bluuebunny/crossref_metadata_2025 huggingface dataset:
Propranolol therapy in experimental heart failure in rabbits improves cardiac response to catecholamines without beta‐adrenoceptor up‐regulation
Authors: Xiong L. , Bouanani NEH , Su JB , Crozatier B.
Published: August 2009

Summary— Beta‐blockade has been shown to improve cardiac response to catecholamines in heart failure but cellular mechanisms of the improvement are unknown. The effect on left ventricular function of a 14 day propranolol treatment was studied in seven treated and eight non‐treated rabbits with experimental heart failure. All animals were subjected to a volume (aortic insufficiency) plus pressure (aortic constriction) overload and were instrumented with a left ventricular catheter and ultrasonic crystals measuring anteroposterior left ventricular diameter. Beta‐adrenoceptors were measured using 125I‐Cyanopindolol in crude membranes. With isoproterenol, the heart rate was slower in treated rabbits than in non‐treated rabbits (p < 0.005) and isoproterenol increased more systolic diameter shortening in treated than in non‐treated rabbits (p < 0.05). With norepinephrine, for matched pressures, % ΔD increased in the treated group but it did not change in the non‐treated group. This improvement of ventricular function was due, in a large part, to an increased diastolic response to norepinephrine: end‐diastolic diameter increased in the treated group but not in the non‐treated group. In contrast with the improved ventricular response to catecholamines, beta‐adrenergic receptor density in the treated group was identical to that of the non‐treated group (27.8 fmoles/mg/proteins) and was significantly lower than that of normal rabbits (58.2 fmoles/mg, p < 0.01). The improvement of ventricular response to catecholamines appears to be due to a myocardial protection by propranolol against the toxic effect of catecholamines in heart failure and not, at least in this model, to an up‐regulation of beta‐adrenoceptors.
The effect of cyclosporine A and trifluoperazine on amylase secretion from rat parotid glands in vitro
Authors: Samini M. , Dehpour AR , Ghafourifar P. , Hassanzadeh P.
Published: August 2009

Summary— In the present study the effects of trifluoperazine (TFP) and/or cyclosporine A (CsA) on the amylase secretion of rat parotid gland lobules were investigated. Cyclosporine A, in doses of 10−6, 3 × 10−6 and 10−5 M, caused a dose‐dependent reduction in amylase secretion. Trifluoperazine, a well‐established calmodulin antagonist, also significantly reduced amylase secretion by the gland, confirming that the secretion is calmodulin dependent. Concurrent administration of CsA and TFP showed a marked positive interaction in reducing the secretion of amylase. Thus, the hypothesis that CsA may have Ca2+/calmodulin antagonistic properties is supported by the present study.
Comparison between acute hypoxia‐induced and mechanically‐induced pulmonary artery hypertension on the hemodynamics, myocardial contractility and regional blood flow in dogs
Authors: Girard C. , Fargnoli JM , Fourie P. , Maitrasse B. , Arvieux CC
Published: August 2009

Summary— Two groups of eight anesthetized dogs with pulmonary artery hypertension (PAH) were compared. PAH was induced by submitting one group (HP) to hypoxia (FiO2 range: 6–10%) and the other group (ME) to microemboli through glass microbead injection into the pulmonary circulation. Hypoxia‐induced PAH was moderate (PAP: +65%; PVR: + 152%) contrasting with marked PAH after microbead injection (PAP: +190%; PVR: +389%). For similar effects on left ventricular contractility (LV dP/dt max and segmental myocardial shortening), heart rate and systemic vascular resistance, left ventricular end‐diastolic pressure showed significant differences between the two groups (HP group: +75%, ME group: −9%), and so did left ventricular end‐diastolic length (HP: +9%, ME: −11%). Thus, contrary to the injection of microbeads, hypoxia did not give rise to any pulmonary barrier, and consequently the changes in cardiac output (HP: +19%, ME: −15%) and hepatic blood flow (HP: +383%, ME: −77%) were significantly different. Hypoxia, and not microbead injection, was responsible for systemic hypertension (MAP: +34% and −4%, respectively). The microbead model resulted in a significantly higher PVR/SVR ratio compared to the hypoxic model (HP: 0.14, ME: 0.41). Hypoxia increased left and right myocardial blood flows whereas microbead injection affected only right ventricular blood flow, leading to significantly different RV/LV endocardial perfusion ratios (HP: +10%, ME: +98%). We conclude that microbead‐induced PAH is more appropriate than hypoxia‐induced PAH for hemodynamic and pharmacological studies.
Pharmacokinetics of mefloquine, when given alone and in combination with artemether, in patients with uncomplicated falciparum malaria
Authors: Na‐Bangchang K. , Karbwang J. , Molunto P. , Banmairuroi V. , Thanavibul A.
Published: August 2009

