bluuebunny/crossref_metadata_2025 huggingface dataset:
A combination of plant extracts in the treatment of outpatients with adjustment disorder with anxious mood: controlled study versus placebo
Authors: Bourin M. , Bougerol T. , Guitton B. , Broutin E.
Published: August 2009

Summary— Euphytose (EUP) is a combination of six extracts: Crataegus, Ballota, Passiflora and Valeriana, which have mild sedative effects, and Cola and Paullinia, which mainly act as mild stimulants. This multicenter, double‐blind, placebo‐controlled general practice study was carried out in outpatients with ajustment disorder with anxious mood. The study was coordinated by psychiatrists. Ninety‐one patients were included in the EUP group and 91 patients in the placebo group. They all received two tablets three times a day over 28 days (D). Evaluation using the Hamilton‐anxiety (HAM‐A) rating scale were carried out on D0, D7, D14 and on D28. Comparing the two groups, 42.9% of the patients (EUP group) had a HAM‐A score of less than 10 at D28 versus 25.3% in the placebo group (P = 0.012). Changes in the HAM‐A score between D0 and D28 were as follows: D0 (EUP: 26.12 ± 4.0, placebo: 26.27 ± 4.5), D7 (EUP: 19.65 ± 5.7, placebo: 21.37 ± 5.6), D14 (EUP: 15.36 ± 5.7, placebo: 17.48 ± 6.7), D28 (EUP: 12.63 ± 7.3, placebo: 15.2 ± 8.1). From D7 to D28 there was a statistically significant difference (P = 0.042) between the two treatments, indicating that EUP is better than placebo in the treatment of adjustment disorder with anxious mood.
Design of the cardiac insufficiency bisoprolol study II (OBIS II)
Authors: Committee The CIBIS II Scientific
Published: August 2009

Summary— Clinical research in chronic heart failure has recently focused on the stimulated neuro‐hormonal compensatory mechanisms that could contribute to auto‐aggravation of the disease. On the basis of such a hypothesis, and apart from the inhibition of the renin angiotensin system, the antagonism of beta‐receptors has evolved as a promising approach for improving quality of life and prognosis. However, the definite proof of beta‐adrenoceptor blockade induced benefit on survival remains to be demonstrated. On the basis of CIBIS I data, the objective of the Cardiac Insufficiency Bisoprolol Study II (CIBIS II) is to evaluate effects of the selective beta‐1 adrenoceptor blocker, bisoprolol, on mortality (primary endpoint) in patients with ischaemic or non‐ischaemic chronic heart failure. Eligible patients will be symptomatic ambulatory patients with left ventricular ejection fraction ≤ 35% in NYHA functional class III or IV, receiving a background treatment of diuretics and angiotensin converting enzyme inhibitors. A total of 2,500 patients are planned to be included with a mean follow up of at least 3 years. Secondary endpoints include hospitalisations, cardiovascular mortality and combination of both as well as permanent treatment withdrawal. Bisoprolol will be titrated up to 10 mg, starting with 1.25 mg daily. Randomization began in November 1995. CIBIS II results will represent a basis for definite conclusions on the evaluation of beta‐adrenoceptor blockade induced benefit with bisoprolol in chronic heart failure.
Stress‐induced alterations of somatodendritic 5‐HT1Aautoreceptor sensitivity in the rat dorsal raphe nucleus — in vitro electrophysiological evidence
Authors: Laaris N. , Le Poul E. , Hamon M. , Lanfumey L.
Published: August 2009

Summary—Somatodendritic 5‐HT1Aautoreceptors play a key role in the control of the electrical and metabolic activity of serotoninergic neurons in the dorsal raphe nucleus. These neurons also possess intracellular glucocorticoid receptors which may be involved in the well established modulation of serotonin (5‐hydroxytryptamine, 5‐HT) metabolism by corticosterone in stressed animals. The possible mediation by somatodendritic 5‐HT1Aautoreceptors of such corticosterone‐dependent changes in serotoninergic neuron activity was investigated using an in vitro electrophysiological approach. 5‐HT1Aautoreceptor‐mediated inhibition of the firing of serotoninergic neurons was examined in brain stem slices from rats whose serum corticosterone concentrations had been markedly increased (+ 100–200%) by two different stressful conditions. Immobilization for 30 or 90 min (restraint stress) did not modify the concentration‐dependent inhibition of the firing of serotoninergic neurons by the 5‐HT1Areceptor agonist ipsapirone. In contrast, placing the rats in novel uncontrolled environmental conditions for 16 h significantly reduced the cell response to ipsapirone, indicating a decreased sensitivity of somatodendritic 5‐HT1Aautoreceptors. Such a change was not observed in adrenalectomized rats subjected to the same stressful conditions. These data show that some forms of stress can reduce the 5‐HT1Aautoreceptor‐dependent inhibitory control of the electrophysiological activity of serotoninergic neurons in the dorsal raphe nucleus. Both the nature and duration of stress seem to be critical factors for triggering the (corticosterone‐dependent) mechanism(s) responsible for the functional desensitization of 5‐HT1Aautoreceptors in stressed rats.
Effects of octreotide on experimental neurogenic orthostatic hypotension in anaesthetized dogs
Authors: Bordet R. , Verwaerde P. , Tran MA , Marques MA , Montastruc JL , Senard JM
Published: August 2009

