bluuebunny/crossref_metadata_2025 huggingface dataset:
Histamine and serotonin released from the rat perfused heart by compound 48/80 or by allergen challenge influence noradrenaline or acetylcholine exocytotic release
Authors: Fuder H. , Ries P. , Schwarz P.
Published: August 2009

Summary—Terminal nerve fibres of the autonomic nervous system closely approach mast cells in peripheral organs, and mutual influences between release of neurotransmitters or mast cell mediators may cause neuro‐immunological interactions. We have studied the influence of mast cell degranulation on the release of endogenous noradrenaline and newly incorporated acetylcholine (such as14C‐choline/acetylcholine overflow) evoked by stimulation of extrinsic postganglionic sympathetic or preganglionic vagal nerves in the rat Langendorff heart perfused with Tyrode solution. Compound 48/80 perfused in normal hearts, or ovalbumin infused into hearts from rats sensitized to ovalbumin, enhanced the overflow of endogenous histamine and serotonin. Both stimuli increased the release of mediators to a similar extent and with fast kinetics. Maximum average concentrations in the perfusate of histamine were about 800 nmol/l, and of serotonin 40 nmol/l, in a sample collected within 4 min after mast cell degranulation. Stimulation of autonomic nerves did not affect basal histamine or serotonin overflow. Whereas basal overflows were unaffected, the stimulation‐evoked releases of both noradrenaline and acetylcholine, were facilitated when compound 48/80 was perfused before and during nerve stimulation. The facilitation of noradrenaline overflow was more pronounced (by 60%) when compound 48/80‐induced mediator overflow started 4 min before nerve stimulation as compared to 30 s (15%), and was reduced by cocaine (by 50%), and, in the presence of cocaine, abolished by cimetidine (but was unaffected by mepyramine and thioperamide) and NG‐nitro‐(L)‐(‐)‐arginine. In the presence of cimetidine and cocaine, when the facilitatory components were abolished, the evoked noradrenaline overflow observed 30 s after the start of infusion of compound 48/80 was inhibited, and the inhibition was partly reduced by methiotepin and ketanserin. Ovalbumin infusion in hearts from sensitized animals caused an inhibition of evoked noradrenaline overflow sensitive to methiotepin and also partly to ketanserin, and no facilitation was observed. The facilitation (> 100%) of evoked overflow of acetylcholine observed at 4 min after the start of perfusion with compound 48/80 was partly reduced by thioperamide (but not mepyramine or cimetidine) and to a comparable extent either by tropisetron (3 μmol/l) alone or by tropisetron plus methiotepin. In conclusion, degranulation of immunological cells is followed by histamine and serotonin release in the rat heart and may affect the release of autonomic neurotransmitters in rather unusual ways, by i) an uptake1‐dependent and ii) an H2‐mediated facilitation which probably involves nitric oxide as a permissive mediator, and iii) a serotonergic inhibition, of noradrenaline release, and iv) an H3‐ and serotonergic facilitation of acetylcholine release.
Clinical application of mefloquine pharmacokinetics in the treatment of P falciparum malaria
Authors: Karbwang J. , Na‐Bangchang K.
Published: August 2009

Summary— Malaria remains a major public health problem in large areas of the world. One of the major factors responsible for the resurgence is the emergence of Plasmodium falciparum, resistant to available antimalarials. An antimalarial, mefloquine, has been considered since its introduction as a promising alternative antimalarial drug to overcome the situation of widespread multidrug resistant P falciparum. Pharmacokinetic studies of mefloquine have been investigated in several groups of subjects either as mefloquine alone or as combined regimens. The oral absorption of mefloquine is relatively rapid, reaching peak concentrations within 24 hours. Metabolism takes place in the liver, with carboxymefloquine as a major metabolite. Mefloquine has a large apparent volume of distribution of 200 L and is highly bound (98%) to plasma proteins. The elimination is slow; the terminal half‐life is 13 10 to 14 days in Thai patients with falciparum malaria. Vomiting within 1 hour of drug administration has an influence on blood concentrations of mefloquine and this may result in treatment failure. The whole blood concentrations of mefloquine on the first two days of treatment are important determinants of parasitological response. There appear to be no pharmacokinetic interactions between mefloquine and the other two components of FansimefR in patients with uncomplicated falciparum malaria. The advantage of this combination over mefloquine alone in multidrug resistant P falciparum is still debatable. However, recent data seem to support the higher efficacy of FansimefR over mefloquine alone. Concurrent administration of antibiotics, ie ampicillin and tetracycline with mefloquine results in a significant increase in maximum concentration, reduction of the apparent volume of distribution and shortening of the terminal elimination half‐life of mefloquine. An antiemetic drug metoclopramide accelerates the absorption of mefloquine and increases the maximum concentration. In contrast, mefloquine concentrations are decreased in the presence of an antimalarial, artesunate. Primaquine has no effect on the pharmacokinetics of mefloquine when given concurrently.
Effects of oxodipine and elgodipine on (+)‐[3H]‐isradipine binding to cardiac and vascular membranes: cardiovascular selectivity
Authors: Rakotoarisoa L. , Leprêtre N. , Mironneau J. , Galiano A. , Mironneau C.
Published: August 2009