Summary— The pharmacokinetics of mefloquine at a single oral dose of 750 mg, when given alone or 24 hours after a single oral dose of artemether. (300 mg) was investigated in 27 Thai patients with acute uncomplicated falciparum malaria (17 with mefloquine alone, 10 with the combination). The oral bioavailability of mefloquine was significantly decreased when administered 24 hours after an oral dose of artemether. This was evident by the significantly lower values of Cmax, AUC[0–24 h], AUC[0–48 h], AUC[0–72 h], as well as total AUC[Cmax: 1,290 (827‐2,619) vs 1,820 (1,283‐2,531) ngṁml−1; AUC[0–24 h]: 0.99 (0.64‐1.41) vs 1.33 (1.07–1.95) μgṁdayṁml−1; AUC[0–48 h]: 1.78(1.23‐2.58) vs 2.67 (2.09‐3.84) μgṁdayṁml−1; AUC[0–72 h]: 2.74 (1.63‐3.6) vs 4.54 (2.88‐5.38) μgṁdayṁml−1; AUC: 11.11 (6–20.96) vs 15.29 (9.3–36.71) μgṁdayṁml−1]. Tmax was also delayed with the combination regimen [14 (5–24) vs 6 (4–16) h). Terminal elimination half‐lives were comparable [t1/2z: 11.1 (6.8–14.3) vs 13.4 (10.5–19.1) h].
Evaluation of different doses of formoterol from a newly developed powder inhalation device in asthmatic patients
Authors: Van den Berg BTJ , Smeets JJ , Van Boxtel CJ , Maesen FPV
Published: August 2009

Summary— Administration of different doses of formoterol from a recently developed multiple dose dry powder device was tested in a placebo‐controlled, single‐centre, double‐blind, within‐patient trial. Eighteen patients of both sexes, aged 18–65 years, with a FEV1 of 50–80% and a reversibility of at least 15% were randomized. During four treatment periods of 8 days each, divided by aproximately 6 days, patients received placebo or 6, 12 or 24 μg (PL, F6, F12 and F24, respectively) of formoterol from the powder device. Efficacy parameters (FEV1) and safety parameters (primarily pulse rate, electrocardiogram [ECG] and subjective experiences) were evaluated during 24 hours on the last day of each treatment period. Peak flow and the number of puffs of used rescue medication (100 μg of salbutamol) were registered during treatment periods. For efficacy analysis, 17 patients remained. For FEV1 0.5 hour before the last dose and 12 and 24 hours after the last dose all formoterol doses were statistically significant superior to placebo. Clinically relevant differences from placebo were found up to 8 hours (F6) and 12 hours (F12 and F24). The difference between doses was clinically relevant for the area under the FEV1 curve between F6 and F24. PEF on the treatment days corresponded to these findings. In three cases of 13 reported adverse effects, the relation to trial medication was probable (tremor) or possible (insomnia and hyperaesthesia). All other safety measurements showed no significant differences. We conclude that formoterol dry powder in the newly developed multiple dose inhalation device is an effective and safe β2‐stimulant with a long duration of action in doses of 6, 12 and 24 μg. The 24 μg dose is superior to the 6 μg dose. Efficacy decreased considerably between the 12th and 24th hour after dosing.
Distinct isoforms (COX‐1 and COX‐2) of cyclooxygenase: possible physiological and therapeutic implications
Authors: Pairet M. , Engelhardt G.
Published: August 2009

Summary—The discovery of an inducible isoform of cyclooxygenase (COX‐2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic and side effects of non‐steroidal anti‐inflammatory drugs (NSAIDs). Indeed, new pharmacological results suggest that COX‐2 inhibition provides the therapeutic (ie, anti‐inflammatory) activity of NSAIDs, whereas inhibition of constitutive COX‐1 is responsible for their gastric and renal side effects as well as for their antithrombotic activity. However, a role of COX‐1 in inflammation cannot be excluded. Furthermore, the functional relevance of COX‐2 expression and induction in various tissues warrants further investigation. These studies should help in predicting potential adverse effects as well as new indications for selective COX‐2 inhibitors.
Role of 5‐HT1Aautoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies
Authors: Gardier AM , Malagié I. , Trillat AC , Jacquot C. , Artigas F.
Published: August 2009

Summary—Although a new generation of selective serotonin reuptake inhibitors (SSRIs) has been introduced in therapeutics as antidepressant drugs, a two to four week lag period still occurs between starting treatment with SSRIs and the onset of therapeutic effects in man. In vivo cerebral microdialysis can be used to measure extracellular concentrations of serotonin (5‐hydroxytryptamine, 5‐HT), which reflect intrasynaptic events. With the coupling of this new experimental method to very sensitive analytical assays such as liquid chromatography with electrochemical detection, it has recently been possible to obtain two major arguments supporting the hypothesis that somatodendritic 5‐HT1Aautoreceptors situated in the raphe nuclei play an important role in the mechanism of action of SSRIs. First, in the rat, single administration of SSRIs at low doses comparable to those used therapeutically increases extracellular 5‐HT concentrations in the vicinity of the cell body and the dendrites of serotoninergic neurones of the raphe nuclei. This effect is more marked than that observed in regions rich in nerve endings (frontal cortex). The magnitude of the activation of the serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous activation of somatodendritic 5‐HT1Aautoreceptors by endogenous 5‐HT in the raphe nuclei, thereby limiting the corticofrontal effects of the antidepressant. Second, SSRIs cause a larger increase in extracellular 5‐HT concentrations in the nerve endings when administered chronically: 5‐HT autoreceptors may have gradually desensitized during the 2–4 weeks of treatment with SSRIs. Preliminary studies of patients with depression appear to confirm these experimental results, as co‐administration of a 5‐HT1Aautoreceptor antagonist and a SSRI accelerated the onset of the antidepressant effect (< 1 week).
Recent status of the antisense oligonucleotide approaches in oncology
Authors: Ma L. , Calvo F.
Published: August 2009

Summary— Antisense oligonucleotides designed to complement a region of a particuler messenger RNA may inhibit gene expression potentially through sequence‐specific hybridization. Their inhibiting effect has been shown in a variety of in vitro and in vivo models in oncology, whereas much rarer clinical trials have been carried out. Rigorous demonstration of in vitro and in vivo specific effects upon their targets is mandatory before their use as drugs in cancer therapy.
Systemic, pulmonary, brachial, renal and hepato‐splanchnic hemodynamic effects of spirapril in severe congestive heart failure
Authors: Bellissant E. , Annane D. , Pussard E. , Thuillez C. , Giudicelli JF
Published: August 2009