Summary—This paper investigates the effects of octreotide (0.1 mg/kg, subcutaneous) on cardiovascular adaptation during head‐up tilt test in an experimental model of neurogenic orthostatic hypotension (OH) obtained by chronic sinoaortic denervation in anaesthetized dogs. Blood pressure (BP), heart rate (HR), spectral variability (Fast Fourier transformation on 512 consecutive points, Δt: 2 Hz) and plasma catecholamine levels were measured in a double blind cross‐over randomized study versus placebo, in supine position and during a head‐up tilt test (80°, 10 min) in six sinoaortic denervated and six control (normal) dogs. In normal dogs, head‐up tilt test significantly increased HR and diastolic blood pressure (DBP). Plasma noradrenaline levels and energy of the low frequency band (40–150 mHz) of systolic blood pressure (SBP) significantly increased whereas the energy of the low frequency band of HR significantly decreased. Placebo and octreotide failed to modify supine and head‐up tilt values of the measured parameters (except the value of low frequency band of SBP, which increased after octreotide). In sinoaortic denervated dogs, supine values of BP, HR and plasma noradrenaline levels were significantly higher than in controls whereas the energy of the low frequency spectral band of HR and SBP was similar to controls. Head‐up tilt test induced a dramatic decrease in BP. HR, plasma noradrenaline levels and energy of the low frequency band of SBP and HR remained unchanged during head‐up tilt tests. Neither supine nor head‐up tilt values of these parameters were modified 45 min after octreotide or placebo administration. These results show that sinoaortic denervation is a reproducible model of OH characterized by a lack of activation of sympathetic efferent pathways during head‐up tilt tests. Octreotide, at the dose used, remains ineffective to prevent the fall in BP under these experimental conditions.
Effect of efonidipine, a novel dihydropyridine derivative, on myocardial metabolic changes induced by coronary artery ligation in dogs: comparison with nifedipine
Authors: Yokoyama T. , Ichihara K. , Abiko Y.
Published: August 2009

Summary—Efonidipine is a dihydropyridine derivative having a vasodilating action, which is slower in onset and longer in duration than that of nifedipine. In the present study, we compared the effects of efonidipine with those of nifedipine on the ischemic myocardial metabolism in anesthetized dogs. The heart was made ischemic by ligating the left anterior descending coronary artery (LAD) completely for 3 or 30 min. Efonidipine or nifedipine was injected intravenously, 10 or 3 min, respectively, before the start of LAD occlusion. Efonidipine (0.01 or 0.03 mg/kg) decreased both blood pressure and heart rate, whereas nifedipine (0.003 mg/kg) decreased blood pressure and increased heart rate. The magnitude of decrease in mean blood pressure induced by 0.03 mg/kg efonidipine was similar to that induced by 0.003 mg/kg nifedipine. Although efonidipine did not modify the changes in myocardial carbohydrate metabolism induced by ischemia, it attenuated the ischemia‐induced decrease in the myocardial level of adenosine triphosphate and energy charge potential. Nifedipine, however, did not modify the changes in both myocardial energy and carbohydrate metabolism induced by ischemia. The results suggest that efonidipine has a cardioprotective effect in the dog, probably because of its negative chronotropic effect.
Metabolism of clozapine by human neutrophils: evidence for a specific oxidation of clozapine by the myeloperoxidase system with inhibition of enzymatic chlorination cycle
Authors: Frimat B. , Gressier B. , Odou P. , Brunet C. , Dine T. , Luycky M. , Cazin M. , Cazin JC
Published: August 2009

Summary—The use of clozapine, an unique antipsychotic drug, raises the real problem of drug‐induced polymorphonuclear neutrophil cytoxicity. Clozapine prescription has been restricted due to a 1–2% incidence of drug‐induced agranulocytosis. The exact mechanism of this adverse effect is not yet known. The myeloperoxidase‐hydrogen peroxide system could play a key role in the initiation of agranulocytosis. Therefore, we have investigated the clozapine effects on hydrogen peroxide and hypochlorous acid, evaluated the peroxidase‐mediated metabolism of clozapine by mass spectrometry analysis because myeloperoxidase uses hydrogen peroxide and chloride producing hypochlorous acid in its chlorination cycle, and thus could oxidise clozapine in its peroxidation cycle. First, evidence for inhibition of hypochlorous acid production and scavenging of hydrogen peroxide by clozapine were demonstrated in vitro, in different cell‐free and cellular systems. Results are consistent with an inhibition of the myeloperoxidase chlorination cycle when clozapine is oxidised in the peroxidation cycle. Secondly, ion‐spray mass spectrometry analysis allowed us to confirm clozapine oxidation by the myeloperoxidase system. Actually, clozapine N‐oxide with a m/z at 343 was formed. It could be the final step of the metabolisation of clozapine via two successive univalent oxidations mediated by peroxidase. We suggest that generation of a free cation radical, CLZo+, was the initial step. CLZo+is a very reactive species and may play an important role in the onset of agranulocytosis either by direct toxicity or via an immunological mechanism. However, this assumption does not exclude the possible role of other metabolic ways involving, in particular, N‐desmethylclozapine.
Effects of pretreatment with clonidine, lithium and quinine on the activities of antidepressant drugs in the mouse tail suspension test
Authors: Redrobe JP , Bourin M.
Published: August 2009

Summary—The aim of the present study was the investigation of pretreatment effects with clonidine (0.06 mg/kg, intraperitoneal [ip]), lithium (1 mEq, ip) or quinine (0.5 mg/kg, ip) on the activities of various drugs acting on noradrenergic and/or serotonergic systems in the mouse tail suspension test. Drugs used in the present study included: the tricyclic antidepressants imipramine and dothiepin, the heterocyclic antidepressant trazodone, the 5‐HT reuptake inhibitor (SSRI) fluoxetine, the atypical antidepressants mianserin and iprindole, the 5‐HT1Areceptor agonist ipsapirone, the 5‐HT2A/2Creceptor antagonist ritanserin, and the 5‐HT3receptor antagonist ondansetron. Clonidine, lithium and quinine differentially enhanced the effects of several psychotropic drugs administered at sub‐active doses. The activity of iprindole (32 mg/kg, ip) was not potentiated by pretreatment with clonidine, lithium or quinine. Our results suggest that lithium exerted additive effects via postsynaptic 5‐HT1Areceptor activation, quinine via potassium ion channel blockade of 5‐HT3receptors, while clonidine did so primarily via action at 5‐HT2receptors.
Pharmacological profile of TH‐142177, a novel orally active AT1‐receptor antagonist
Authors: Nozawa Y. , Haruno A. , Oda N. , Yamasaki Y. , Matsuura N. , Miyake H. , Yamada S. , Kimura R.
Published: August 2009