Summary—We studied the effects of six dihydropyridines on the specific binding of (+)‐[3H]‐isradipine to vascular (portal vein) and cardiac isolated membranes to achieve the relative cardiovascular selectivity of these compounds. Elgodipine, (+)‐oxodipine and nifedipine had a significantly higher affinity for the vascular L‐type calcium channel than for the cardiac calcium channel while nicardipine showed opposite properties. The other dihydropyridines (nitrendipine and (+)‐isradipine) had similar affinities for the cardiac and vascular calcium channels. As the membrane potential of isolated membranes is about 0 mV, these results suggest that the differences in binding of these dihydropyridines to L‐type calcium channels in vascular and cardiac cells may be attributed to differences in the molecular structure of these calcium channels.
Gallium chloride effects on neonatal rat heart cells in culture, in standard and oxidative conditions
Authors: Leperre A. , Millart H. , Prévost A. , Kantelip JP , Lamiable D. , Collery P.
Published: August 2009

Summary—The effects of gallium chloride (GaCl3) at 7.17, 28.68 and 114.7 μm (0.5, 2 and 8 mg/l of Ga3+) were checked in cardiac cells derived from 2–4 day‐old newborn rats, cultured for 72 h in Eagle's minimum essential medium (MEM), enriched with 10% foetal calf serum (v/v) and 2 mM of glutamine at 37°sC, with 95% air plus 5% CO2. After 3 hours of standard culture conditions (MEM with glucose 5 mM), Ga treatment induced an increase of glycogen stores without any influence on ATP, ADP, and AMP concentrations. A slight and transient decrease in the beat rate was noted after 15 min of exposure to GaCl3at all concentrations, whereas there was no difference in the beat rate nor in the cell contraction amplitude after 3 hours of exposure. After 1.5 h in conditions of oxidation (Tyrode solution without glucose, FeCl220 μM, ascorbic acid 0.2 mM), GaCl3at 8 mg/l decreased the malondialdehyde (MDA) production as assessed by the decrease of intracellular concentrations and the decrease of its release in the supernatant. The decreased MDA production following oxidative stress, the increase in glycogen stores in normal oxygen concentrations, as well as the maintenance of ATP concentrations and the lack of any chronotropic effect induced by GaCl3suggests a protective rather than a deleterious cardiac effect.
Central analgesic effects of aspirin‐like drugs
Authors: Bannwarth B. , Demotes‐Mainard F. , Schaeverbeke T. , Labat L. , Dehais J.
Published: August 2009

Summary—Aspirin‐like drugs mainly include paracetamol, salicylates and other non‐steroidal anti‐inflammatory drugs, and metamizole. Their analgesic effect is classically ascribed to a peripheral site of action, within the pain‐processing site. There is, however, convincing evidence that a central component contributes to the overall analgesia provided by these agents. Experimental and clinical studies referring to this challenging proposal are reviewed here. The exact site and mode of action of aspirin‐like drugs within the central nervous system remains controversial. It is likely that supraspinal mechanisms play an important role. Some experiments lend support to the involvement of monoaminergic control systems. Other data indicate that these drugs act centrally through the inhibition of cyclo‐oxygenase activity. The interactions between prostaglandins and various neurotransmitters suggest that both mechanisms may be linked.
Prevention of restenosis after coronary angioplasty: towards a molecular approach?
Authors: Feldman LJ , Riessen R. , Steg PG
Published: August 2009

Summary— Restenosis after coronary angioplasty, the main limitation of interventional cardiology, remains an unsolved issue. The failure to‐date of all pharmacological attemps at prevention has prompted the development of alternative strategies. A mechanistic approach to the problem of restenosis is based on the assumption that creating a more satisfactory acute angioplasty result would reduce the development of restenosis. With the exception of coronary stenting, however, none of the new angioplasty devices have convincingly reached this goal. Furthermore, recent advances in the field of vascular biology have opened new avenues for a molecular approach of restenosis. Better understanding of the pathophysiology of restenosis, in conjunction with high‐pace development of catheter, polymer, and virus technologies, provide opportunities to deliver agents — drugs, genes, or antisense oligonucleotides — locally, at the site of angioplasty to interfere specifically with the restenosis process. Some of these molecular strategies are currently being investigated in animal models. Clinical application of a molecular approach to prevent restenosis, however, will require close collaboration between physicians, molecular biologists, and bio‐engineers.
Effects of losartan on short‐term variability of blood pressure in SHR and WKY rats*
Authors: Gaudet E. , Blanc J. , Elghozi JL
Published: August 2009

Summary— Objective: to examine the effect of losartan on short‐term variability of blood pressure (BP) in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. Design and methods: variability of BP was characterized during baseline condition and 20 minutes after blocking the renin‐angiotensin system (RAS) with the ATI receptor antagonist losartan (10 mg/kg, iv). A Fast Fourier Transform algorithm was used for analysis. Results: under baseline conditions, SHR exhibited enhanced variability of BP compared to WKY, reflected by increased standard deviation (SD) of systolic BP (SBP). On the other hand, the mid frequency (0.2–0.6 Hz, MF) and the low frequency (0.02–0.2 Hz, LF) components of SBP were exaggerated. Enhanced MF area probably reflected a hyperactivity of the sympathetic nervous system in SHR. After a single injection of losartan, the mean BP was lowered in SHR by 13 ± 5 mmHg, mean ± SEM, P < 0.05). In WKY, losartan solely decreased the LF component of BP. In SHR, losartan increased the MF component of BP. Conclusion: losartan resulted in differential effects on BP variability in the two strains. In WKY, the RAS contributed to the genesis of LF fluctuations. In SHR, the increase in the MF component of BP after losartan probably indicated a reflex sympathetic activation triggered by vasodilation.
Endothelial and smooth muscle properties of coronary and mesenteric resistance arteries in spontaneously hypertensive rats compared to WKY rats
Authors: Pourageaud F. , Freslon JL
Published: August 2009

