bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of asynchronous activation of the ventricular fibres by an ectopic pacemaker in the accidents, especially fibrillation, caused by Icantiarrhythmic drugs
Authors: Timour Q. , Aupetit JF , Loufoua‐Moundanga J. , Kiouch I. , Omar S. , Chevrel G. , Faucon G.
Published: August 2009

Summary—Class Icantiarrhythmic drugs, which are known to slow down conduction in the ventricular muscle, are likely to impair synchrony in activity of the ventricular fibres. Asynchronous activation was first investigated between an ischaemic and a normal area by the simultaneous recording in anaesthetized, open‐chest pigs of two left ventricular monophasic action potentials (MAPs) under ventricular pacing at a high rate of 180 beats‐min−1. Asynchronous activation was then investigated in the intact myocardium according to the distance separating the recording from the pacing electrode. Furthermore, mechanical effects of left ventricular systole were observed by recording dP/dtmaxand mean arterial blood pressure during the pacing periods. Ischaemia was produced by transient complete occlusion of the left anterior descending coronary artery near its origin; as a result, activation time reached 85 ms in the ischaemic area under flecainide administered iv in a 2.5 mg·kg−1dose instead of approximately 60 ms in the normal area for fibres equidistant from the pacing electrode. Similar delays in activation were observed in the intact myocardium, depending on whether the explored region was close to or far from the pacing electrode. In the latter case, the difference in activation time may become markedly greater if the distance or the dose of flecainide are increased. This difference, which possibly exceeds one‐third of the MAP duration (practically unchanged by flecainide), may account for the occurrence of fibrillation or the sudden loss of systole mechanical efficacy.
CRL41405: a drug with a new pharmacological profile on pancreatic exocrine secretion in the rat
Authors: Nagain C. , Chariot J. , Vaille C. , Rozé C.
Published: August 2009

Summary— The recently described compound CRL41405 displays central effects suggesting possible antidepressive and awakening properties. In order to further analyze the pharmacology of this compound, its effects were studied on basal and stimulated pancreatic secretion in anaesthetized rats. CRL41405 alone (7–20 mg/kg, sc) had no effect on basal pancreatic secretion. Larger doses (67–200 mg/kg) increased basal secretion through the stimulation of cholinergic muscarinic receptors, the effect being antagonized by atropine. CRL41405 (20 mg/kg) suppressed the 2‐deoxyglucose‐induced (but not the acetylcholine‐induced) stimulation of pancreatic secretion through an alpha‐2 adrenoceptor inlibitory mechanism that was blocked by idazoxan (0.3 mg/kg, sc). In addition, a beta adrenoceptor mediated stimulation of sodium and bicarbonate excretion (blocked by propranolol) was evidenced when the alpha‐2 inhibition was suppressed by idazoxan. Under alpha‐2 adrenoceptor blockade, water and electrolyte stimulation by CRL41405 could be demonstrated on basal, 2‐deoxyglucose‐induced and acetylcholine‐induced pancreatic secretion. This original profile makes CRL41405 a unique drug in pancreatic pharmacology.
Could saliva stand for plasma in theophylline monitoring in asthmatic children? Still a controversial problem
Authors: Gao Y. , Pons G. , Rey E. , Richard MO , D'Athis P. , Bertin L. , Thiroux G. , de Blic J. , Scheinmann P. , Olive G.
Published: August 2009

Summary— Theophylline determination in saliva was proposed several years ago as a convenient and non‐invasive alternative to monitoring plasma in children and adults. Published data demonstrated that theophylline saliva concentration linearly correlates plasma concentration. However, the variability found in interindividual serum/saliva ratios and the wide scattering among the data points precluded the clinical use of saliva for theophylline monitoring. The purpose of this study was to compare different standardized methods for obtaining stimulated saliva intending to reduce the variability in plasma/saliva ratios and to determine the most reliable one. A group of 150 ambulatory chronic asthmatic 4.5 to 20.83 (10 ± 3.7; M ± SD) year‐old patients receiving theophylline 6.85 ± 1.88 mg/kg every 12 h as slow release preparations for 4 to 100 days was studied. One ml venous blood and salivary specimens were simultaneously collected 5.15 ± 0.36 h after the morning maintenance dose. In a subgroup of 75 patients, saliva was collected using first a new device called salivette, immediately followed by the collection of an expectorated sample 30 s after citric acid crystals stimulation. In the other patients saliva was collected using citric acid containing salivette. Theophylline concentration was determined using HPLC. For all types of saliva collection, salivary and plasma theophylline concentrations correlated significantly. However whichever method was used, based on the − 2 to + 2 SD interval, a large range of plasma theophylline was predicted from a single salivary theophylline concentration. Despite a further standardization of the sampling of saliva, saliva theophylline could not accurately predict plasma concentration.
Study on the effect of oral administration of carbocisteine on ventilatory parameters in the SO2 inhalation model of bronchitis in the rat
Authors: Levrier J. , Duval D. , Lloyd KG
Published: August 2009

Summary— In order to study the physiological correlates of the beneficial action of carbocisteine (S‐carboxy‐methyl‐cysteine), we have measured the changes occurring in ventilatory parameters in rats made bronchitic by prolonged exposure (2 weeks) to air containing sulfur dioxide (SO2). In animals treated with distilled water (1 ml/100 g/day), statistically significant (P < 0.05) changes in respiratory frequency (‐20%) and tidal volume (+ 31%) were found. As a result of these opposing changes, the ventilation/min was stable. Moreover, the compliance was decreased (33%, P < 0.05) and the resistance was greatly enhanced (+ 99%, P < 0.05). The concomitant administration of carbocisteine (500 mg/kg po/day) with SO2 inhalation significantly (P < 0.05) prevented the development of resistance without effecting significant changes in the other parameters except for a slight improvement in ventilation/min. In conclusion, this improved respiratory resistance in the bronchitic carbocisteine‐treated animals tallies with a decrease in mucus retention associated with the return to normal of rheological characteristics of the secreted mucus.
Rolipram inhibits PAF‐induced airway microvascular leakage in guinea‐pig: a comparison with milrinone and theophylline
Authors: Ortiz JL , Cortijo J. , Vallés JM , Bou J. , Morcillo EJ
Published: August 2009