Summary—The pharmacological properties of TH‐142177 (N‐n‐butyl‐N‐[2′‐(1‐H‐tetrazole‐5‐yl)biphenyl‐4‐yl]‐methyl‐(N‐carboxymethyl‐benzylamino)‐acetamide), a novel antagonist of the angiotensin II (AII) AT1receptor, were studied in vitro and in vivo, and compared to those of losartan. In the rat isolated aorta, TH‐142177 produced parallel shifts to the right of the concentration‐response curves for AII‐induced contractions without affecting the maximal response (pA2= 9.07). The inhibitory potency of TH‐142177 in the aorta was about three times greater than that of losartan. TH‐142177 completely inhibited the specific binding of [125I]AII to AT1receptor in rat aortic membranes (Ki= 1.6 × 10−8M), whereas specific [125I]AH binding to AT2receptor in bovine cerebellum and human myocardium was not affected by concentrations of TH‐142177 up to 10−5M. Losartan also inhibited the [125I] AII binding to rat aortic membranes (Ki= 2.2 × 10−8M). Following the intravenous administration to anesthetized normotensive rats, TH‐142177 dose‐dependently inhibited the increase in systolic blood pressure induced by an intravenous bolus injection of AII that was 1.5 times less potent than losartan. Furthermore, the oral administration of TH‐142177 to conscious renal hypertensive rats exerted a dose‐dependent reduction of systolic blood pressure without significantly effecting the heart rate. TH‐142177 was at least three times more potent than losartan. These results demonstrate that TH‐142177 is a potent and selective antagonist of AT1receptors and by oral administration has a long‐lasting antihypertensive activity.
Tonic block of the Na+ current in single atrial and ventricular guineapig myocytes, by a new antiarrhythmic drug, Ro 22‐9194
Authors: Hiroe K. , Hisatome I. , Tanaka Y. , Ahmmed GU , Sasaki N. , Shimoyama M. , Tsuboi M. , Inoue Y. , Manabe I. , Yamamoto Y. , Ohtahata A. , Kinugawa T. , Ogino K. , Igawa O. , Yoshida A. , Shigemasa C. , Sato R.
Published: August 2009

Summary— Ro 22‐9194 reduced the Na+ current in the atrial myocytes as well as ventricular myocytes in a tonic block fashion. Ro 22‐9194 had a higher affinity to the inactivated state Na+ channels (Kd1 = 3.3 μM in atrial myocytes, Kd1 = 10.3 μM in ventricular myocytes) than to those in the rested state (KdR = 91 μM in atrial myocytes, KdR = 180 μM in ventricular myocytes), which indicated that Ro 22‐9194 had a higher affinity to the Na+ channels in atrial myocytes than in ventricular myocytes. Ro 22‐9194 shifted the inactivation curve in the hyperpolarized direction in both atrial and ventricular myocytes. These findings suggest that Ro 22‐9194 more strongly inhibited the Na+ channel of the atrial myocytes of the diseased hearts with the depolarized membranes potentials than the Na+ channels in ventricular myocytes.
2‐Methyl‐thiazolidine‐2,4‐dicarboxylic acid as prodrug of L‐cysteine. Protection against paracetamol hepatotoxicity in mice
Authors: Wlodek L. , Rommelspacher H.
Published: August 2009

Summary—Toxic doses of paracetamol (acetaminophen) destroy the cellular defense system in hepatic tissue. The degree of the destruction can be assessed be measuring the metabolism of sulfhydryl compounds, oxygen radicals and the release of certain enzymes. Administration of 2‐methyl‐thiazolidine‐2,4‐dicarboxylic acid (CP; 1.2 mmol/kg) to mice 12 h prior to a toxic dose of paracetamol (600 mg/kg) suppressed the increase of aminotransferase activities in blood serum and the levels of reactive oxygen species in liver tissue. A protective effect of CP was also observed with respect to depletion of non‐protein sulfhydryl compounds, cysteine and glycogen. The findings demonstrate that the cysteine prodrug CP is effective in preventing liver damage of a hepatotoxic dose of paracetamol in vivo. A further advantage of the new compound is the long duration of the effect of more than 12 h.
Modulation of the calcium sensitivity of the smooth muscle contractile apparatus: molecular mechanisms, pharmacological and pathophysiological implications
Authors: Savineau JP , Marthan R
Published: August 2009

Summary—Smooth muscle contraction is the basis of the physiological reactivity of several systems (vascular, respiratory, gastrointestinal, urogenital…). Hyperresponsiveness of smooth muscle may also contribute to a variety of problems such as arterial hypertension, asthma and spontaneous abortion. An increase in cytoplasmic calcium concentration ([Ca2+]i) is the key event in excitation‐contraction coupling in smooth muscle and the relationship linking the [Ca2+]ivalue to the force of contraction represents the calcium sensitivity of the contractile apparatus (CaSCA). Recently, it has become evident that CaSCA can be modified upon the action of agonists or drugs as well as in some pathophysiological situations. Such modifications induce, at a fixed [Ca2+]ivalue, either an increase (referred to as sensitization) or a decrease (desensitization) of the contraction force. The molecular mechanisms underlying this modulation are not yet fully elucidated. Nevertheless, recent studies have identified sites of regulation of the actomyosin interaction in smooth muscle. Sensitization primarily results from the inhibition of myosin light chain phosphatase (MLCP) by intracellular messengers such as arachidonic acid or protein kinase C. In addition, phosphorylation of thin filament‐associated proteins, caldesmon and calponin, increases CaSCA. Activation of small (monomeric) G‐proteins such as rho or ras is also involved. Desensitization occurs as a consequence of phosphorylation of myosin light chain kinase (MLCK) by the calcium‐calmodulin activated protein kinase II, or stimulation of MLCP by cyclic GMP‐activated protein kinase. In the present review, examples of physiological modulation of CaCSA as well as pharmacological and pathophysiological implications are illustrated for some smooth muscles.
Chronotropic and inotropic effects of terikalant on isolated, blood‐perfused atrial and ventricular preparations of dogs
Authors: Lakhe M , Furukawa Y , Yonezawa T , Nagashima Y , Chiba S
Published: August 2009