Summary— To investigate if the functional alterations observed in resistance arteries of spontaneously hypertensive rats (SHRs) were also present at the coronary level, in vitro experiments were performed in mesenteric resistance arteries (MRA) and in right (RIC) and left interventricular coronary (LIC) arteries taken from 15–25‐week‐old SHR and age‐matched Wistar Kyoto rats WKYs. Using a passive extension protocol, internal diameters corresponding to 100 mmHg intraluminal pressure (D100) were determined and vessels were set up to a normalized internal diameter (0.9 D100). SHR mesenteric resistance arteries had a significantly smaller diameter compared to WKY arteries, whereas both types of SHR coronary arteries had a greater diameter compared to those of WKY rats. In arteries in the absence of contracting agonist, nitro‐L‐arginine (NOLA, 100 μM) induced a progressive rise in basal tone, which could be reversed by subsequent addition of L‐arginine (100 μM) but not D‐arginine (100 μM). When expressed as percent of maximal contractions induced by agonists (noradrenaline, NA [10 μM] in MRA; serotonin, 5‐HT [10 μM], in RIC and LIC), these contractions were significantly stronger in WKY compared to SHR coronary and mesenteric resistance arteries. In NA‐precontracted MRA and 5HT‐precontracted coronary arteries in the presence of indomethacin (10 μM), the magnitude of acetylcholine‐induced maximal relaxations (expressed as percent of maximal contractions induced by agonists) was greater in WKY compared to SHR arteries. After a 30‐min incubation period, NOLA (100 μM) completely inhibited relaxations induced by acetylcholine (0.01–10 μM) in all types of precontracted arteries. Subsequent additions of sodium nitroprusside, (SNP, 10 μM) induced complete relaxations in all preparations. These results show that a basal release of NO or NO‐like compound by endothelial cells is present in isolated mesenteric resistance and coronary arteries of WKY rats and SHRs. The contribution of endothelium‐derived relaxing factor‐nitric oxide (EDRF‐NO) to arterial tone was lower in MRA compared to coronary arteries in both strains and in SHR compared to WKY arteries. In the SHR preparations, the impaired relaxation induced by acetylcholine appeared to be due to a functional alteration of the endothelium in the presence of normal reactivity of the smooth muscle cells.
Population pharmacokinetics of amikacin in intensive care unit patients studied by NPEM algorithm
Authors: Debord J. , Pessis C. , Voultoury JC , Marquet P. , Lotfi H. , Merle L. , Lachâtre G.
Published: August 2009

Summary— The population pharmacokinetics of amikacin was studied in 40 intensive care unit patients (212 plasma concentrations) by NPEM algorithm using a one‐compartment model. The population was best characterized by the following pharmacokinetic parameters: renal clearance relative to creatinine clearance (Cs = 0.96 ± 0.33), and either the total volume of distribution (Vd = 23.9 ± 7.0 I) or the volume of distribution relative to body weight (Vs = 0.36 ± 0.10 1·kg−1. The volume of distribution was increased with respect to the usual value of 0.25 1·kg−1. The statistical distribution of these pharmacokinetic parameters was approximately gaussian, with no significant correlation between volume of distribution and clearance. The medians and standard deviations of Cs and Vs were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 29 patients by the bayesian method, with two blood samples per patient. For each patient, the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 h with no significant bias and good precision (2.9 mg·1−1 for peaks and 0.5 mg·1−1 for troughs). This study confirms the ability of the NPEM algorithm to provide reference population values for use in bayesian monitoring of aminoglycoside therapy.
Molecular pharmacology of somatostatin receptors
Authors: Viollet C. , Prévost G. , Maubert E. , Faivre‐Bauman A. , Gardette R. , Kordon C. , Loudes C. , Slama A. , Epelbaum J.
Published: August 2009