Summary—The effects of 3 phosphodiesterase (PDE) inhibitors, rolipram (PDE IV), milrinone (PDE III) and theophylline (nonselective) on PAF (50 ng kg−1; iv)‐induced airway vascular leakage have been evaluated in guinea‐pigs. Rolipram (3–300 μg kg−1; iv) reduced the increase in permeability induced by PAF at all airway levels whereas milrinone (10–1000 μg kg−1; iv) and theophylline (30 mg kg−1; iv) were without effects. The anti‐leakage activity of rolipram may be of therapeutic value in asthma.
Effects of ibogaine on naloxone‐precipitated withdrawal in morphine‐dependent mice
Authors: Francés B. , Gout R. , Cros J. , Zajac JM
Published: August 2009

Summary— In naive mice, ibogaine at a tremorigenic dose (30 mg/kg, ip), did not produce antinociception but did potentiate the antinociceptive potency of morphine in the tail‐flick test. In morphine‐dependent mice, ibogaine did not eliminate withdrawal symptoms but significantly increased the number of repetitive vertical jumps induced by naloxone, whatever the duration of the chronic morphine treatment. By comparison, repetitive jumping induced by α‐napthoxyacetic acid (α‐NOAA), a non‐convulsant drug which induced jumping without affecting other morphine‐withdrawal signs, was not significantly modified by ibogaine. These results indicate that while acute antinociceptive effects of morphine are modulated by ibogaine, this drug, shown to alleviate opiate dependence in man, does not attenuate in mice opioid withdrawal manifestations.
Lack of effect of isradipine on cyclosporin pharmacokinetics
Authors: Vernillet L. , Bourbigot B. , Codet JP , Le Saux L. , Moal MC , Morin JF
Published: August 2009

Summary—The influence of isradipine as a long acting form (IcazRLP 5 mg) on cyclosporin pharmacokinetics was studied in six hypertensive renal transplant patients (mean age 37 yrs; mean body weight 62 kg). These patients received a mean daily cyclosporin dose of 307 mg in two equal intakes. Isradipine was orally administered once a day at a dose of 5 mg before the morning cyclosporin intake. Cyclosporin kinetics was assessed over a 0–12‐h period, the day before (D‐1) and 13 days (D+13) after isradipine treatment. Whole blood concentrations of cyclosporin were determined by radioimmunoassay (RIA) using the SandimmuneR‐RIA kit (specific and non‐specific monoclonal antibodies). Area under the blood concentration‐time curve (AUC), the maximum blood concentration (Cmax) and the time to reach Cmax(Tmax) on D‐1 and D+13 were not significantly different whatever the specificity of the RIA method. For example, the mean AUC ± sd values were 5 247 ± 2 255 (D‐1)vs5 317 ± 1 675 (D+13) μg·1−1·h for the specific and 20 905 ± 8 317vs19 327 ± 5 758 μg·1−1·h for the non‐specific determinations. Therefore, the pharmacokinetics of cyclosporin is not influenced by co‐administration of isradipine at a therapeutic dosage. Moreover, the clinical results show that isradipine treatment was effective after 13 days administration (mean systolic blood pressure 132vs158 mm Hg,P< 0.05 and mean diastolic blood pressure 77vs93 mm Hg,P< 0.05 in supine position), and well tolerated throughout the study. Thus, the use of isradipine in its long acting form allows cyclosporin to be administered to transplant patients with no special adjustment of the dosage, unlike most other calcium channel blocking agents.
Protection of erdosteine on smoke‐induced peripheral neutrophil dysfunction both in healthy and in bronchitic smokers
Authors: Ciaccia A. , Papi A. , Tschirky B. , Fregnan B.
Published: August 2009

Summary— The purpose of the present study was to determine whether erdosteine and its metabolites (substances containing thiol groups) can prevent the alteration of the chemotactic function of polymorphonuclear cells (PMN) from peripheral blood induced by cigarette smoke of eight healthy non‐smoking volunteers, when incubated in vitro before smoke exposure, and whether oral treatment with erdosteine (900 mg/day) for two weeks might restore the chemotaxis of PMN, either from eight healthy or from 16 chronic bronchitic smokers. The chemotactic stimuli in vitro were casein, lipopolysaccharides (LPS), and formyl‐methionyl‐leucyl‐phenyalanine (FMLP). The results of the study in vitro have confirmed that PMN from non‐smoking volunteers shows a reduced chemotactic responsiveness when exposed in vitro to smoke. This can be partially prevented in a dose‐related manner by pre‐incubation with erdosteine, its metabolites, cysteine, and glutathione (metabolites I and II being at least 10 times more active than the intact substance and the known biological standards also containing thiol groups). The experiment on PMN from healthy smokers (in a double‐blind crossover design versus placebo) has indicated that the chemotaxis can be improved only after treatment with erdosteine. The same observation has been made in the experiment on PMN from smokers affected by chronic bronchitis (in a double‐blind design versus placebo with two distinct groups). In these patients the phagocytic and bactericidal activities of PMN were not affected by the smoke and therefore, neither one was influenced by erdosteine treatment. Since smoke can form free oxidant radicals which have toxic effects on some biological structure, the most likely explanation of the protective action of erdosteine is due to the presence of the blocked SH groups in its molecule which are released during the metabolization process and which exhibits a free radical scavenging action.
Effects of catecholamines on plasma potassium: the role of alpha‐ and beta‐adrenoceptors
Authors: Moratinos J. , Reverte M.
Published: August 2009