Summary—The effects of a single oral dose (6 mg) of the angiotensin‐I converting enzyme inhibitor, spirapril, on systemic, pulmonary and regional (brachial, renal, hepato‐splanchnic) hemodynamics as well as on biological parameters investigating the renin‐angiotensin‐aldosterone and sympathetic nervous systems were studied over a 24‐hour period in eight patients with severe congestive heart failure (CHF). As compared to pretreatment values, spirapril significantly decreased mean arterial (‐19%, peak effect), right atrial (‐42%), mean pulmonary arterial (‐38%) and pulmonary capillary wedge (‐46%) pressures. Spirapril significantly decreased heart rate (‐14%) and increased stroke volume index (+43%) thus resulting in a slight increase in cardiac index. All these effects were maximal between 2.5 and 4 h. Brachial artery diameter (+12%) and brachial (+41%) and renal (+36%) blood flows increased significantly whereas brachial (‐41%) and renal (‐36%) vascular resistances decreased significantly. All these effects were usually maximal between 1 and 2.5 h. Hepato‐splanchnic hemodynamics were not drug‐affected. Spirapril significantly inhibited plasma converting enzyme activity (‐96% at 4 h), increased plasma renin activity (+505% at 4 h), and decreased plasma aldosterone (‐46% at 24 h), norepinephrine (‐31% at 24 h) and atrial natriuretic factor (‐33% at 7 h). Thus, in severe CHF, acute administration of spirapril, 6 mg orally, exerts both arterial and venous vasodilating properties and improves both the systemic and regional hemodynamics and the biological status of the patients.
Permutation distribution estimation applied to the comparison of the profile of the activity of two antianginal drugs
Authors: Harpey C. , Coker S. , Sellier P. , Maccario J. , Détry JM
Published: August 2009

Summary— The comparison of the anti‐ischemic activity of trimetazidinc and propranolol was evaluated by multiple end points (clinical, exercise test, and ambulatory electrocardiogram [ECG] monitoring criteria) in 149 male patients with effort angina who received either trimetazidine 20 mg tid or propranolol 40 mg tid during a period of 3 months. The distribution of the standardized differences between the two treatments for each variable was obtained by a permutation method. The medians (estimation of the actual difference between the two treatments) and the 5, 25, 75 and 95% quantiles were represented on the same diagram for all end points. The pattern of the standardized distribution of the differences showed a similar activity of both drugs on symptoms and nitrates consumption, on exercise tolerance and increase in ischemic threshold at exercise, and on ischemia recorded at ambulatory ECG monitoring. Conversely, only propranolol decreased heart rate and rate pressure product at rest as well as at exercise, underlining the difference in the mode of action of the two drugs. This descriptive technique is an attractive method to evaluate the differences between drugs considering multiple criteria favouring the estimation of these differences together with their variability.
Electrophysiology of ion channels of the heart
Authors: Ravens U. , Wettwer E. , Ohler A. , Amos GJ , Mewes T.
Published: August 2009

Summary— The contribution of Na+, Ca2+, and various K+ currents to the shape of the cardiac action potential is outlined based on the relation between electrophysiological properties and structure of channel molecules. These currents have also been found in human ventricular myocytes, where the most prominent K+ current is a transient outward current that is not influenced by methylsulfonanilide antiarrhythmic drugs. Combined knowledge of electrophysiological and molecular properties of ion channels is likely to form the basis for rational design of future drugs.
Pharmacodynamic behaviour of isolated resistance vessels obtained from hypertensive‐diabetic rats
Authors: Kam KL , Pfaffendorf M. , van Zwieten PA
Published: August 2009

Summary— The influence of various vasodilator and constrictor drugs was studied in isolated mesenteric arteries obtained from obese and lean Zucker rats. The obese Zucker rats were moderately hypertensive and their isolated small arteries were not hypertrophied. All vasoconstrictor agents studied (noradrenaline, methoxamine, serotonin, calcium chloride, potassium chloride) caused the same effects in isolated arteries taken from obese and lean (control) Zucker rats, respectively. In vessels from obese Zucker rats, the vasodilator responses to sodium nitroprusside, methacholine, the K+‐channel opener cromakalim and nifedipine were the same as in control preparations. In conclusion, isolated mesenteric arteries from obese Zucker rats do not show relevant structural changes, and the pharmacodynamic behaviour of such vessels appears to be the same as that of control preparations. Neither the diabetic hyperinsulinaemic state nor the hyperlipoproteinaemia in the obese Zucker rats appear to cause serious vascular damage.
NMDA antagonist blockade of AT8 tau immunoreactive changes in neuronal cultures
Authors: Couratier P. , Lesort M. , Terro F. , Dussartre C. , Hugon J.
Published: August 2009

Summary—Antagonists at four distinct regulatory sites on the N‐methyl‐D‐aspartate (NMDA) receptor were tested for their ability to attenuate NMDA‐mediated chronic excitotoxicity and the consequences on AT8 tau immunoreactivity in neuronal cultures. Excitotoxicity was monitored in cultures by diacetate fluorescein staining. Immunoreactivity of tau phosphorylated at serine 202 was quantified by laser confocal microscopy. The NMDA‐receptor antagonists MK801, AP7 and 7‐chlorokynurenate significantly blocked NMDA‐induced cell death and significantly reduced AT8 tau immunoreactivity. NMDA antagonism by the polyamine site antagonist, ifenprodil, did not completely reverse the increase in AT8 tau immunolabeling induced by NMDA and did not completely protect NMDA‐sensitive neurons, suggesting an heterogeneity in the NMDA receptor population.
Rilmenidine activates postjunctional alpha1‐ and alpha2‐adrenoceptors in the canine saphenous vein
Authors: Marsault R. , Taddei S. , Boulanger CM , Illiano S. , Vanhoutte PM
Published: August 2009