Summary—Somatostatin was discovered for its ability to inhibit growth hormone (GH) secretion. Later, it was found to be widely distributed in other brain regions, in which it fulfills a neuromodulatory role, and in several organs of the gastrointestinal tract where it can act as a paracrine factor or as a true circulating factor. In mammals, two molecules of 14 (somatostatin 14) and 28 (somatostatin 28) amino acids are the only biologically active members of the family. They originate from a single gene which gives rise to a single propeptide alternately cleaved in different tissues. In 1992, a major breaktrough in our understanding of somatostatin functions was made with the cloning of five different receptor genes (sstr1 tosstr5) which belong to the seven transmembrane domain receptor family. Their closer relatives are opioid receptors. In first approximation, the tissular expression of thesstrsmatches quite well with the distribution of somatostatin binding sites in the “classical” targets of the peptideiebrain, pituitary pancreatic islets and adrenals. The pharmacology of GH inhibition is very close tosstr2 binding but other actions of somatostatins have not yet been attributed clearly to a single receptor subtype. All clinically relevant agonists tested so far (octreotide, lanreotide and vapreotide) are selective ofsstr2 being less potent onsstr3 and inactive forsstr1 andsstr4. Surprisingly, ratsstr5 displays nanomolar affinities for octreotide and vapreotide while these agonists are only active at much higher concentrations on humansstr5. All five receptors can be more or less efficiently coupled to inhibition of adenylate cyclase activity in transfected cell systems. However, the transduction of somatostatin antisecretory and antiproliferative actions through multiple intracellular effectors and their relation to the diversity of the receptors remain to be established as yet.
In vitropharmacological characterization of UP 269‐6, a novel nonpeptide angiotensin II receptor antagonist
Authors: Caussade F. , Virone‐Oddos A. , Delchambre C. , Cazes M. , Versigny A. , Cloarec A.
Published: August 2009

Summary—Thein vitropharmacology of UP 269‐6, a novel nonpeptide angiotensin II antagonist, was examined in radioligand binding and functional isolated tissue assays. UP 269‐6 bound selectively to AT1receptors as evidenced by the inhibition of specific [125I] Sar1, Ile8‐AII binding in rat adrenal membranes (IC50= 35.8 nM) and in cultured vascular smooth muscle cells (IC50= 23.8 nM). UP 269‐6 displayed a very high selectivity for the AT1compared to the AT2receptor subtype (IC50> 10,000 nM). UP 269‐6 inhibited the AII‐induced contraction of isolated rabbit aortic strips. The pattern of AII antagonism suggested competitive antagonism at low concentrations (10−10, 3 × 10−10, 10−9M) of UP 269‐6 and insurmountable antagonism at higher concentrations (3 × 10−9, 10−8, 3 × 10−8M). Based on the calculatedpA2values, UP 269‐6 (9.86 ± 0.25) was an angiotensin II receptor antagonist as potent as L‐158,809 (9.82 ± 0.37) and much more potent than losartan (7.96 ± 0.38). UP 269‐6 was devoid of affinity (IC50> 10,000 nM) for many other receptors, ion channels and uptake sites, demonstrating its high specificity for AII receptors. Furthermore, this compound did not affect the contractile response to KCl or phenylephrine in rabbit aorta and exhibited no effect on angiotensin converting enzyme activity. These data demonstrate that UP 269‐6 is a highly potent, selective and specific AT1receptor antagonist.
Analgesic effect of the direct D2dopamine receptor agonist RU 24926 and cross tolerance with morphine
Authors: Suaudeau C. , Costentin J.
Published: August 2009

Summary—The direct D2dopamine receptor agonist RU 24926, administered subcutaneously to mice, elicited, starting at the dose of 0.125 mg/kg, a dose dependent analgesic effect, assessed as the jump latency from a hot plate (55°C). The analgesic effect induced by 0.25 mg/kg RU 24926 was dose dependently antagonized by the preferential D2dopamine receptor antagonist haloperidol (ID50= 15.1 ± 3.3 μg/kg sc) as well as by the opioid receptor antagonist naloxone (ID50= 0.59 ± 0.17 mg/kg sc). The reversion of RU 24926‐induced analgesia by naloxone was not accompanied by a reversion of hypothermia. Semi‐chronic administration of RU 24926 (2.5 mg/kg, sc, 3 times a day for 3 days) completely desensitized to the analgesic effect induced by a 0.25 mg/kg test dose of RU 24926 and partially reduced the analgesic effect of low doses of morphine (0.5, 1, 1.5 mg/kg). Conversely, semi‐chronic administration of morphine (32 mg/kg sc, twice daily for 4 days) completely desensitized the analgesic effect induced by a 2 mg/kg test dose of morphine and partially reduced the analgesic effect of RU 24926 (0.25, 0.5 and 1 mg/kg). The RU 24926‐induced analgesia did not seem to be the nonspecific consequence of its hypothermic effect since: i) the time course of hypothermia was shorter than that of analgesia, ii) the analgesic effect was observed in inbred C3H mice which have a low sensitivity to the hypothermic effect of direct agonists of D2dopamine receptors and iii) in mice semi‐chronically treated with morphine and thereby made tolerant to the RU 24926‐induced analgesia, the hypothermic effect of RU 24926 was found unchanged. It is suggested that the stimulation of D2dopamine receptors, without obvious link with the resultant hypothermia, releases an opioid material which induces analgesia.
Acute hemodynamic effects of combined inhibition of neutral endopeptidase and angiotensin converting enzyme in spontaneously hypertensive rats
Authors: Pham I. , Lévy B. , Fournié‐Zaluski MC , Poitevin P. , Roques BP , Michel JB
Published: August 2009