Summary—The sympathetic nervous system plays an important role in the control of plasma potassium levels. Administration of adrenaline or noradrenaline evokes, in the majority of mammal species a dual response: first a short transient hyperkalaemia, followed by a maintained hypokalaemia. Alpha1‐ and alpha2‐adrenoceptors mediate the initial hyperkalaemia through the activation of hepatic Ca2+‐dependent‐K+‐ channels. Stimulation of beta1‐ and beta2‐adrenoceptors induces the late hypokalaemia by stimulation of skeletal muscle Na+‐K+‐ATPase. Beta3‐adrenoceptor stimulation may also have an effect on plasma potassium control since administration of selective beta3‐adrenoceptor agonists induces a decrease in plasma potassium. The simultaneous infusion of phenyleprine (alpha‐adrenoceptor agonist) and isoprenaline (beta‐adrenoceptor agonist) increases plasma potassium levels: this effect is several times larger than the algebric summation of the changes in plasma potassium when each agent is infused separately, thus suggesting potentiation. The physiological (changes in cell volume and function secondary to changes in ion fluxes) and clinical implications (pathophysiological conditions with hypo or hyperkalaemia, hyperkalaemic periodic paralysis, ventricular arrythmias) of these findings are discussed.
Carbocisteine improves the mucociliary transport rate in rats with SO2‐induced bronchitis
Authors: Zahm JM , Levrier J. , Duval D. , Pierrot D. , Puchelle E.
Published: August 2009

Summary— In order to study the effect of carbocisteine on the mucociliary function of the respiratory tract, we performed a double‐blind study on rats with SO2‐induced (400 ppm) hypersecretion. During the experimental bronchitis, the treated group of rats received carbocisteine through a stomach tube at a dose level of 500 mg/kg for 15 days, whereas the untreated group of rats received distilled water. After killing the rats, and following lung excision, the respiratory mucus was scraped off and collected by using a glass capillary. The mucus degree of purulence was macroscopically estimated and the mucus transport rate was measured by using the frog palate technique. The mean mucus relative transport rate, measured on the frog palate, was 0.60 ± 0.17 in the untreated group and was significantly higher (P < 0.01) in the treated group (0.73 ± 0.14). Carbocisteine also significantly altered (P < 0.01) the mucus macroscopical aspect, leading to a decrease in the number of rats with purulent mucus. These results suggest that carbocisteine maintains an efficient mucus transport rate, leading to a less infected respiratory tract.
The antagonist properties of S 11978 on 5HT3receptors in N1E‐115 neuroblastoma cells
Authors: Morain P. , Abraham C. , Lacoste JM , Malen C. , Laubie M. , Giesen‐Crouse E.
Published: August 2009

Summary—The effects of the novel antagonist S 11978 (Endo‐7‐[(8‐methyl‐8‐azabicyclo[3,2,1]‐3‐octyl)oxycarbonyl] benzo[b] thiophene) on 5HT3receptors were examined in N1E‐115 mouse neuroblastoma x rat glioma hybrid cells, with radioligand binding and whole cell patch clamp techniques. The 5HT3receptor ligand [3H] quipazine was displaced by ICS 205–930, GR 38032F and S 11978 with KIvalues of 2.25 nM, 36.5 nM and 1.75 nM respectively. Electrophysiological studies showed that S 11978 is a potent 5HT3antagonist: IC50values for inhibition of 5HT‐induced inward current by ICS 205–930, GR 38032F and S 11978 were 0.22 nM, 0.63 nM and 0.43 nM respectively at a holding potential of‐65 mV. It is concluded that S 11978 is a potent, high affinity 5HT3receptor antagonist.
Anti‐immobility activity of different antidepressant drugs using the tail suspension test in normal or reserpinized mice
Authors: Teste JF , Pelsy‐Johann I. , Decelle T. , Boulu RG
Published: August 2009

Summary—The tail suspension test is a screening procedure recently used in mice to detect antidepressant activity of drugs. The ability of amine re‐uptake inhibitors to decrease immobility in non‐reserpinized and in reserpinized mice was studied. Reserpine (4 mg/kg ip) was injected 4 h previously. Anti‐depressants were administered ip, 60 min before tail suspension. Animal activity was recorded for 6 min. Preferential serotonin re‐uptake blockers (fluoxetine, fluvoxamine, clomipramine) were poorly active in non‐reserpinized mice and inactive in reserpine‐treated mice. Noradrenergic drugs (desipramine, demexiptiline, viloxazine) were more efficient in reserpinized than in non‐reserpinized mice. The mixed serotonin‐ noradrenaline re‐uptake inhibitor (imipramine) shows an activity which should be considered between serotonin re‐uptake inhibitors and noradrenaline re‐uptake inhibitors. DA re‐uptake inhibitors (amineptine, GBR 12909) exhibited the highest anti‐immobility effect in non reserpinized animals but were of low efficacy after reserpine treatment. Amphetamine differed from dopamine re‐uptake inhibitors by its better activity in reserpinized animals. Moreover, it was the only drug showing an equal anti‐immobility effect in non reserpinized and reserpinized mice because the dose of 8 mg/kg of amphetamine reduced immobility in reserpinised mice with the same intensity as the dose of 4 mg/kg in non reserpinised mice whereas no other drugs tested in this study achieved the same effect. Comparison of anti‐immobility activities of putative antidepressants in non‐pre‐treated and in reserpine‐pre‐treated mice, using the tail suspension test, may be useful to discriminate amphetamines from antidepressant drugs and to differentiate between categories of amine re‐uptake blockers.
Pharmacokinetics of apomorphine in parkinsonian patients
Authors: Nicolle E. , Pollak P. , Serre‐Debeauvais F. , Richard P. , Gervason CL , Broussolle E. , Gavend M.
Published: August 2009