Summary—Experiments were performed to determine the subtypes of alpha‐adrenoceptors involved in the contraction induced by rilmenidine in isolated canine cutaneous veins. Rings of saphenous vein (without endothelium) were suspended for the recording of isometric force in physiological salt solution. All experiments were performed in the presence of propranolol (to antagonize betaadrenoceptors), cocaine (to inhibit neuronal uptake) and hydrocortisone (to inhibit extraneuronal uptake). In the presence of rauwolscine (an alpha2‐adrenergic blocker), rilmenidine caused concentration‐dependent contractions which were inhibited by prazosin (nonselective alpha1‐antagonist) and by (+)niguldipine (selective alpha1A‐adrenergic antagonist), but not by (‐)niguldipine. After treatment with phenoxybenzamine (to alkylate alpha1‐adrenoceptors), rilmenidine evoked contractions of the canine saphenous vein which were antagonized competitively by rauwolscine. The combination of rauwolscine and prazosin did not abolish contractions evoked by the highest concentrations of rilmenidine. Although binding experiments using3H‐idazoxan suggested the existence of a nonadrenergic binding site (around 20% of the total binding), contractile studies failed to demonstrate their involvement in the increases in tension evoked by rilmenidine. These experiments suggest that the contractions evoked by rilmenidine in isolated canine veins are mediated by both alpha1A‐ and alpha2‐adrenoceptors.
Blood flow acceleration in the carotid and brachial arteries of healthy volunteers: respective contributions of cardiac performance and local resistance
Authors: Chemla D. , Démolis P. , Thyrault M. , Annane D. , Lecarpentier Y. , Giudicelli JF
Published: August 2009

Summary— The influence of local resistance and cardiac performance on peripheral blood acceleration was investigated in 14 healthy male volunteers. Steady and pulsatile flow was studied in the brachial and in the common carotid arteries, ie, two territories that exhibit marked differences in resistive characteristics. Instantaneous blood velocity (V), mean blood velocity (Vm) and artery diameter (D) were evaluated at rest by an ultrasonic range‐gated pulsed Doppler flowmeter using a double transducer probe, thus allowing the calculation of mean blood flow (Q). Mean local resistance (R) was obtained by dividing the mean arterial pressure by Q. The peak value of the local acceleration of the blood was obtained by computer‐assisted calculation of the first derivative of instantaneous blood velocity (Gmax = +dV/dtmax). Peak aortic blood acceleration (GAo) was simultaneously measured from the suprasternal notch using a pulsed Doppler velocity meter. In the brachial and the common carotid arteries, Gmax was of a similar magnitude (551 ±30 and 555 ± 44 cm/s2, respectively) despite major differences in the respective D, Vm, Q and R values. In neither artery was there a relationship between Gmax and either resting Q or R. At the brachial artery level, Gmax was positively related to GAo (r = 0.79, P = 0.0008). At the common carotid artery level, there was a weak, although non significant relationship between Gmax and GAo (P = 0.08). Our results indicate that the local acceleration of peripheral blood flow in the brachial artery is related rather to upstream central impulse than to downstream hemodynamics, and suggest some regional differences in the hemodynamic determinants of the local acceleration of peripheral blood flow.
Effect of angiotensin converting enzyme inhibitors on quality of life in hypertensive patients. Pharmacodynamic basis
Authors: Govantes C. , Marín J.
Published: August 2009

Summary—The aim of this review is to comment the results described in the literature concerning the possible pharmacodynamic mechanisms involved in the improvement of quality of life of angiotensin converting enzyme inhibitors that is just a working hypothesis. These drugs, widely used in the treatment of hypertension, prevent the formation of angiotensin II and the generation of free radicals, as well as the hydrolysis of bradykinin, enkephalins and endorphins. Different mechanisms have been implicated on quality of life: 1) increase of bradykinin levels in the central nervous system that would trigger the release of nitric oxide (NO), noradrenaline, acetylcholine, excitatory amino acids and vasopressin which are involved in memory and cognition; 2) increase of brain blood supply by enhanced NO synthesis; 3) interference with cholinergic mechanisms in the central nervous system by angiotensin II inhibition of acetylcholine release; 4) decrease of endorphin metabolism; and 5) interaction with hypothalamicpituitary‐adrenal axis that releases ACTH and vasopressin.
Delayed protection of the ischemic heart — from pathophysiology to therapeutic applications
Authors: Richard V. , Kaeffer N. , Thuillez C.
Published: August 2009