Summary—We investigated the effects of terikalant, which blocks inward rectifier K+current, on the sinus rate, atrial and ventricular contractile force in the isolated, blood‐perfused right atrial and left ventricular preparations of dogs, and the effects of terikalant on the negative cardiac responses to acetylcholine, adenosine or pinacidil (an ATP‐sensitive K+channel opener) and on the positive cardiac responses to norepinephrine. Terikalant (1–100 nmol) decreased sinus rate and briefly and slightly increased atrial contractile force in isolated atria. However, terikalant did not increase ventricular contractile force in isolated ventricles. Neither propranolol nor atropine inhibited the positive inotropic and negative chronotropic responses to terikalant, respectively. Terikalant (10 or 30 nmol) did not significantly affect the negative cardiac responses to acetylcholine, adenosine nor pinacidil and the positive responses to norepinephrine. These results suggest that terikalant decreases sinus rate with a small changes in myocardial contractile force and does not affect the cardiac responses to muscarinic and adenosine receptor agonists, ATP‐sensitive K+channel openers nor β‐adrenoceptor agonists in the dog heart.
α‐Methylnoradrenaline‐induced contractions in rat aorta are mediated via α1D‐adrenoceptors
Authors: Castillo EF , Valencia I , Bobadilla RM , Villalon CM , Castillo C
Published: August 2009

Summary— The subtype(s) of α‐adrenoceptor‐mediating contractions to α‐methynoradrenaline in the rat aorta has been investigated by using α‐adrenoceptor‐selective competitive antagonists and the α1‐adrenoceptor selective agonist, phenylephrine, for comparison. α‐Methylnoradrenaline and phenylephrine elicited concentration‐dependent contractions in the endothelium‐denuded and endothelium‐intact aortic rings with similar potencies and maximal effects. α‐Methylnoradrenaline‐ and phenylephrine‐induced contractions in endothelium‐denuded aortic rings were competitively antagonized by prazosin (pA2 = 9.38 and 9.13; respectively) and rauwolscine (pA2 = 7.19 and 6.60, respectively). This confirms that there is an α1‐ and a non α2‐adrenoceptor response to α‐methylnoradrenaline in the rat aorta. The subtype selective α1D‐adrenoceptor antagonist, BMY 7378, was found to antagonize contractions to α‐methylnoradrenaline and phenylephrine competitively in endothelium‐denuded and endothelium‐intact aortic rings. The pA2 values of BMY 7378 against α‐methylnoradrenaline (8.39 and 8.41; endothelium‐intact and endothelium‐denuded, respectively) and phenylephrine (8.64 and 8.76; endothelium‐intact and endothelium‐denuded, respectively), are consistent with its published functional potency and clonal α1d‐adrenoceptor binding affinity. In addition, contractions to α‐methylnoradrenaline and phenylephrine in endothelium‐denuded aortic rings, were potently inhibited by WB 4101 with pA2 values of 9.75 and 9.25, respectively. The high pA2 values for WB 4101 indicate that the α1B‐adrenoceptor subtype does not seem to participate in α‐methylnoradrenaline (and phenylephrine) induced contractions in this artery. These results suggest that the α1D‐subtype plays a determining role in rat aorta contractions induced by α‐methylnoradrenaline.
The influence of pregnancy on endothelium‐derived nitric oxide mediated relaxations in isolated human resistance vessels
Authors: Van de Voorde J , Depypere H , Vanneel B
Published: August 2009

Summary—Pregnancy is associated with drastic hemodynamic adaptations, including a decrease in peripheral resistance. Vascular resistance is substantially influenced by endothelium‐derived nitric oxide (NO). This study was designed to investigate whether pregnancy might influence endothelium‐derived NO‐mediated relaxations in human resistance arteries. Reactivity of isolated human subcutaneous arteries, dissected out of abdominal fat from women who underwent a laparotomy or cesarean section, was studied using a small vessel myograph. Addition of acetylcholine (1 nM–10 μM) or bradykinin (1 nM–10 μM) to precontracted preparations elicited concentration‐dependent relaxation responses that were dependent on the presence of the endothelium and were partially inhibited by the NO‐synthase inhibitor nitro‐L‐arginine (0.1 mM). The relaxations to acetylcholine and bradykinin were similar in vessels isolated from pregnant and non‐pregnant women. Nitro‐L‐arginine (0.1 mM) had no influence on basal tone and had a similar inhibitory influence on the endothelium‐mediated relaxations in vessels from non‐pregnant and pregnant women. These results indicate that the influence of endothelium‐derived NO in human subcutaneous resistance arteries is not altered at the end of pregnancy.
Effect of nitric oxide donors on endogenous dopamine release from rat striatal slices
Authors: Büuyükuysal R Levent
Published: August 2009