Summary— Apomorphine, a dopamine agonist, has been used efficiently in parkinsonian patients to treat severe levodopa‐induced on‐off phenomenon. Motor improvement has been obtained both with continuous subcutaneous (SC) infusions, and multiple SC injections. So as to assist in the understanding of the clinical results, we studied the peripheral pharmacokinetics of apomorphine in 20 patients after intravenous (IV) or SC injections in the anterior abdominal wall and in the thigh at various doses, or SC infusion. Plasma apomorphine levels were measured by high‐performance liquid chromatography with electrochemical detection. After an SC injection in the abdominal wall, the Tmax was brief (16 ± 11 min) the drug was rapidly cleared from the plasma and had a short plasma half‐life (69.7 ± 25.8 min). The AUC was similar following SC and IV injections, suggesting that apomorphine was completely absorbed from subcutaneous tissue. Inter‐subject variability in drug absorption was large. We noticed a trend towards a more complete absorption following injection in the abdominal wall rather than in the thigh. In patients chronically treated by continuous SC infusion, the apparent plasma half‐life was five times longer than that following SC or IV injections. These pharmacokinetic data may explain the rapid onset and brief duration of clinical effects, and the usefulness of individual titration for intermittent SC apomorphine injections, and the smoother motor response obtained with continuous SC infusions.
Epithelial factors: modulation of the airway smooth muscle tone
Authors: Bertrand C. , Tschirhart E.
Published: August 2009

Summary—The airway epithelium is composed of a heterogeneous population of cells. This epithelial layer is not only a physical barrier but also a target responding to a variety of inflammatory mediators. These cells can respond by releasing contracting and relaxing factors to modulate airway responsiveness. They can also metabolize some of the inflammatory mediators. Epithelial damage is a consistent feature of some respiratory conditions, but whether or not such damage contributes to airway disease is for the moment unknown. This review summarizes the literature on the known and proposed roles of the epithelium in the modulation of the airway smooth muscle tone.
Effect of zolpidem during sleep on ventilation and cardiovascular variables in normal subjects
Authors: Cann C Crowe Mc , Quera‐Salva MA , Boudet J. , Frisk M. , Barthouil P. , Borderies P. , Meyer P.
Published: August 2009

Summary— A double‐blind study comparing the effect of zolpidem 10 mg, and placebo, on sleep architecture, nocturnal ventilation, cardiovascular parameters (heart rate, systolic, diastolic and mean blood pressures) was carried out. Ten healthy middle‐aged males took part in the study. No significant differences were found between zolpidem and placebo in relation to sleep architecture. Mean respiratory disturbance index (RDI) and SaO2 values (mean SaO2, time spent with SaO2 < 90%) were similar under both conditions. The diastolic and mean blood pressure readings taken from REM periods which occurred during the first third of the night were significantly higher with zolpidem. No changes in systolic blood pressure or heart rate were found with zolpidem in comparison to placebo.
Differential cardiovascular effects of 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT), flesinoxan, 5‐methyl‐urapidil and MDL 75,608A in conscious spontaneously hypertensive rats
Authors: Buisson‐Defferier S. , Hibert M. , van den Buuse M.
Published: August 2009

Summary—The effects of intravenous (iv) administration of four agonists at central 5‐HT1Areceptors were investigated and compared. Acute iv injection of 0.1 mg/kg of 8‐OH‐DPAT induced a decrease in blood pressure both in spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto rats (WKY). The maximal hypotensive effect was observed 15 and 10 min after injection, respectively, but the effect was greater and longer‐lasting in the SHR. 8‐OH‐DPAT significantly decreased heart rate in WKY and, to a lesser extent, in SHR. The iv injection of 1 mg/kg of flesinoxan caused a similar fall in blood pressure and heart rate in SHR and WKY. The iv administration of 1 mg/kg of 5‐methyl‐urapidil or MDL 75,608A caused a fall in blood pressure which was significantly more pronounced in SHR than in WKY. 5‐methyl‐urapidil induced a significant tachycardia in WKY, but had little effect on heart rate in SHR. MDL 75,608A caused a short‐lasting tachycardia in SHR and WKY. In conscious SHR, the intracerebroventricular (icv) injection of 10 μg of 8‐OH‐DPAT or 100 μg of either flesinoxan or MDL 75,608A caused a decrease in blood pressure and heart rate. The icv injection of 100 μg of 5‐methyl‐urapidil caused only a decrease in blood pressure. Chronic pre‐treatment with these compounds, by daily iv injection, did not significantly influence the hypotensive or bradycardic effects in an acute experiment. The involvement of α1‐adrenoceptors in the effects of these compounds was studied by administering phenylephrine (1 μg/iv) at 5‐ min intervals before and after the iv injection of the experimental compounds. The injection of phenylephrine reproducibly increased blood pressure by 35–40 mm Hg after saline pre‐treatment, and these responses were not affected by the iv injection of 0.1 mg/kg of either 8‐OH‐DPAT or 1 mg/kg of flesinoxan. In contrast, the phenylephrine‐induced pressor responses were markedly diminished at 5 min after treatment with 1 mg/kg of either 5‐methyl‐urapidil or MDL 75,608A, but slowly recovered thereafter. These results show that the 5‐HT1Arecptor agonists 8‐OH‐DPAT, flesinoxan, 5‐methyl‐urapidil and MDL 75,608A show antihypertensive properties in conscious SHR after iv or icv injection. However, the mechanism of action of the compounds differs: 8‐OH‐DPAT and flesinoxan may act predominantly as 5‐HT1Areceptor agonists, where as 5‐methyl‐urapidil and MDL 75,608A also seem to have an effect on peripheral α1‐adrenoceptors.
Indapamide inhibits endothelium‐dependent contractions in the aorta of the spontaneously hypertensive rat
Authors: Boulanger CM , Mombouli JV , Vanhoutte PM
Published: August 2009