Summary—Neutral endopeptidase inhibitors (NEPI) potentiate the hypotensive effect of converting enzyme inhibitors (CEI) in conscious spontaneously hypertensive rats (SHR) but the mechanism of this potentiation remains unknown. The present study assesses the hemodynamic effects of a CEI (enalaprilat 1 mg/kg;n= 9), a NEPI (retrothiorphan 25 mg/kg + 25 mg/kg/h;n= 9) and the combination (CEI + NEPI;n= 9)versusa control group (n= 9) in anesthetized spontaneously hypertensive rats. CEI alone induced a significant hypotensive effect due to a decrease (–35.1%) in total peripheral resistance (TPR), with no significant increase in cardiac output (CO). NEPI alone had a slight hypotensive effect due to a small decrease in CO. CEI + NEPI decreased the mean arterial pressure to the same extent (–26.7%) as the CEI‐induced hypotensive effect, decreased TPR (–44.4%) and induced an increase in CO (+ 38.2%) with an increase in heart rate. In summary, NEPI combined with CEI induces large decreases in blood pressure and in TPR which do not significantly differ from the CEI‐induced effects. It also induces increases in heart rate and in cardiac output in anesthetized SHR.
Effect of Na+ reduction and monensin on ion content and contractile response in normoxic and ischaemic reperfused rat hearts
Authors: van den Ende R. , Guttmann I. , Scheufler E. , Pfaffendorf M. , van Zwieten PA
Published: August 2009

Summary—The possibility was explored whether the functional properties of Na+/Ca2+exchange are altered after ischaemia, thereby contributing to the elevated intracellular (i) Ca2+levels in ischaemic reperfused hearts. The intracellular Na+, K+ and Ca2+contents in rat Langendorff heart preparations were determined by atomic absorption spectrometry under normoxic conditions, after ischaemia (30 min) and after ischaemia (30 min) plus reperfusion (30 min). In addition, the influence of modulating the Na+ gradient (Na+o/Na+i) across the sarcolemma was studied with respect to cardiac contractility and intracellular ion content. This was done by either decreasing extracellular (o) Na+ or by increasing Na+iwith monensin, both in normoxic and reperfused hearts. Both Na+oreduction and monensin led to an increase in contractility and coronary flow, an effect which was nearly abolished in reperfused hearts. Under normoxic conditions the intracellular ion contents amounted to Na+ = 12.4 ± 0.4, K+ = 99.0 ± 3.1 and Ca2+= 0.64 ± 0.02 mmol/kg cell (means ± SEM,n= 7). In normoxic hearts, lowering Na+oreduced and monensin increased Na+i, thereby both leading to a decrease in Na+ gradient; no effect on total Ca2+icontent was observed. Na+iincreased twofold after ischaemia as compared to the normoxic situation, an effect which was aggravated (4 fold increase) in reperfused hearts. The opposite effects were observed for K+iwith a 25% decrease after ischaemia and a 40% decrease in reperfused hearts. Only after ischaemia plus reperfusion was Ca2+iincreased (6 fold). In reperfused hearts, lowering Na+oagain reduced and monensin increased Na+i, whereas a further rise in Ca2+iwas now observed depending on the Na+ gradient across the sarcolemma: the larger the drop in Na+ gradient, the more pronounced the increase in Ca2+iin the reperfused heart. We conclude that the Ca2+iincrease in reperfused hearts can be modulated by changing the Na+ gradient across the sarcolemma. This suggests that inhibited or reversed Na+/Ca2+exchange is predominantly responsible for the rise in Ca2+iin ischaemic hearts that are subjected to reperfusion.
The effect of LU‐49938 (nexopamil) on the activation by serotonin of mesangial cells
Authors: Montero A. , Rodríguez‐López A. , Reverte M. , López‐Novoa JM
Published: August 2009

Summary— Intraglomerular platelet activation may release vasoactive agents such as serotonin (5‐hydroxytryptamine, 5‐HT) that may affect local hemodynamics and promote mesangial proliferation, eventually leading to glomerular sclerosis. The main purpose of this study is to analyze whether nexopamil, a verapamil derivative, with the property of blocking simultaneously calcium channels and 5‐HT2 receptors, could modify the contractile and mitogenic effects of serotonin on cultured rat mesangial cells. Serotonin caused a concentration‐dependent increase in [3H]thymidine incorporation into DNA, and mesangial cell proliferation. The effects of 5‐HT on thymidine uptake and cell proliferation were blocked by the selective 5‐HT2 receptor blocker ketanserin 10−5 M. Nexopamil abolished in a concentration‐dependent way the serotonin‐induced [3H]thymidine incorporation into DNA, and the serotonin‐induced increase in number of cells. Using 5‐HT 10−4 or 10−5 M, nexopamil had significant effects at concentration above 10−7 M. Serotonin induced a concentration‐ and time‐dependent reduction of planar cell surface area. This effect was also completely blocked by ketanserin. Nexopamil partially blocked the serotonin‐induced mesangial cell contraction, in a dose‐dependent manner. All these data suggest that nexopamil inhibits both 5‐HT‐induced mesangial cell contraction and proliferation by blocking 5‐HT2 receptors and the voltage‐operated Ca2+ channels.
Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha2‐adrenoceptor antagonist*
Authors: Bagheri H. , Chale JJ , Guyen LN , Tran MA , Berlan M. , Montastruc JL
Published: August 2009