Summary— Incubation of striatal slices with sodium nitroprusside (SNP) or hydroxylamine (HA) for 60 min caused a dose‐dependent increase in dopamine (DA) release. This effect was inhibited completely by tetrodotoxin (TTX) (1 //M) if low concentrations of SNP (1 fiM) or HA (10 and 100 /JM) were tested. Although higher concentration of SNP (10 and 100 /JM) and HA (500 /JM) were still effective in stimulating DA release, increases observed under these conditions were less than the values found in the absence of TTX. Verapamil (10 /JM), but not co‐conotoxin (100 nM), significantly reduced DA release stimulated by high concentrations of SNP or HA. When verapamil was combined with TTX, moreover, SNP and HA failed to stimulate DA release. If striatal slices were incubated in the presence of nomifensine (10 /JM), SNP and HA did not enhance DA release. SNP and HA‐induced depletions in tissue DA levels were also protected by nomifensine. Inhibition of guanylate cyclase with 10 fjM of methylene blue could not reduce the effects of NO‐donors. SNP and HA also failed to alter endogenous glutamate release from striatal slices. Similarly, SNP and HA‐induced increases in DA release were not affected by kynurenic acid and MK‐801. These results indicate that NO‐donors SNP and HA stimulate DA release by facilitating reverse DA transport. This effect seems to be dependent on the activation of both voltage dependent sodium channels and L‐type of calcium channels. Results presented here also indicate that neither endogenous glutamate nor guanylate cyclase activation plays an intermediary role in stimulatory effects of NO‐donors on DA release from rat striatal slices.
Evaluation of bosentan, pinacidil and nitroprusside on human pulmonary arteries: comparison with rat pulmonary arteries*
Authors: Wanstall JC , Kay CS , O'Donnell SR , Wilson K , Cole PH , Matar K
Published: August 2009

Summary—Bosentan (endothelin ETA/ETBantagonist), pinacidil (potassium channel opener) and nitroprusside (nitric oxide donor) were examined on isolated ring preparations of human intralobar pulmonary artery (3rd‐5th generation; internal radius > 1 mm), rat main pulmonary artery (1st generation; internal radius > 1 mm) and rat intralobar pulmonary artery (3rd generation; internal radius ≥ 0.1–0.3 mm). The potency of endothelin‐1 was the same in all three artery types. In human intralobar artery and rat main pulmonary artery, bosentan (3 and 10 μM) shifted the endothelin‐1 concentration response curve to a higher concentration range (endothelin‐1 concentration ratios, in human intralobar and rat main pulmonary artery, respectively: 3 liM bosentan, 4.5 and 8.1; 10 /xM bosentan, 13.5 and 19.5), but caused no significant block of endothelin‐1 in rat intralobar artery. The latter finding may be due to the reported presence of ETBreceptors in rat intralobar arteries and the higher potency of bosentan on ETAthan on ETBreceptors. In contrast, the potencies of nitroprusside and pinacidil (relaxation of submaximal contractions to the thromboxane‐mimetic, U46619) agreed on human and rat intralobar arteries but were 6 to 16‐fold lower than on rat main pulmonary artery. We conclude that data obtained on pulmonary arteries from rats can be useful in predicting the effects of vasoactive drugs in human pulmonary arteries but selection of the most appropriate rat artery for study will depend on the drug group under investigation. For potassium channel openers and nitric oxide donors, good agreement between human and rat data will be found when using pulmonary arteries from the same anatomical location even though they differ markedly in size. In contrast, for endothelin antagonists, agreement is more likely to be found in arteries of comparable size, despite their different anatomical locations.
CENTRAL NEUROGENIC NEUROPROTECTION: PROTECTION OF BRAIN FROM FOCAL ISCHEMIA BY CEREBELLAR STIMULATION
Authors: Reis DJ , Feinstein D , Galea E , Golanov EV
Published: August 2009

Electrical stimulation of the cerebellar fastigial nucleus (FN) elevates regional cerebral blood flow (rCBF) independently of cerebral metabolism (rCGU) throughout brain. One hour of FN stimulation also reduces, by up to 50%, the volume of the focal ischemic infarction produced by occlusion of the middle cerebral artery in rat. Protected areas correspond to the ischemic penumbra. Neuroprotection, while reversible, persists for weeks after 1h of stimulation. It cannot be attributed to increasing rCBF and/or reducing rCGU to improve matching of flow and metabolism. Conditional stimulation of FN initiates long‐lived inhibition of expression of peri‐infarction depolarizing waves, possibly by altering potassium‐channel function and suppresses induction of inducible nitric oxide synthase (iNOS) and ICAM in cerebral microvessels. The brain contains intrinsic networks which may protect the brain from ischemic injury, possibly by producing widespread and longterm suppression of electrical excitability and/or and expression of proinflammatory molecules.
RESTRAINING EFFECTS OF LOSARTAN ON BLOOD PRESSURE AND HEART RATE VARIABILITY INDUCED BY STRESS
Authors: Gaudet E , Blanc J , Elghozi JL
Published: August 2009

Summary— The effects of chronic treatment with losartan on blood pressure (BP) and heart rate (HR) variability responses during air‐jet stress were studied in WKY and SHR. In untreated animals, air‐jet stress induced an increase in systolic BP (SBP) (9 ± 2 mmHg for WKY and 8 ± 2 mmHg for SHR) and HR (56 ± 19 bpm for WKY and 76 ± 8 bpm for SHR). These changes were accompanied by an increase of the mid frequency (0.2–0.6 Hz, MF) component of HR in WKY (183%) and by an increase of the MF component of SBP in SHR (65%). Chronic suppression of the renin‐angiotensin system (RAS) by losartan reduced resting BP only in SHR (‐20 mmHg for SBP) without affecting HR and did not modify the resting MF components of BP and HR. This pretreatment did not alter the BP response in WKY to stress but impaired it in SHR. In both strains, treatment with losartan abolished all BP and HR variability changes, whereas the tachycardia response was unaltered. Losartan caused inhibition of BP and HR variability changes in response to stress in WKY and SHR. We provided evidence for the importance of the angiotensin II‐sympathetic interaction in the BP and HR variability responses to a stressful environment.
Experimental study of antidiarrheal activity of Salicairine®
Authors: Brun Y , Wang X‐P , Willemot J , Sevenet T , Demenge P
Published: August 2009