Summary—Experiments were designed to determine whether or not indapamide, an antihypertensive agent with vasodilator properties, inhibits endothelium‐dependent contractions. Rings of aortae with and without endothelium from spontaneously hypertensive rats (SHR) were suspended in conventional organ chambers for the measurement of isometric force. Acetylcholine and adenosine diphosphate‐β‐S in the presence of a nitric oxide synthase inhibitor, caused endothelium‐dependent contractions, which were inhibited by indapamide. The compound (10−4M) also slightly reduced the contractions of rings without endothelium evoked by U‐46,619, which activates thromboxane‐endoperoxide receptors. These results demonstrate that indapamide inhibits endothelium‐dependent contractions in the SHR aorta, and suggest that the inhibition is due, at least in part, to the action of the drug on the hypertensive vascular smooth muscle.
The nicardipine‐isoprenaline interaction in human and guinea‐pig isolated airways
Authors: Sarriá B. , Zhang Y. , Naline E. , Brisac AM , Laurent S. , Cortijo J. , Advenier C.
Published: August 2009

Summary— The effects of the dihydropyridine calcium antagonist nicardipine on the concentration‐response curves of relaxant compounds acting through the adenylate‐cyclase/cAMP system (isoprenaline, forskolin, adenosine and theophylline) or by the cGMP pathway (sodium nitroprusside) were studied on human isolated bronchus and guinea‐pig isolated trachea. These effects were compared with those of nifedipine (a dihydropyridine derivative) and theophylline (a non‐selective phosphodiesterase inhibitor). Nicardipine, in the range of 0.01 to 1 μM, significantly potentiated the relaxant effects of isoprenaline, forskolin, adenosine and theophylline, whereas the effects of sodium nitroprusside were significantly potentiated at 10 μM only. These results suggest that nicardipine behaves as an inhibitor of phosphodiesterases III and IV. One such effect may be involved in the potentiation of the isoprenaline relaxation of human and guinea‐pig isolated airways.
Characterization of endothelium‐derived relaxing factor involvement in the potentiating effect of parathyroidectomy on norepinephrine‐induced rat aortic contraction
Authors: Boulebda N. , Gairard A.
Published: August 2009

Summary—Previous results have shown that the contractile response to norepinephrine (NE) was enhanced in isolated aortae from SHR and normotensive Wistar parathyroidectomized rats. In this work we sought to characterize the contribution of endothelium‐derived relaxing factor (EDRF) release to this effect which is not linked to hypertension. Parathyroidectomy (PTX) was performed by surgery on 5 week‐old male Wistar rats. Five weeks later intact (E+) and rubbed (E–) aortic rings were mounted in an organ chamber for isometric tension recording. KCl‐induced contractions were potentiated in PTX E+ aortae compared to sham operated (SO), (P< 0.05), but not in denuded E‐ aortae. Similarly NE (1.nM‐ 10 μM) induced a potentiated contractile response in PTX E+ (P< 0.01), but not in PTX E‐ rings; nevertheless the sensitivity did not change. After removal of endothelium, the expected enhanced contraction and sensitivity observed in SO rats was not present in PTX. The NO synthase inhibitor L‐NAME (20 μM), enhanced sensitivity to NE in SO but not in PTX E+ aortic rings. In addition, hemoglobin (Hb, 10 μM) enhanced NE contraction in SO (P< 0.01) aortic rings, but to a lesser extent in PTX rat aortae. Moreover, in the presence of L‐NAME or Hb, SO and PTX aortae displayed a similar contraction. Superoxide dismutase (SOD, 150 U/ml) diminished the NE contraction since NO was protected from degradation but the difference was still present between SO and PTX rat aortae, ruling out the possible implication of superoxide anions in the hyperreactivity of PTX aortae. On the other hand, A23187, which induces EDRF release, reduced the level of NE contraction as expected, but suppressed the PTX enhancing effect and in calcium‐free solution the enhancement of contraction after PTX was not observed. These experiments extend to the rat the observations previously obtained in rabbit aorta: extracellular calcium is a major determining factor in NO production. Acetylcholine and A23187 (cumulative doses) produced an endothelium‐dependent relaxation which was not significantly modified in NE‐pre‐contracted PTX aortae compared to SO aortae. L‐arginine (100 μM), reversed the L‐NAME inhibitory effect and induced an attenuated endothelium‐dependent relaxation in PTX vessels (P< 0.01). In conclusion, in rat isolated aortae the enhancing effect of parathyroidectomy on norepinephrine and KCl contractions is due to a diminished endothelial nitric oxide production. This might ariseviaa decrease of the constitutive NO synthase activity in an extracellular calcium‐dependent manner.
Purinergic receptors on insulin‐secreting cells
Authors: Hillaire‐Buys D. , Chapal J. , Bertrand G. , Petit P. , Loubatières‐Mariani MM
Published: August 2009