Summary— Preconditioning the heart with brief episodes of ischemia paradoxically increases its resistance to subsequent ischemic episodes, and markedly limits infarct size. Although preconditioning is now considered as the most powerful antiischemic intervention known, its beneficial effects are short‐lived since they are lost if the reperfusion period after preconditioning is extended past 2–3 h. There is, however, some evidence of a delayed phase of protection, manifest 24 h after the initial preconditioning stimulus, associated with a decrease in infarct size, a prevention of postischemic contractile dysfunction (stunning) and a reduction in endothelial injury. The delayed beneficial effects of preconditioning resemble those induced by prior heat stress, and might be related to the expression of stress proteins (heat shock proteins or HSP). Evidence for a role of HSP derives from observations showing that brief ischemia is a potent stimulus for HSP expression. Moreover, transfection of isolated cells with HSP or overexpression of HSP in transgenic mice renders the myocytes more resistant to ischemia. Once produced, HSP are believed to facilitate protein synthesis, stabilize newly formed proteins and repair denatured ones. Alternatively, delayed preconditioning may be mediated by antioxidant enzymes such as superoxide dismutase or catalase, which are also upregulated by ischemia, and this could lead to a lesser production of oxygen‐derived free radicals during reperfusion. Indeed, in isolated myocytes, prevention of hypoxia‐induced expression of superoxide dismutase (using an antisense oligonucleotide) abolished the delayed protective effect of preconditioning. Importantly, recent in vivo evidence suggests that the delayed protection may be mediated by adenosine, through activation of A1‐receptors, and by stimulation of protein kinase C. Finally, although the exact mechanisms by which preconditioning induces delayed protection are still mostly unknown, the fact that the expression of protective proteins such as HSP can be induced by many other means than ischemia suggests that it is possible to pharmacologically stimulate this expression and thus possibly mimic the endogenous protective pathway. This could lead to the development of new pharmacological interventions which induce delayed myocardial protection in clinical situations such as angioplasty, coronary bypass surgery or even in patients at high risk of infarction.
Analysis of stimulant locomotor effects of modafinil in various strains of mice and rats
Authors: Simon P. , Hémet C. , Costentin J.
Published: August 2009

Summary— Locomotor effects of modafinil were analysed and compared in various strains of mice and rats. A stimulation of locomotor activity was evidenced in all tested strains of mice: Swiss CD1, BALB/c, DBA2, C3H, B6CBAF1/JICO, Nude CD1 and in all tested strains of rats: Long Evans, Sprague Dawley, Wistar. In mice, from 10 mg/kg intraperitoneal, a precocious stimulant effect was observed. The drug seems to operate in its native form on the mouse brain since its intracerebroventricular administration (from 15 μg/mouse) elicited a stimulation of locomotion. In rats, the effective doses were higher (from 40 mg/kg ip); the effects of modafinil mainly oppose to the decrease in locomotion (habituation) which normally occurs in control animals. In addition, it was observed that administration of modafinil in rats habituated to their environment induced a recovery of locomotor activity.
Influence of methoctramine on the acetylcholine‐isoprenaline functional antagonism in the guinea pig isolated trachea
Authors: Zhang Y. , Molimard M. , Advenier C.
Published: August 2009

Summary—It has been suggested that activation of muscarinic M2receptors is one of the components of the functional antagonism between muscarinic and β‐adrenoceptor agonists in canine and guinea pig tracheal smooth muscle. The aim of the present study was to determine in the guinea pig trachea the importance of this component according to the magnitude of the acetylcholine‐induced contraction. Cumulative concentration‐response curves for isoprenaline were obtained in the absence or presence of the muscarinic M2receptor antagonist methoctramine (3 × 10−7M) in tracheal rings under basal tension or precontracted by acetylcholine 2 × 10−7, 3 × 10−6and 10−4M, giving contractions of 25, 50 or 75%, respectively, of the maximal tension induced by acetylcholine 3 × 10−3M. In the absence of methoctramine, acetylcholine induced a concentration‐dependent shift of the concentration‐response curves of isoprenaline (‐log EC50of isoprenaline are 8.09 ± 0.07, 7.85 ± 0.08, 7.38 ± 0.12 and 6.49 ± 0.12,n= 6 for basal tension and for acetylcholine concentrations of 2 × 10−7, 3 × 10−6and 10−4M, respectively). In the presence of methoctramine, the basal ‐log EC50of isoprenaline was unmodified, whereas the acetylcholine‐induced shifts of concentration‐response curves of isoprenaline were abolished for low levels of contraction (25%) and significantly reduced to 50 and 75% levels of contraction. Under similar conditions, acetylcholine‐induced shifts of concentration‐response curves of isoprenaline were unmodified by the muscarinic M1receptor antagonist pirenzepine (10−7M). These results suggest that the inhibitory effect of M2receptors on β‐adrenoceptor agonists effects is important for low contraction levels induced by acetylcholine, and that this effect becomes less important for higher concentrations of acetylcholine.
Actions of galanin and some of its analogues on rat isolated gastric fundus*
Authors: Śliwiński W. , Korolkiewicz R. , Rekowski P. , Halama A. , Korolkiewicz KZ
Published: August 2009

Summary—The study was undertaken to characterize the effects of porcine galanin (pGal) and some of its analogues on rat gastric fundus muscle strips. pGal, galantide (M15) and pGal(1–14)‐[Abu8]SCY‐I evoked reproducible concentration‐dependent contractions in concentrations of 1–300, 3–1,000 and 100–3,000 nM, respectively, with EC50values of 13, 70 and 187 nM. Hill's coefficient for pGal is 1.03, indicating an interaction of one pGal molecule with one receptor, fulfilling criteria of classical receptor theory. For M15 and pGal(1–14)‐[Abu8]SCY‐I, Hill's coefficients are significantly different from 1, namely 0.73 and 1.56, so that one drug molecule may not interact with one receptor. The stimulatory effects of pGal were not modified by dibenamine 10 μM or glybenclamide 1 or 10 μM. Diltiazem 0.1, 1 and 10 μM, papaverine 0.1, 10 μM or dibutyryl cAMP (dib cAMP) 100 and 300 μM, blocked the contraction to pGal in a concentration‐dependent manner, indicating an important role for the influx of extracellular calcium ions and regulation by cAMP the pGal‐evoked contraction. Diltiazem, dibutyryl cAMP and papaverine were not competitive antagonists of pGal in the stomach smooth muscle.
HOE 694 affords protection versus veratrine contractures in rat atria by Na+ channel blockade
Authors: Le Grand B. , Marty A. , Talmant JM , John GW
Published: August 2009