Summary—Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha2‐adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha2‐adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino‐metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the β‐adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mgṁkg−1, iv) increased within 5–15 minutes, plasma noradrenaline (600%), insulin levels (300%), free‐fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mgṁkg−1, iv) suppressed yohimbine‐induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free‐fatty acids (102%) plasma levels. Administration of nadolol (1 mgṁkg−1, iv) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free‐fatty acids (4%) plasma levels. These results show that yohimbine‐induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone. Thus, blockade of alpha2‐adrenoceptors induced a simultaneous activation of adrenergic and cholinergic systems. This pattern can explain the spectrum of side effects observed with yohimbine in man and suggests new potential clinical uses for alpha2‐adrenoceptor antagonists.
Ontogeny of the cell outward dopamine transporter in canine renal tissues
Authors: Soares‐da‐Silva P. , Vieira‐Coelho MA , Pestana M. , Fernandes MH , Guimarães JT
Published: August 2009

Summary—The present work has determined the activities of aromatic L‐amino acid decarboxylase (AAAD) and evaluated the presence of an active transport system for dopamine in renal tissues of developing dogs (newborn puppies less than 24 hours after birth, animals at the age of 10 days and 2 months) and adult animals. AAAD activity (Vmax, in pmol/mg protein/h) as determined in kidney homogenates was found to be in the adult dog kidney (Vmax= 3216 ± 268) higher (p< 0.05) than that occurring in the three other groups of animals; no significant difference on AAAD activity was observed between the 10 day‐old (Vmax= 1139 ± 185) and the 2 month‐old dogs (Vmax= 783 ± 23). AAAD activity in newborn puppies (Vmax= 259 ± 40) was markedly lower than in the three other groups. A considerable amount of the total dopamine formed from added L‐DOPA in kidney slices, depending on the age, was found to escape into the incubation medium. The application of the Michaelis‐Menten equation to the net transport of newly‐formed dopamine has allowed the identification of a saturable (carrier‐mediated transfer) and a non‐saturable component (diffusion). The Vmax(nmol/g/15 min), Km(μM) values for the saturable component and diffusion constant (μmol−1) were as follows: adult (Vmax= 112 ± 16; Km= 319 ± 35; diffusion constant = 0.0009 ± 0.0001), 2 month‐old (Vmax= 19 ± 5; Km= 48 ± 14; diffusion constant = 0.0007 ± 0.0002), 10 day‐old (Vmax= 25 ± 3; Km= 69 ± 20; diffusion constant = 0.0033 ± 0.0007) and newborn (Vmax= 6 ± 1; Km= 16 ± 6; diffusion constant = 0.0095 ± 0.0010). In conclusion, renal AAAD develops with age, though some AAAD activity can already be detected at birth. The dopamine outward transporter appears to be considerably immature at birth, but undergoes rapid maturation within the next 10 days; however, development of AAAD and of the renal dopamine outward transporter still proceedes from the age of 2 months until adulthood.
Sudden infant death syndrome and diphtheria‐tetanus‐pertussis‐poliomyelitis vaccination status
Authors: Jonville‐Bera AP , Autret E. , Laugier J.
Published: August 2009

Summary— Because diphtheria, tetanus, pertussis and poliomyelitis vaccine is routinely given during the period of highest incidence of sudden infant death syndrome (SIDS), we carried out a retrospective case‐control study to assess whether such vaccination increased the risk of SIDS. The vaccination status of 118 SIDS and 332 control children, matched for sex, date of birth and age of the victims at death, was compared: the victims of SIDS were not significantly more often vaccinated than control children, the odds ratio was estimated at 1.9 with a 95% confidence interval from 0.9 to 3.9. There was a statistical difference between vaccination status of SIDS cases and controls aged less than three months. Nine percent of SIDS cases under 3 months had been vaccinated whereas the matched controls had not. In our study DTCP vaccination was not a risk factor for SIDS; although more of the SIDS infants less than 3 months of age had been vaccinated. This result however, concerns only one subgroup of the population studied and needs to be confirmed with another study of only SIDS infants less than 3 months of age, because DTCP vaccination was not a risk factor for SIDS when considering the total sample of the study.
Nitric oxide and the control of renin secretion
Authors: Reid IA , Chiu YJ
Published: August 2009

Summary—Research during recent years has established nitric oxide as a unique signaling molecule that plays important roles in the regulation of the cardiovascular, nervous, renal, immune and other systems. Nitric oxide has also been implicated in the control of the secretion of hormones by the pancreas, hypothalamus, pituitary and other endocrine glands, and evidence is accumulating that it contributes to the regulation of the secretion of renin by the kidneys. The enzyme nitric oxide synthetase is present in vascular and tubular elements of the kidney, particularly in cells of themacula densa, a structure that plays an important role in the control of renin secretion. Guanylyl cyclase, a major target for nitric oxide, is also present in the kidney and is responsive to changes in nitric oxide levels. Drugs that inhibit nitric oxide synthesis generally suppress renin releasein vivoandin vitro, suggesting a stimulatory role for the L‐arginine‐nitric oxide pathway in the control of renin secretion. Under some conditions, however, blockade of nitric oxide synthesis increases renin secretion. Recent studies indicate that nitric oxide not only contributes to the regulation of basal renin secretion, but also participates in the renin secretory responses to activation of the renal baroreceptor,macula densaand beta adrenoceptor mechanisms that regulate renin secretion. Future research should clarify the mechanisms by which nitric oxide regulates the secretion of renin and establish the physiological significance of this regulation.
Differential activation of β1‐, β2‐ and β3‐adrenoceptors by catecholamines in white and brown adipocytes
Authors: Galitzky J. , Carpéné C. , Bousquet‐Mélou A. , Berlan M. , Lafontan M.
Published: August 2009