Summary—The insulin secreting B cell is fitted with the two types of purinergic receptors: P2(for ATP and/or ADP) and P1(for adenosine). The activation of P2purinoceptors by ATP or ADP evokes a biphasic stimulation of insulin secretion from isolated perfused rat pancreas; this stimulation is dose‐dependent between 10−6and 10−4M. Non hydrolysable structural analogues are also effective, and the relative potency of various agonists (2‐methylthio ATP ≫ ATP = ADP = α, β‐methylene ATP ≫ AMP) gave evidence for a P2ypurinoceptor subtype. Proposed mechanisms include both an increased Ca2+uptake and an increased intracellular Ca2+mobilizationviathe hydrolysis of polyphosphoinositides. ATP (or ADP) potentiates physiological insulin‐secreting agents (glucose and acetylcholine) and P2purinoceptors could play a physiological role in the stimulation of insulin secretion. The activation of P1purinoceptors (adenosine receptors) decreases insulin secretion. Using structural analogues of adenosine, the receptor was characterized as an A1subtype; it is coupled to a pertussis toxin sensitive G protein and it inhibits adenylate cyclase. It is of physiological relevance that the B cell has the two types of purinoceptors with opposite effects. Recently, a metabolically stable structural analogue of ADP, adenosine‐5′‐0‐(2‐thiodiphosphate) or ADPßS, has been described as a potent secretory agent, effective at nanomolar concentrations on isolated perfused rat pancreas.In vivo, this substance is able to increase insulin secretion and to improve glucose tolerance after IV administration in rats and oral administration in dogs. Furthermore in streptozotocin‐induced diabetes, ADPßS retains its insulin secreting effects. These results suggest that P2ypurinoceptors could be a new target for antidiabetic drugs.
Modulation of neurotransmitter releaseviahistamine H3heteroreceptors
Authors: Schlicker E. , Malinowska B. , Kathmann M. , Göthert M.
Published: August 2009

Summary—Presynaptic H3receptors occur on histaminergic neurones of the CNS (autoreceptors) and on non‐histaminergic neurones of the central and autonomic nervous system (heteroreceptors). H3heteroreceptors, most probably located on the postganglionic sympathetic nerve fibres innervating the resistance vessels and the heart, have been identified in the model of the pithed rat. Furthermore, we could show in superfusion experiments that H3heteroreceptors also occur on the sympathetic neurones supplying the human saphenous vein and the vasculature of the pig retina and on the serotoninergic, dopaminergic and noradrenergic neurones in the brain of various mammalian species, including man. The effects of three recently described H3receptor ligands were studied in superfused mouse brain cortex slices. The potency of the novel H3receptor agonist imetit exceeded that of R‐(‐)‐α‐methylhistamine (the reference H3receptor agonist) by one log unit and that of histamine by almost two log units. Clobenpropit was shown to be a competitive H3receptor antagonist, exhibiting a pA2as high as 9.6 (exceeding the pA2of the reference H3receptor antagonist thioperamide by one log unit). The irreversible antagonism of N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ) was also studied. Interactions of the H3heteroreceptor with the dopamine autoreceptor in mouse striatal slices and the α2‐autoreceptor in mouse brain cortex slices could be demonstrated. Activation of α2‐autoreceptors decreases the H3receptor‐mediated effect. Blockade of α2‐autoreceptors increases the H3receptor‐mediated effect only if the α2‐autoreceptors are simultaneously activated by endogenous noradrenaline. The H3receptor‐mediated inhibition of noradrenaline release in mouse brain cortex slices was attenuated by the K+ channel blocker tetraethylammonium but this attenuation was abolished by reduction of the Ca2+concentration in the medium (to compensate for the facilitatory effect of tetraethylammonium on noradrenaline release). Accordingly, we assume that the H3receptors are not coupled to voltage‐sensitive K+ channels. Pertussis toxin and N‐ethylmaleimide attenuated the H3receptor‐mediated effect in the mouse brain cortex, suggesting that the H3receptors are coupled to a G protein (egGior Go). However, negative coupling to an adenylate cyclase does not appear to exist since an H3receptor‐mediated inhibition of cAMP accumulation was not obtained in mouse brain cortex membranes. H3receptor ligands are currently undergoing clinical testing and might become new remedies for the treatment of diseases of the gastrointestinal and bronchial system and the CNS.
Central nervous system control of intraocular pressure
Authors: Denis P. , Nordmann JP , Elena PP , Saraux H. , Lapalus P.
Published: August 2009

Summary— Normal intraocular pressure (IOP) is the result of an equilibrium between aqueous humor (AH) production, AH outflow and episcleral venous pressure. Most available antiglaucoma agents produce their effects by interacting with autonomic mechanisms (beta‐blockers, epinephrin or parasympathomimetics). In contrast, the role of the central nervous system (brain and nerves) in the regulation of IOP remains unclear in view of the complex haemodynamic, metabolic or hormonal changes which occur under experimental conditions. In this paper, we discuss a basic understanding of the anatomic and physiological relationships between central nervous system and IOP and describe how the brain can affect functions in ciliary body and trabeculum meshwork.
Short‐term effects of quinapril and nifedipine on early renal changes in streptozotocin‐induced diabetes in rats
Authors: Petitjean P. , Vloemans M. , Barthelmebs M. , Stephan D. , Grima M. , Jund A. , Imbs JL
Published: August 2009

Summary—The effects on renal function of quinapril, an angiotensin I converting enzyme (ACE) inhibitor, and of nifedipine, a dihy‐dropyridine calcium antagonist, were studied in the early stages of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) to induce diabetes; the hyperglycaemia was then controlled with daily insulin therapy (2–3 units NPH insulin/rat). One week after STZ injection, rats were treated orally with quinapril (0.3 or 3 mg/kg/d) or nifedipine (30 mg/kg/day) for 1 week, after which renal functions were compared with those of untreated diabetic rats or non‐diabetic control rats. At the end of these two weeks, diabetic rats had gained less weight and had developed renal hypertrophy and glomerular hyperfiltration (3.21 ± 0.23vs2.36 ± 0.09 ml/min for non‐diabetic rats, mean ± SEM,P< 0.01). Their urinary albumin excretion was higher, as was the urinary excretion of water, sodium, potassium, urea and glucose. One week treatment with quinapril or nifedipine had no significant effect on the increase in the glomerular filtration rate (respectively 2.97 ± 0.18 and 2.99 ± 0.15 ml/min). Quinapril and nifedipine differed with regard to their effects on urinary albumin excretion. Albuminuria was increased by nifedipine but not by quinapril (respectively 0.554 ± 0.158 and 0.149 ± 0.046 mg/day/100 g BW,P< 0.05). This difference between the effects of the dihydropyridine and the ACE inhibitor on albuminuria may be linked to different effects on the glomerular functions.
Comparative pharmacokinetics of two diastereoisomers dexamethasone and betamethasone in plasma and cerebrospinal fluid in rabbits
Authors: Trenque T. , Lamiable D. , Vistelle R. , Millart H. , Leperre A. , Choisy H.
Published: August 2009