Summary—Experimental antidiarrheal activity of a traditionally used medication, Salicairine®, was demonstrated in comparison to loperamide by significant inhibition of castor oil‐induced diarrhea in mice (increases in hard faeces/total faeces ratio of 38 and 54 and 5 and 54% with respect to controls, at 0.5 and 1 mL/kg and 1 and 2 mg/kg, respectively) and bisacodyl‐induced increase in large intestine transit in rats (125 and 280 and 210% with respect to controls, at 0.4 and 2 mL/kg Salicairine® and 5 mg/kg loperamide, respectively). Salicairine® was able to reduce contractions of isolated rat duodenum induced by barium chloride and acetylcholine, although not completely (that is about 60%) as seen with loperamide. Also, it did not change normal gastrointestinal transit in mice at doses of 0.5 to 1 mL/kg, conversely to loperamide which had a significant effect (decrease of 50%) at 2 mg/kg. Finally, Salicairine® at 0.01 mL/mL, like loperamide at 0.2 mg/mL, significantly increased net fluid absorption in rat colon, either in basal conditions (30 and 64% respectively) or after a prostaglandin E1‐induced increase in net fluid secretion (41 and 35%, respectively). The antidiarrheal activity of Salicairine® is possibly related, at least in part, to an increase in colon net fluid absorption or a decrease in net fluid secretion.
Effects of carbamazepine on plasma extravasation and bronchoconstriction induced by substance P, capsaicin, acetaldehyde and histamine in guinea‐pig lower airways
Authors: Bianchi M , Rossoni G , Maggi R , Panerai AE , Berti F
Published: August 2009

Summary— We evaluated the in vivo effects of the pretreatment with carbamazepine (CBZ) at different doses (10, 20 and 40 mg/kg p.o.) on the Evans‐blue extravasation and on bronchoconstriction induced by different substances in guinea‐pig tracheal tissue. The drug dose‐dependently inhibited the extravasation induced by substance P (SP), capsaicin and acetaldehyde, but not that induced by histamine. At the highest dose (40 mg/kg) CBZ inhibited the bronchoconstriction induced by SP, capsaicin and acetaldehyde, but not that produced by histamine administration. The in vitro study with guinea‐pig tracheal preparation indicates that the drug does not interfere with the binding of SP to its receptors. Our results suggest that CBZ exerts a protective activity against the pro‐inflammatory action of SP.
Nasal nitric oxide concentration is decreased in heart failure patients receiving nitrates
Authors: Arnal JF , Galinier M , Mazerolles M , Rami J , Besombes JP , Fauvel JM , Bounhoure JP
Published: August 2009

Summary— Nitric oxide (NO) is a free radical gas and a short‐lived messenger which has many paracrine functions. Direct assessment of NO production is very difficult in vivo. However, the paranasal cavities generate a high amount of NO which diffuses in the nasal cavity where it can be easily measured. Several studies have suggested alterations of the NO production in heart failure. Thus, we assessed nasal NO concentration in normal subjects and in heart failure patients. The nasal NO concentration averaged 227 ± 10 ppb in the control group (n = 20), and 210 ± 10, 198 ± 20 and 159 ± 54 ppb in New York Heart Association (NYHA) class II (n = 30), III (n = 28) and IV (n = 7) patients, respectively (mean ± standard error [SE], not significant using analysis of variance [ANOVA]). Nasal NO level was not influenced by age, sex or etiology of the heart failure or by treatment with frusemide, angiotensin‐converting enzyme inhibitor or digoxin. However, treatment with NO‐releasing drugs (nitrates or molsidomine) significantly decreased the nasal NO level in heart failure patients. A two‐way ANOVA revealed that treatment with a NO‐releasing drug influenced nasal NO concentration (P = 0.0005), whereas NYHA class did not (P = 0.23), with a trend towards an interaction between the two parameters (P = 0.09): the inhibitory effect of NO‐releasing drug on nasal NO concentration was more pronounced in severe heart failure. In an additional group of 12 patients (NYHA class II or III), the nasal NO concentration was 174 ± 19 ppb during NO‐releasing drug treatment and increased to 231 ± 27 ppb 3 days after withdrawal of the nitrates (P = 0.0007 using paired t‐test). Conversely, the nasal NO concentration in another group of seven patients (NYHA class II or III) was 219 ± 32 ppb without nitrate treatment and decreased to 188 ± 28 ppb 7 days after nitrate addition (P = 0.02 using paired (test). In contrast, the nasal NO concentration in another group of ten ischemic patients without heart failure was 203 ± 25 ppb without nitrate treatment and was similar (207 ± 28 ppb) 7 days after nitrate addition (not significant using paired t‐test). In conclusion, nasal NO production is normal in heart failure, except in patients receiving NO‐releasing drugs. Nasal NO concentration could be useful for investigating the mechanism(s) by which exogenous NO donors decrease endogenous NO production.
Drugs interacting with G protein α subunits: selectivity and perspectives
Authors: Chahdi A , Daeffler L , Gies JP , Landry Y
Published: August 2009

Summary— Extracellular signal molecules as diverse as hormones, neurotransmitters and photons use a signal transduction pathway involving a receptor, a G protein and effectors. Compounds that interact directly with G proteins can mimic the receptor‐G protein interaction or can block the activation of G proteins by receptors. Several binding sites exist on the Gα protein that may be exploited for the design of synthetic stimulatory or inhibitory ligands. The effector binding site is regulated by endogenous proteins and appears to be a target for selective exogenous ligands. The GTP binding site presents a large homology within the G protein families and therefore the nucleotide analogs might not be considered as a tool to discriminate between the G protein subclasses. In contrast, different experimental strategies have substantiated the specificity in the interaction between a receptor and a G protein, the receptor binding site of G proteins should be considered as potential drug targets. Drugs interfering with this site such as mastoparan and related peptides, GPAnt‐2 and suramin, are lead compounds in the design of selective G protein antagonists. Benzalkonium chloride and methoctramine have agonist or antagonist properties, depending on G protein subtypes. Such compounds would be very useful to delineate the functions of G proteins and G protein‐coupled receptors, to understand some side effects of drugs used in therapy and to develop new therapeutic agents.
Cardioprotective profile of MET‐88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts
Authors: Asaka N , Muranaka Y , Kirimoto T , Miyake H
Published: August 2009

Summary— 3‐(2,2,2‐trimethylhydrazinium) propionate (MET‐88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts.