Summary—This review summarizes the experiments performed by various groups to determine how the activation of the different β‐adrenoceptors (β‐ARs) is ordinated when they are present in the same fat cell and involved in the same biological event. When expressed after the transfection of their genes in Chinese hamster ovary cell (CHO cells), β1‐ and β2‐ARs present a higher affinity for catecholamines than β3‐ARs.In vitro, the lipolytic effect induced by low concentrations of catecholamines in dog and rat white fat cells is due to the selective activation of β1‐ and/or β2‐ARs. Higher concentrations only are able to activate β3‐ARs. Similar results have been obtained in rat brown adipocytes. On the other hand, the lipolytic effect of catecholamines in human and primate adipocytes does not involve a β3‐AR component whatever the concentration used.In vivoexperiments in the dog have also shown that lipomobilization induced by low doses of isoprenaline only involved β1‐ and β2‐AR activation, this effect being blocked by β1‐/ β2‐antagonist pretreatment. However, in the same blockade conditions, perfusion of a 10‐fold higher dose of isoprenaline revealed a β3‐AR contribution in the lipomobilizing effect. These data showed that brown and white adipocyte β3‐ARs possess a lower affinity for catecholamines than β1‐ and β2‐ARs and are only recruited by high concentrations of the amines. Thus, even if the β3‐AR plays an indisputable role in the white and brown adipose tissue of some species, its physiological status and its expression are still subject to debate in human white fat cells.
How good are volunteers at searching for published randomized controlled trials?
Authors: Moher D. ,   The OSTR Collaborative Group
Published: August 2009

Summary— The Ottawa Stroke Trials Registry (OSTR) collects information on all randomized controlled trials (RCTs), in all languages, in which the primary focus is stroke. Published trials are added to the registry database once they have been identified by volunteers hand searching journals. We undertook this study to assess volunteer sensitivity, specificity, positive and negative predictive values, accuracy and reliability in identifying RCTs. Three volunteers participated in this study. The complete contents of five years of one journal were searched (n = 240) as were ten research reports from five journals. Volunteer sensitivity, specificity, positive and negative predictive values, and accuracy was 89.5%, 100%, 100%, 99.1%, and 99% respectively. Inter volunteer reliability was 0.87. Searching the published literature to identify RCTs is an enormous task. These results indicate that volunteers, with minimal training, can effectively contribute to this endeavour.
A meta‐analysis of randomized, double‐blind, placebo‐controlled studies of the effect of buflomedil on intermittent claudication
Authors: Walker GA , Hannaford JC Mac
Published: August 2009

Summary— A meta‐analysis was performed on the results of clinical trials of buflomedil in intermittent claudication. The analysis used results from 744 patients enrolled in ten studies, conducted at 42 centers in seven countries. All studies were randomized, double‐blind, placebo‐controled trials which measured improvement in “pain‐free” walking distance by treadmill ergometry as the primary measure of efficacy. The meta‐analysis results were based on “effect size”, a standardized difference in mean response between buflomedil and placebo. Results demonstrated a statistically superior response to buflomedil compared with placebo, indicating that the average buflomedil treated patient was likely to have a greater improvement in walking distance than at least 60% of the placebo treated patients. Results were corroborated using various weighting schemes proportional to study quality ratings and sample sizes.
Opioid and anti‐opioid peptides
Authors: Cesselin F.
Published: August 2009

Summary— The numerous endogenous opioid peptides (β‐endorphin, enkephalins, dynorphins…) and the exogenous opioids (such as morphine) exert their effects through the activation of receptors belonging to four main types: μ, Δ, k and ε. Opioidergic neurones and opioid receptors are largely distributed centrally and peripherally. It is thus not surprising that opioids have numerous pharmacological effects and that endogenous opioids are thought to be involved in the physiological control of various functions, among which nociception is particularly emphasized. Some opioid targets may be components of homeostatic systems tending to reduce the effects of opioids. “Anti‐opioid” properties have been attributed to various peptides, especially cholecystokinin (CCK), neuropeptide FF (NPFF) and melanocyte inhibiting factor (MIF)‐related peptides. In addition, a particular place should be attributed, paradoxically, to opioid peptides themselves among the anti‐opioid peptides. These peptides can oppose some of the acute effects of opioids, and a hyperactivation of anti‐opioid peptidergic neurones due to the chronic administration of opioids may be involved in the development of opioid tolerance and/or dependence. In fact, CCK, NPFF and the MIF family of peptides have complex properties and can act as opioid‐like as well as anti‐opioid peptides. Thus, “opioid modulating peptides” would be a better term to designate these peptides, which probably participate, together with the opioid systems, in multiple feed‐back loops for the maintenance of homeostasis. “Opioid modulating peptides” have generally been shown to act through the activation of their own receptors. For example, CCK appears to exert its anti‐opioid actions mainly through the activation of CCK‐B receptors, whereas its opioid‐like effects seem to result from the stimulation of CCK‐A receptors. However, the partial agonistic properties at opioid receptors of some MIF‐related peptides very likely contribute to their ability to modulate the effects of opioids. CCK‐ and NPFF‐related drugs have potential therapeutic interest as adjuncts to opioids for alleviating pain and/or for the treatment of opioid abuse.
Mechanisms of substance P‐induced pulmonary oedema in the rabbit: interactions between parasympathetic and excitatory NANC nerves
Authors: Delaunois A. , Gusti P. , Ansay M.
Published: August 2009

