‐Cyclopentyl‐1,3‐dimethylxanthine (CPT) and 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) (10 μM), both selective and potent A1‐adenosine receptor antagonists, induced only a weak inhibition of CPA while 3,7‐dimethyl‐1‐propargylxanthine (DMPX) (10 μM), a selective A2‐adenosine receptor antagonist, failed to antagonize the relaxant activity of CPA. These results indicate that a major component of the tracheal relaxant activity of CPA occurred by a mechanism which is insensitive to the antagonist potency of A1‐ and A1‐xanthine adenosine antagonists and therefore was not mediated by A1‐ or A1‐adenosine receptors activation. The relaxant activity of CPCA was inhibited by DMPX, which supported the involvement of A2‐adenosine receptors. Glibenclamide (10 μM), an inhibitor of KATP‐channels, inhibited the relaxant activity of CPCA, whereas it was without effect on CPA. Iberiotoxin (180 nM), an inhibitor of the large‐conductance CA2+‐activated K+ channel, inhibited the relaxant action of CPA and CPCA. However, verapamil can offset the inhibition of CPA provided by iberiotoxin which suggests that such an antagonism does not represent an interaction between the toxin and CPA at the level of the large‐conductance CA2+‐activated K+‐channel gating but rather functional antagonism attributable to the promotion of CA2+ influx by the toxin. In contrast, verapamil only partially reversed the inhibition of CPCA relaxant activity provided by iberiotoxin. Taken together, these results suggest that A2‐adenosine receptor subtypes are coupled to KATP‐channels and large‐conductance CA2+‐activated K+‐channels in the guinea pig trachea whereas the unidentified adenosine receptor subtype, involved in CPA relaxant activity, is not.
Interactions between acetylcholine and substance P effects on lung mechanics in the rabbit
Authors: Delaunois A. , Gustin P. , Segura P. , Vargas M. , Ansay M.
Published: August 2009

Summary— The pharmacological mechanisms involved in the acetylcholine (ACh)‐ and substance P (SP)‐induced changes in pulmonary mechanics were studied in isolated perfused rabbit lungs. Tracheal pressure (Ptr) and airflow were measured by a Fleisch pneumotachograph and pressure transducers. Air volume, lung resistance (RL) and dynamic compliance (Cdyn) were calculated. ACh induced a dose‐dependent increase in Ptr and RL, and a decrease in Cdyn. These effects were strongly prevented by atropine, and partly by SR140333, a neurokinin NK1 receptor antagonist; SR48968, a neurokinin NK2 receptor antagonist; indomethacin and antihistaminics. Ketanserin had no significant protective effect against ACh. SP also induced concentration‐dependent increases in RL and decreases in Cdyn. SR140333 and atropine strongly inhibited the effects of SP, while ketanserin, SR48968, antihistaminics and indomethacin did not protect the lungs against this drug. 5‐hydroxytryptamine induced no significant change in lung mechanic parameters. Cumulative concentrations of histamine increased RL and decreased Cdyn. We conclude that ACh‐induced changes in lung resistance and compliance are in part mediated by a direct effect on airway smooth muscle and in part by the stimulation of C fibers, by the release of histamine from mast cells and by the synthesis of arachidonic acid metabolites. In turn, the effects of SP on lung mechanics are partly due to cholinergic activation.