Summary—We examined the effects of the benzoylguanidine derivative HOE 694, an inhibitor of Na+‐H+ exchange, against veratrine‐induced diastolic contractures and action potentials recorded in rat isolated left atria. Concentration‐dependent protective effects against veratrine‐contractures, in the absence of negative inotropic responses, were observed with HOE 694 (IC50= 20.1(7.6–27.0) μM,n= 24) and with the chemically related amiloride derivatives DMA, EIPA, HMA and MIA, but not with amiloride itself. Concomitant Na+‐H+ exchange blockade by a high concentration of amiloride (100 μM) failed to significantly modify the protective effects of HOE 694. HOE 694 decreased Vmaxsignificantly at 10 μM (166.7 ± 21 vs 154.7 ± 20 V/s, P < 0.05,n= 6) without any effect on resting potential or action potential duration. High concentrations (100 μM) of HOE 694 further decreased Vmaxand increased action potential duration. The protective effects of HOE 694 were compared with three of the class 1 antiarrhythmic agents, quinidine, lidocaine and flecainide against veratrine contracture. These Na+ channel blockers exerted protective effects in the same range of concentrations as HOE 694. Our findings demonstrate that HOE 694 prevents veratrine contractures at concentrations which presumably affect Na+‐H+ exchange. However, the mechanism by which HOE 694 affords protection is apparently mediated by class 1‐type Na+ channel blockade.
α‐Adrenergic regulation of human renal function
Authors: Michel MC , Rump LC
Published: August 2009

Summary—Pharmacological and molecular cloning techniques have identified six human subtypes of α‐adrenoceptors which are designated α1A, α1B, α1D, α2A, α2Band α2C. At the protein level human kidney expresses predominantly α2A‐adrenoceptors while other α2‐adrenoceptor subtypes or α1‐adrenoceptors have not been detected consistently in radioligand binding studies. However, the presynaptic receptors, which inhibit noradrenaline release in the human kidney, appear to belong to the α2C‐subtype. Intrarenal infusion of the nonselective α1‐adrenoceptor antagonist, phentolamine, and of the selective α2‐adrenoceptor antagonist, yohimbine, but not of the selective α1‐adrenoceptor antagonist, doxazosin, increase renal blood flow and renin release in hypertensive patients undergoing diagnostic renal angiography. Thus, α2‐ but not α1‐adrenoceptors appear to mediate a tonic renal vasoconstriction and inhibition of renin release. Effects of systemically given α‐adrenoceptor agonists and antagonists are difficult to interpret on a mechanistic level since direct effects in the kidney and indirect effects due to baroreflex activation and peripheral presynaptic and central sympatholytic actions may at least partially offset each other. Moreover, some of these drugs may additionally act independent of α‐adrenoceptors, for example, via imidazoline recognition sits. The net result in a given subject may depend on the endogenous sympatho‐adrenal tone. Thus, for each target population of interest, effects have to be described empirically for each drug.
Metabolism and toxicity of coumarin on cultured human, rat, mouse and rabbit hepatocytes
Authors: Ratanasavanh D. , Lamiable D. , Biour M. , Guédès Y. , Gersberg M. , Leutenegger E. , Riché C.
Published: August 2009

Summary— We compared the cytotoxic effect of coumarin and its derivatives, 7‐hydroxycoumarin (7‐OHC), 4‐hydroxycoumarin (4‐OHC), o‐hydroxyphenyl acetic acid (OHPAA) and o‐coumaric acid (CA), on cultured hepatocytes from human, rat, mouse and rabbit liver. At 10−5 and 5 × 10−5 M, coumarin and its derivatives did not give rise to any signs of toxicity on cultured hepatocytes of the four species. At 10−4 M, coumarin, but not its derivatives, induced release of lactate dehydrogenase (LDH) into the medium, especially in rat hepatocyte cultures. Intracellular LDH activities were correspondingly reduced. The cytotoxic effect of coumarin in cultured rat hepatocytes was evidenced on morphological examination and from the results of the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium (MTT) reduction test. At higher concentrations (5 × 10−4 M), 7‐OHC and CA were also found to be cytotoxic in cultured rat hepatocytes. The cytotoxic effect of coumarin (5 × 10−4 M) was decreased in the presence of SKF 525‐A, a cytochrome P450 inhibitor. Interspecies comparisons showed that rat hepatocytes were the most sensitive to the toxicity of coumarin and its derivatives, whereas human hepatocytes were the most resistant. Our results suggest that the cytotoxicity of coumarin is metabolism and species‐dependent. Thus, the rat may not be a suitable model for evaluating the pharmacological hazards of coumarin in humans.
The effect of the potassium channel activator, cromakalim, on antidepressant drugs in the forced swimming test in mice
Authors: Redrobe JP , Pinot P. , Bourin M.
Published: August 2009