Summary—The two diastereoisomers dexamethasone (DXM) and betamethasone (BTM) were infused at two different doses (2, 10 mg·kg−1) in anesthetized rabbits. Samples of plasma and cerebrospinal fluid were collected over a 180‐min period. Steroid concentrations were measured by high performance liquid chromatography. The terminal half life (85.7 ± 20.8 min and 102.2 ± 29.6 min for DXM; 117.6 ± 19.8 min and 118.5 ± 15.8 min for BTM) and the mean residence time (121.4 ± 27.7 min and 146.1 ± 41.3 min for DXM; 168.6 ± 28.1 min and 172.2 ± 20.6 min for BTM) were unchanged between the doses. Dose‐dependent changes in the area under the curve normalized by the dose, then volume distribution and clearance were observed. The average percentage of DXM and BTM bound to plasma proteins were 78.1 ± 11.5% and 88.3 ± 5.1% respectively at the lower dose, and decreased significantly with 10 mg·kg−1. DXM appeared more rapidly in the CSF, the highest concentrations of DXM were obtained within 15 min after the end of the injection. The CSF levels were lower than that of plasma unbound and the passage through the blood‐brain barrier was saturable. These results will complicate pharmacokinetic and pharmacodynamic analysis.
Mice plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after half‐life repeated administration. Comparison with acute administration
Authors: Coudoré F. , Fialip J. , Eschalier A. , Lavarenne J.
Published: August 2009

Summary—Kinetics of amitriptyline (AMI), its demethylated metabolites nortriptyline (NOR) and demethylnortriptyline (DM‐NOR), and its hydroxylated metabolites, the E and Z isomers or 10‐hydroxy‐amitriptyline (E‐ and Z‐10‐OH‐AMI) and of 10‐hydroxynortriptyline (E‐ and Z‐10‐OH‐NOR) were studied in plasma and brain from Swiss CD1 mice after six successive intraperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half‐life time (t1/2= 3.1 h) to obtain the steady state. In these conditions, AMI was metabolised rapidly. Compared with acute administration, hydroxylation reactions were saturated by the repeated AMI injections and demethylation became preponderant both in plasma and brain. Thus, plasma levels of demethylated metabolites, NOR and DM‐NOR, increased (49% and 13% of total AUC against 22% and 7% in acute conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10‐OH‐AMI and 10‐OH‐NOR, decreased (8%, 2.5% and 27.5% against 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM‐NOR increased (62% and 22% against 29% and 11%, respectively) while AMI and 10‐OH‐AMI decreased (11.5% and 1% against 47% and 9%, respectively). These differences may account for modified pharmacological effects seen after half‐life repeated administration of AMI since demethylated metabolites exert a more marked inhibiting effect than AMI on noradrenaline reuptake.
Intracoronary infusion of bradykinin: effects on noradrenaline overflow following reperfusion of ischemic myocardium in the anesthetized dog
Authors: Ribuot C. , Yamaguchi N. , Godin D. , Jetté L. , Adam A. , Nadeau R.
Published: August 2009

Summary—Objective: The aim of this study was to investigate the effects of intracoronary bradykinin (BK) infusion on noradrenaline release and ventricular arrhythmias induced by coronary occlusion and reperfusion in the anesthetized dog. Methods: 14 anesthetized adult mongrel dogs of either sex underwent a 60 min occlusion of the left anterior descending coronary artery (LAD) followed by a 30‐min reperfusion period. BK (1 ng.kg−1·min−1,n= 7), or its vehicle (Lactate Ringer,n =7), infusions just distal to the left coronary ostium started 15 min before the LAD occlusion and were maintained throughout the experimental period. An epicardial vein, running parallel to the LAD was cannulated to enable the biochemical determinations. The effects of BK on ventricular arrhythmias, cardiac noradrenaline and lactate releases and creatine kinase activity were assessed. Results: BK significantly reduced the amount of noradrenaline released at reperfusion by ischemic myocardium (from 82.1 ± 31.7 to 11.9 ± 9.6 ng·min−1), as well as plasma creatine kinase activity at 30 min of reperfusion. This is accompanied by a significant reduction in the incidence of reperfusion‐induced sustained ventricular tachycardia. Conclusion: This suggests that the protective effect of bradykinin against reperfusion‐induced sustained ventricular tachycardia could be associated with a reduction in cardiac noradrenaline release.
Influence of 5‐HT3 receptor antagonists in visceromotor and nociceptive responses to rectal distension before and during experimental colitis in rats*
Authors: Morteau O. , Julia V. , Eeckhout C. , Bueno L.
Published: August 2009