Rats were divided into four groups: 1) vehicle control; 2) pretreatment with MET‐88 (MET‐88); 3) application of insulin (500 μU/mL) in the perfusate (insulin); and 4) pretreatment with MET‐88 and application of insulin (MET‐88 + insulin). MET‐88 (100 mg/kg) was orally administered once a day for 10 days until the day before the experiments. Hearts were initially perfused for a 10 min period under normoxia, followed by a 30 min period under hypoxia. Hearts were frozen at the end of hypoxia for the measurement of high‐energy phosphates, carnitine derivatives, and glycolysis intermediates. In a separate series of untreated and MET‐88 treated hearts, exogenous glucose and palmitate oxidation was measured.

MET‐88 decreased the extent of the depression of cardiac contractility (+dP/dt), and aortic flow during the hypoxic state. Insulin also improved cardiac function, and co‐treatment of MET‐88 and insulin additionally improved cardiac function during hypoxia. MET‐88 prevented the decrease of high‐energy phosphate and the increase of long‐chain acylcarnitine after 30 min of hypoxic perfusion. In addition, MET‐88 increased the steady state of glucose oxidation in hypoxic perfused rat hearts. These results indicate that MET‐88 has cardioprotective effects on contractile function and energy metabolism of isolated perfused rat hearts in a hypoxic condition. Preventing the accumulation of long‐chain acylcarnitine may serve to protect hypoxic hearts.
Vitamin E analogues reduce the incidence of ventricular fibrillations and scavenge free radicals
Authors: Walker MK , Vergely C , Lecour S , Abadie C , Maupoil V , Rochette L
Published: August 2009

Summary— The aim of our study was to analyse the protective effects of different α‐tocopherol analogues 1) against fibrillations induced by an ischemia‐reperfusion sequence, and 2) to further investigate in vitro the radical scavenging properties of these analogues by two sensitive methods. Concerning 1: isolated rat hearts underwent 10 min of coronary ligation followed by reperfusion and the α‐tocopherol analogues were infused IS min before occlusion. Functional parameters including heart rate and fibrillations were recorded. Concerning 2: the β‐phycoerythrin assay was utilised to determine the oxygen radical absorbing capacity (ORAC) of these vitamin E analogues against peroxyl radicals. Electron paramagnetic resonance (EPR) was used to measure their scavenger abilities on hydroxyl radical and superoxide anion production. Concerning 1: ventricular fibrillation times were reduced for all analogues treated hearts at concentrations of 1 μM and 5 μM, with Trolox being the most efficacious. Concerning 2: in our experimental conditions of intense production of free radicals, scavenging IC50 values for hydroxyl radical were 1.15, 2.17 and 4.04 mM for Trolox, MDL 74270 and MDL 74366 respectively. Superoxide anion IC50 values were 1.0 and 6.75 mM for Trolox and MDL 74270.

Our results show that water‐soluble analogues of vitamin E are effective in the prevention of coronary ligation induced reperfusion arrhythmia, under our experimental conditions. Moreover, our data demonstrate that these vitamin E analogues are effective scavengers for a variety of radicals. Our studies support the view that compounds that can either inhibit the formation or scavenge free radicals can protect the heart against arrhythmia associated with ischemia‐reperfusion.
Plasma iron status and lipid peroxidation following thrombolytic therapy for acute myocardial infarction
Authors: Cottin Y , Doise JM , Maupoil V , Tannière‐Zeller M , Dalloz F , Maynadié M , Walker MK , Louis P , Carli PM , Wolf JE , Rochette L
Published: August 2009

Summary— Free radical species have been implicated as important agents involved in myocardial ischemic and reperfusion injuries. Superoxide is capable of mobilizing iron from ferritin and the released iron can cause hydroxyl formation from H2O2. The aim of this study was to evaluate the time‐dependent increase in lipid peroxidation assessed by plasma thiobarbituric acid reactive substances (TBARS) and the relationship between lipid‐peroxidation and the iron status. Peripheral venous blood samples were obtained from 17 men with acute myocardial infarction (AMI) before thrombolytic treatment (T0***) and 1, 2, 3, 4, 8, 12, 16, 20, 24 and 48 hours after commencing fibrinolytic treatment. The concentration of TBARS, the parameters of iron metabolism, serum myoglobin, creatine kinase, and creatine kinase‐MB were measured. Early reperfusion was judged by regression of sinus tachycardia (ST) elevation and reduction of chest pain. Recanalization of coronary artery was evaluated by a late coronary angiography 24–96 hours after thrombolysis. After thrombolytic therapy, the TBARS level was raised from 2.98 ± 0.80 (T0***) to 4.57 ± 1.24 (peak), and decreased to 2.96 ± 0.40 nmol/mL plasma at T48 (T0 vs peak: P < 0.001, peak vs T48: P < 0.001, TO vs T48: NS). The mean time of the peak was observed at 9.7 ± 7.5 hours. The iron increased significantly from 0.67 ± 0.34 (T0) to 1.15 ± 0.52 mg/L (peak), and returned to the pre‐reperfusion to levels: 0.53 ± 0.28 UI/L at T48 (T0 vs peak: P < 0.001, peak vs T48: P < 0.001, TO vs T48: NS). The mean time of the peak was observed at 9.4 ± 7.3 hours. In return, no correlation was found between the increase of plasma creatine‐kinase activity, myoglobin and iron or between the biochemical markers and time of fibrinolytic therapy. The results confirmed the importance of the temporal relationship between lipid peroxidation and iron status after thrombolytic therapy. Our results are in agreement with the concept that antioxidant agents used in association with thrombolytic therapy might be useful.
Passage of S‐(+)‐ and R‐(‐)‐ketoprofen across the human isolated perfused placenta
Authors: Lagrange F , Pehourcq F , Bannwarth B , Leng JJ , Saux MC
Published: August 2009