Summary— The forced swimming test (FST) is a widely used behavioural model to predict potential antidepressant (AD) action of compounds in humans. It has been previously shown that pretreatment with lithium, quinine and clonidine had additive effects on AD drugs in the FST, an effect proposed to be a result of potassium channel blockade. It is possible that pretreatment with potassium channel openers may induce opposite effects to those seen following pretreatment with potassium channel blockers in the FST. Pretreatment with cromakalim (CROM) (1 mg/kg, intraperitoneally [ip]) antagonized the anti‐immobility effects of the mixed noradrenaline (NA)/5‐hydroxytryptamine (5‐HT) reuptake inhibitors imipramine and amitriptyline (P < 0.05). CROM administration (0.06 and 1 mg/kg, ip) also blocked the AD‐like effects of the specific NA reuptake inhibitor, desipramine, and the selective serotonin reuptake inhibitor, paroxetine (P < 0.05 and P < 0.01, respectively). Pretreatment with CROM via gavage (1 mg/kg) antagonized the AD‐like effects of imipramine, amitiptyline, desipramine and paroxetine. CROM treatment (via ip route or gavage) did not have any significant effect on the anti‐immobility activity of the atypical AD mianserin at any of the doses employed. Another potassium channel opener, minoxidil (MINOX), which does not cross the blood‐brain barrier, was also tested to eliminate the possibility that CROM may be acting via peripheral/local mechanisms. MINOX (32 mg/kg) failed to antagonize anti‐immobility effects of any of the AD tested. In conclusion, the results of the present study suggest that CROM is only acting on drugs involved with neurotransmitter uptake inhibition.
Thromboxane A2and related prostaglandins in airways
Authors: Devillier P. , Bessard G.
Published: August 2009

Summary—Asthma is now thought to be a chronic inflammatory disease of the airways. The roles of prostanoids, thromboxane A2(TXA2) and the prostaglandins (PGs) in the pathogenesis and pathophysiology of asthma have fostered a wealth of studies but remain controversial. TXA2and the bronchoconstrictor PGs, PGD2and PGF2α, are generated in greater amounts in asthmatic than in normal subjects. TXA2is a potent constrictor of airway smooth muscle, an inducer of acetylcholine release and of airway microvascular leakage. It may participate in the thickening and the remodeling of the airway wall which may contribute to the airway hyperresponsiveness, a typical feature of asthma. Strategies for inhibition of TXA2effects include antagonism of the TXA2receptor (TP receptor) and inhibition of the thromboxane synthase. TP receptor antagonists could block the effects of all the bronchoconstrictor prostanoids because TXA2as well as the bronchoconstrictor PGs act through activation of lung TP receptor. The recent development of specific and potent TP receptor antagonists and inhibitors of thromboxane synthase has provided tools to assess the role of TXA2and bronchoconstrictor PGs in the pathophysiology of asthma.
Heart rate and blood pressure variability in cardiac diseases: pharmacological implications
Authors: Cloarec‐Blanchard L.
Published: August 2009

Summary—Even at rest, blood pressure and heart rate fluctuate continuously around their mean values. Considerable interest has recently focused on the assessment of spontaneous fluctuations in heart rate and blood pressure, ie, heart rate and blood pressure variability, using time or frequency domain indexes. Heart rate variability has been extensively studied in cardiovascular disease and has emerged as a valuable parameter for detecting abnormalities in autonomic cardiovascular control, evaluating the prognosis and assessing the impact of drug therapy on the autonomic nervous system in patients with myocardial infarction, congestive heart failure or a heart transplant. In contrast, until the recent development of noninvasive methods for continuous blood pressure recording, blood pressure variability received little attention, and this parameter remains to be evaluated in cardiovascular disease.
The direct effects of thyroid hormones on rat mesenteric resistance arteries
Authors: Zwaveling J. , Pfaffendorf M. , van Zwieten PA
Published: August 2009

Summary—The direct relaxant effects of thyroid hormones on mesenteric resistance vessels were investigated using an isometric wire myograph. Both the L‐ and the D‐isomers of thyroxine (T4) and triiodothyronine (T3) were studied. In contrast with the long‐term effects of thyroid hormones, both T4enantiomers proved more potent in inducing vascular relaxation than the two T3enantiomers. The interaction between thyroid hormones and calcium‐induced contractions was studied. T4concentration dependently inhibited the Ca2+induced contractions, showing noncompetitive interaction. Furthermore, we investigated whether the endothelium was involved in the relaxant effect to L‐T4. The T4induced relaxation proved impaired by prior incubation with the nitric oxide (NO) inhibitor N‐ω‐nitro‐L‐arginine methylester HCl (L‐NAME, 0.1 μM), indicating that T4is able to stimulate the production of endothelium‐derived NO. L‐T4‐induced relaxation was enhanced by prior incubation with indomethacin (10 μM), whereas in endothelium‐denuded preparations an unaltered response was found. The present results indicate that L‐T4‐induced relaxation is established by an indirect effect via the endothelium and by a direct effect on vascular smooth muscle cells, possibly by influencing calcium fluxes. Because vascular relaxation is established at supraphysiologic concentrations (approximately 100 times the basal level) of thyroid hormone, it is concluded that the direct effect of thyroid hormone on mesenteric vascular smooth muscle cells are not relevant for the in vivo situation.
Hemodynamic and neurohormonal effects of flosequinan in patients with heart failure
Authors: Isnard R. , Lechat P. , Pousset F. , Carayon A. , Kalotka H. , Chikr H. , Salloum J. , Thomas D. , Komajda M.
Published: August 2009