Summary— We investigated the possible involvement of 5‐HT3 receptors in the colonic motor alterations and abdominal pain evoked by rectal distension (RD) in rats, under normal and inflammatory conditions. Responses to RD were evaluated by electromyography in rats treated with 5‐HT3 antagonists (ondansetron and cilansetron, 0.1 and 1 mg/kg, intraperitoneally), before and 3 days after intrarectal administration of TNB/ethanol. RD evoked a significant (P < 0.05) and gradual inhibition of the occurrence of colonic spike bursts (SB) and a gradual increase in abdominal SB from 11 mm in diameter on wards. Ondansetron and cilansetron (0.1 mg/kg) significantly reduced both the colonic (62 and 66%, respectively) and the abdominal response (28 and 61%, respectively) for an 11 mm diameter of RD. After TNB/ethanol, both colonic and abdominal responses to RD were significantly (P < 0.05) enhanced and appeared for a lower diameter (9 mm) (colon: 4.8 ± 0.9 vs 8.4 ± 1.1, abdomen: 7.7 ± 1.5 vs 0.5 ± 0.4). Cilansetron (0.1, 1 mg/kg) significantly (P < 0.05) attenuated the TNB‐induced colonic motor inhibition, while ondansetron and cilansetron (0.1, 1 mg/kg) reduced the TNB‐induced increase in abdominal response. We conclude that 5‐HT and 5‐HT3 receptors mediate RD‐induced viscerosensitive alterations in rats, both in normal conditions and during TNB‐induced rectocolitis. However, the relative efficacy of the 5‐HT3 receptor antagonists depends on the experimental conditions (intact or inflamed bowel) and does not appear to increase with the dose.
Effects of SR 49059, a non‐peptide antagonist of vasopressin V1areceptors, on vasopressin‐induced coronary vasoconstriction in conscious rabbits
Authors: Gal C Serradeil‐Le , Villanova G. , Boutin M. , Maffrand JP , Fur G Le
Published: August 2009

Summary—The effect of SR 49059, a new potent non‐peptide vasopressin (AVP) V1areceptor antagonist, was investigated on AVP‐induced electrocardiogram modifications. A high intravenous dose of AVP (0.5 IU or 1.23 μg/animal) produced an important transientt‐wave elevation (from 4.7 ± 0.2 to 8.9 ± 0.7 mm) and heart rate decrease (from 199 ± 5 to 99 ± 6 bpm) in conscious rabbits. Thet‐wave increase was a significant index of coronary vasoconstriction‐induced cardiac ischemia. SR 49059 had potent protective effects in this model both by intravenous (0.125 to 0.5 mg/kg) and oral (2.5 to 10 mg/kg) routes. After a 30‐min pre‐treatment, SR 49059 showed dose‐dependent protection ont‐wave elevation and heart rate decrease with ED50's of 95 (95% CL: 168‐22) and 30 (95% CL:54‐6) μg/kg iv, respectively. Complete blockade occurred with doses of 2 mg/kg iv and upwards. By the oral route, SR 49059 was rapidly absorbed and a dose of 10 mg/kg displayed a protective effect lasting more than 6 hours on both electrocardiogram parameters. Moreover, SR 49059 exerted a high stereospecific inhibitory effect since its enantiomer was totally inactive at 0.5 mg/kg iv, suggesting that protection occurred by interaction with vascular AVP V1areceptors. Thus, SR 49059 is the first specific non‐peptide V1aantagonist with long‐lasting oral activity on AVP‐induced coronary vasoconstriction and bradycardia. With this original profile, SR 49059 could be a promising therapeutical antivasospastic agent for preventing AVP‐ induced cardiac damage.
Influence of the vascular endothelium on angiotensin II‐induced contractions in rabbit renal artery
Authors: Zhang J. , Pfaffendorf M. , Zhang JS , van Zwieten PA
Published: August 2009

Summary—The influence of vascular endothelium on angiotensin II‐induced contraction and the underlying mechanisms in the rabbit renal artery were investigated. In endothelium‐intact preparations, angiotensin II (3–100 nM) caused a concentration‐dependent increase in tension by maximally (Emax) 0.74 ± 0.05 g. Removal of the endothelium significantly enhanced the angiotensin II‐induced contractions (Emax: 3.91 ± 0.19 g). Indomethacin (10 μM) did not influence the angiotensin II‐induced contractions. Methylene blue (10 μM) and NG‐methyl‐1‐arginine (L‐NMMA, 5 μM) significantly enhanced angiotensin II‐induced contractions by 418 ± 29% and 200 ± 14%, respectively, in endothelium intact preparations, but not in those devoid of endothelium. L‐arginine (1 mM), but not D‐arginine, reversed the L‐NMMA‐induced enhancement of the angiotensin II‐induced contraction. The present results suggest that angiotensin II‐induced contractions in rabbit renal artery are largely subject to the influence of the endothelium. The endothelium‐derived relaxant factor (EDRF), rather than cyclo‐oxygenase products, appears to be involved in mediating the inhibitory effects of the endothelium. Nitric oxide (NO) derived from endothelium may play a major role in inhibiting angiotensin II‐induced contractions in this preparation.
Beta3‐adrenoceptors and airways*
Authors: Martin CAE , Advenier C.
Published: August 2009

Summary—β3‐adrenoceptors have been identified in a variety of tissues from humans and animals: adipose tissue, gastrointestinal smooth muscle, rat skeletal muscle, bovine skeletal muscle, and human and canine heart. In the airways, the investigation of the β3‐adrenoceptors came from studies with a series of novel selective agonists. Stimulation of the “atypical” β‐adrenoceptor increases the active transport of albumin across the ferret tracheal epithelium and the ciliary beat frequency of canine bronchial epithelium. Furthermore, it has been demonstrated that β3‐adrenoceptors agonists selectively inhibited nonadrenergic noncholinergic contractions of guinea‐pig bronchi induced by electrical field stimulation or capsaicin. The presence of functional β3‐adrenoceptors in the bronchial smooth muscle is disputed and seems to be species‐related. In isolated canine bronchi, selective agonists induced a relaxation whereas they had no or slight effect in isolated human, guinea‐pig and sheep bronchi. Likewise in man, a fall in airway resistance measured by plethysmography, was mediated by β2‐adrenoceptors, but not β3‐adrenoceptors. To conclude, an “atypical” or β3‐adrenoceptor‐mediated modulation of bronchomotricity exists, nevertheless strong species specific differences have been reported.