Summary— Ketoprofen is a chiral non‐steroidal anti‐inflammatory drug (NSAID) available as a racemic (rac) mixture of S‐(+)‐ and R‐(‐)‐isomers. Its inhibitory effect on prostaglandin biosynthesis resides virtually in the S‐form. Interestingly, R‐ketoprofen does not undergo substantial metabolic inversion in humans. Though contraindicated during the last trimester of pregnancy, NSAIDs, including ketoprofen, are used as tocolytic agents in some cases. The S/R plasma concentration ratio was reported to average 2.3 in premature neonates whose mothers were given rac‐ketoprofen and to be close to 1 in the maternal plasma. Thus, we investigated the placental transfer of rac‐ketoprofen in vitro using Schneider's perfused human cotyledon model. Glucosed Earle solutions with and without human serum albumin (HSA) were used. Several maternal perfusates were tested with different rac‐ketoprofen concentrations together with 20 mg L−1 of antipyrine as a reference substance. Ketoprofen enantiomers were assayed by a specific HPLC method with derivatization procedure. HSA concentrations in maternal perfusate influenced the placental transfer of ketoprofen enantiomers. In the absence of HSA in the maternal perfusate, the S‐(+)/R‐(‐) concentration ratio was close to 1 in the fetal perfusate. By contrast, this ratio averaged 1.44 after addition of HSA 10 g L−1 on the maternal side. Similar results were found for dialysis experiments using an inert Spectrapor 2 membrane suggesting that the S‐(+)‐free concentration is superior to the R‐(‐)‐free concentration in the presence of HSA. Direct measurements of the free concentrations by centrifugal ultrafiltration confirmed this hypothesis. Accordingly, the data observed in vivo may result, at least in part, from the stereoselective protein binding of ketoprofen.
Anxiogenic‐like effects of Tagetes minuta L essential oil on T‐maze and tonic immobility behaviour in domestic chicks
Authors: Marin RH , Garcia DA , Martijena ID , Zygadlo JA , Arce A , Perillo MA
Published: August 2009

Summary— In a first experiment, four doses (ranging between 0.04 and 0.45 mg/kg of body weight) of the essential oil from Tagetes minuta L. were subcutaneously injected in two‐day‐old chicks and a dose‐response curve assessed for escape performance in a T‐maze test. The 0.1, 0.25 and 0.45 mg/kg doses impaired the first escape performance suggesting an anxiogenic‐like effect of the essential oil. After 3 h the same chicks were tested for a second escape performance, without being injected again, and no differences were observed compared to controls, suggesting that the essential oil did not affect retention. Furthermore, the effects of the essential oil were observed in the three sections of the T‐maze apparatus. So, the performance was impaired in the isolation chamber section, suggesting the induction of increased anxiogenic behaviour, and also in the mirror section, suggesting that the social reinstatement behaviour was modified by an increased anxiety level. Changes in the principal corridor section were not observed, suggesting that the locomotor activity was not affected by these oil doses. The second escape performance was not affected in any of the T‐maze sections, confirming that these doses did not affect learning ability. In a second experiment, a middle dose of the essential oil (0.25 mg/kg) increased the tonic immobility reaction in 15 days old chicks similarly to an anxiogenic dose of FG 7142 (1 mg/kg), while an anxiolytic dose of diazepam (0.08 mg/kg) did not affect this behaviour. Taken together, the present results suggest that the essential oil from Tagetes minuta L. may exert a negative modulation on the GABAergic function without affecting the learning ability.
Calcium antagonists and thiazide diuretics have opposite effects on blood rheology and radial artery compliance in arterial hypertension: A randomized double‐blind study
Authors: Khder Y , des Boscs L Bray , Ghawi R El , Meilhac B , Montestruc F , Stoltz JF , Zannad F
Published: August 2009

Summary— In addition to their effects on blood pressure, antihypertensive agents may produce additional effects on blood rheology and arterial compliance abnormalities which may play a role in target‐organ damage. However, these effects may depend only on the specific pharmacological properties of certain antihypertensive agents, and may be partly unrelated to blood pressure lowering action. We compared the effects of nitrendipine 20 mg once daily to hydrochlorothiazide 25 mg once daily in 33 mildly to moderately hypertensive and otherwise healthy patients, in a double blind parallel group trial. Blood rheology (blood fibrinogen and protein concentrations, hematocrit, plasma viscosity and whole blood viscosity at shear rates 0.2 to 128 s−1, erythrocyte deformability and aggregation) and radial artery diameter and compliance (Nius I + Finapres) were measured at baseline and after 2 months of treatment. Both drugs produced similar blood pressure lowering. Blood viscosity increased for all shear rates in the hydrochlorothiazide group and decreased in the nitrendipine treated group. Erythrocyte deformability increased in the nitrendipine but not in the thiazide group. Radial artery diameter and compliance were not different between the two groups but there was a trend towards an increase in cross‐sectional compliance in the hydrochlorothiazide group and towards a decrease in the nitrendipine group. Our data show that, in mildly hypertensive patients, blood pressure control by nitrendipine produced more favourable effects on relevant rheological variables than hydrochlorothiazide. Radial artery compliance changes tended to be altered also in opposite directions by the two agents. The significance and the clinical relevance of these effects may require further investigations.