Summary— In a double‐blind, placebo‐controlled study, the central and peripheral hemodynamic effects of 100 mg oral flosequinan and the impact of this drug on neurohormonal activation were noninvasively evaluated in 18 patients with congestive heart failure, after the first administration and after 10 days of treatment. No significant hemodynamic and neurohormonal changes were observed after acute admistration. After 10 days, flosequinan produced central and peripheral hemodynamic improvement characterized by an increase in left ventricular circumferential fiber shortening velocity (+12%), a decrease in total systemic resistance (‐36%), and an increase in leg blood flow (+37%). No significant changes were observed in heart rate and arterial pressure in patients receiving flosequinan, though a slight increase in heart rate (+17%) was recorded. Despite these favorable hemodynamic effects, flosequinan significantly increased plasma norepinephrine (+38%) and plasma renin activity (+13%) after 10 days of treatment. Thus, the beneficial central and peripheral hemodynamic effects of flosequinan are accompanied by activation of the sympathetic and renin‐angiotensin systems. This might be related to the unfavorable effects of the drug on survival in patients with heart failure.
Gene and other biological therapies for vascular diseases
Authors: Stephan D. , Nabel EG
Published: August 2009

Summary— Gene transfer and antisense therapy offer novel approaches to the study and treatment of vascular diseases. The localized nature of vascular diseases like restenosis has made the application of genetic material an attractive therapeutic option. Viral and nonviral vectors have been developed to facilitate the entry of foreign DNA or RNA into cells. Vector improvement and production, demonstration of vector safety and demonstration of therapeutic efficacy are among the main present challenges. Various strategies have already been shown to be successful in preventing restenosis in animal models and include: the transfer of the herpes simplex virus thymidine kinase associated with ganciclovir; transfection of the cell cycle regulatory genes encoding for the active form of retinoblastoma gene product (Rb) or the cyclin‐dependant kinase inhibitor p21, and antisense therapy. Therapeutic angiogenesis using gene transfer is a new strategy for the treatment of severe limb ischemia. Transfection of DNA encoding for the vascular endothelial growth factor has resulted in increasing collateral flow in animal models of peripheral ischemia. This approach is currently being investigated in a clinical trial in patients with distal ischemia. Other potential targets for genetic treatment in cardiovascular diseases include thrombosis, extracellular matrix synthesis and lipid metabolism.
Glucocorticoid modulation of muscarinic and β‐adrenergic receptors in guinea pig lung
Authors: Scherrer D. , Lach E. , Landry Y. , Gies JP
Published: August 2009

Summary—We investigated the effect of the in vivo treatment of guinea pigs with methylprednisolone, 10 mg/kg daily, on lung muscarinic and β‐adrenergic receptors. Receptor densities were assessed by saturation experiments of tritiated N‐methylscopolamine and dihydroalprenolol binding to lung membranes. After 3 h of treatment, methylprednisolone induced a decrease of 19.2% (P< 0.05) of muscarinic receptors but was without effect on β‐adrenergic receptor density. After 24 h, an increase of 39.7% (P< 0.01) and 16.9% (P< 0.05) was observed for muscarinic and β‐adrenergic receptors, respectively. For muscarinic receptors, this increase reached 53.4% (P< 0.01) within 48 h and stayed at this level until 96 h. The increase of β‐adrenergic receptors was maximal (24.9%) after 72 h and returned to the control value after 96 h. The dissociation constant (Kd) values of both ligands were not affected by the glucocorticoid treatment. Functional studies showed that the 96 h treatment did not affect the contractile response of guinea pig lung parenchymal strips to carbachol since the 50% concentration value (EC50) and the maximal contraction value (Emax) were not significatively different from control values. These data show that glucocorticoids control the expression of both muscarinic and β‐adrenergic receptors in guinea pig lung but with different time courses and to a larger extent for muscarinic receptors. The glucocorticoid treament did not modify the contractile response of lung strips to carbachol, confirming the absence of effect on the affinity of muscarinic receptors and suggesting that the receptor reserve exceed the increase of their density by the steroid.
Hypoxic contractile response in isolated rat thoracic aorta: role of endothelium, extracellular calcium and endothelin
Authors: Pape D. , Beuchard J. , Guillo P. , Allain H. , Bellissant E.
Published: August 2009

Summary—The effects of hypoxia on isolated arteries remain controversial, depending on the species, vascular beds and protocols. The aims of the study were to characterize the response of rat thoracic aorta to hypoxia and to examine the roles of endothelium, extracellular calcium and endothelin in this response. Hypoxia was induced by bubbling Krebs solution with 95% N2and 5% CO2instead of 95% O2and 5% CO2. Experiments were performed during 1 h in norepinephrine (0.01 μM) precontracted rings. Hypoxia produced a biphasic response consisting of an initial transient partial relaxation (67% at 14 min) followed by a slow but sustained contraction (27% from 40 to 60 min). After endothelium removal, relaxation appeared faster with increased magnitude (82% at 12 min) and was followed by a weak transient contraction (16% at 25 min). In endothelium‐intact rings, Ca2+free medium (EGTA, 0.1 mM) and Ca2+channel blockers, verapamil (0.05, 0.5 and 5 μM) or nicardipine (0.1, 1 and 10 μM), had no effect on relaxation but inhibited the contraction, the effects of both calcium antagonists being concentration‐dependent. Similarly, the ETA/ETBreceptor antagonist, bosentan (0.1, 10 and 1,000 nM), induced a concentration‐dependent decrease in the contraction. We conclude that 1) the response of rat thoracic aorta during 1 h of hypoxia is biphasic (relaxation followed by contraction); 2) the endothelium is involved in the contraction whereas its role in the relaxation remains to be elucidated; 3) extracellular calcium is involved in the contraction; and 4) endothelin may play a role in the contraction.