Summary— The pharmacological mechanisms involved in the substance P (SP)‐induced pulmonary oedema were studied in isolated perfused rabbit lungs. Substance P induced a dose‐dependent increase in the capillary filtration coefficient (Kf,c), responsible for oedema. Atropine, hemicholinium‐3 and ruthenium red pretreatment partly protected the lungs against SP effects, while tetrodotoxin and hexamethonium did not significantly modify them. (±)CP96,345, a NK1 receptor antagonist, completely inhibited the SP‐induced increase in the Kf,c. Like SP, acetylcholine (ACh) and capsaicin also increased the Kf,c. Atropine and (±)CP96,345 completely blocked the oedema induced by both drugs. Tetrodotoxin and ruthenium red strongly inhibited the response to capsaicin and acetylcholine. It was concluded that SP‐induced pulmonary oedema is in part mediated by a stimulating action on cholinergic efferent nerves, with subsequent release of endogenous acetylcholine. Acetylcholine can, in turn, stimulate the release of SP from excitatory non adrenergic, non cholinergic nerves. The effects induced by capsaicin and exogenous acetylcholine, thus endogenous SP, involve tetrodotoxin‐sensitive mechanisms, while those produced by exogenous SP are tetrodotoxin‐resistant.
Restoration of brain protein synthesis in mature and aged rats by a DA agonist, piribedil
Authors: Bustany P. , Trenque T. , Crambes O. , Moulin M.
Published: August 2009

Summary—Brain ageing affects numerous cerebral metabolic pathways such as cerebral glucose consumption or protein synthesis rate. The pharmacological effect of a mixed D1‐D2dopaminergic agonist, piribedil, on this last metabolism is reported. Cerebral Protein Synthesis Rate (CPSR) was measured by the [35S]L‐methionine autoradiographic procedure in 38 main brain regions of 11 and 26‐month‐old Wistar rats after a 2‐month treatment per os at 9 and 30 mg/kg/day with piribedil. Mean decrease of CPSR was −21% during the 15‐month ageing we followed, with important local variations. Mean CPSR increased with the two treatments, +25% in mature and +35% in aged rats. Treatments restored CPSR of aged rats to the exact mature subjects levels in quite all the brain regions. No dose‐effect or asymetrical modification was statistically revealed for the two treatments. Metabolic increases involved particularly central brain gray structures, especially some DA‐targeted brain nuclei concerned with behaviour and learning. This effect argued for a general metabotrophic effect of D1‐D2dopamine stimulation of the brain. The original pattern of local ageing of brain protein synthesis in rat was also incidentally reported. This was the first direct report of a wide and effective metabolic activation of CPSR in the brain during ageing by a curative dopaminergic agonist treatment.
Are vasopressin peripheral V1 receptors involved in the development of malignant hypertension and stroke in SHR‐SPs?
Authors: Vacher E. , Richer C. , Cazaubon C. , Fornes P. , Nisato D. , Giudicelli JF
Published: August 2009

Summary— The aim of this study was to determine whether activation of vasopressin (AVP) peripheral V1 receptors is involved in the development of malignant hypertension, stroke, and end‐organ damage in stroke‐prone spontaneously hypertensive rats (SHR‐SPs). For this purpose, young salt‐loaded SHR‐SPs were treated orally daily from their 5th to 34th week of age, by a selective AVP V1 receptor antagonist, SR 49059, used in a dose (30 mg/kg) that achieved complete peripheral V1 receptor blockade. Untreated SHR‐SPs served as controls. SR 49059 slightly and transiently (8th to 10th week of age) limited the rise in blood pressure, but thereafter systolic blood pressure values were similar in the two groups of SHR‐SPs. Stroke‐related mortality was not significantly different in SR 49059‐treated and in control animals (65% vs 65% at 30 weeks, 65% vs 83% at 34 weeks). SR 49059 did not prevent the increases in fluid intake, diuresis and proteinuria seen in controls. Histological examination of the brain, kidneys and heart revealed that the development of fibrinoid necrosis and arterial thickening was not prevented by SR 49059, nor was that of malignant nephroangiosclerosis and of myocardial infarction and fibrosis. These data strongly suggest that AVP peripheral V1 receptor activation is not involved in the pathological processes that develop in SHR‐SPs.
Is there a relationship between antipsychotic blood levels and their clinical efficacy? An analysis of studies design and methodology
Authors: de Oliveira IR , Dardennes RM , Amorim ES , Diquet B. , de Sena EP , Moreira EC , de Castro‐e‐Silva EJ , Payan C. , Fermanian J. , Marcílio C. , Samuel‐Lajeunesse B.
Published: August 2009

Summary— There are now more than 50 studies concerning neuroleptic blood levels and clinical outcome relationships. Haloperidol, the most studied, is the only antipsychotic permitting some conclusions. A number of authors suggest that the striking lack of agreement between different studies results from heterogeneity of their quality. Here, we have used a scoring system for assessing the quality of those studies. According to this system, none (0/14) of the studies having a score <0.60 was able to show a therapeutic window, as compared to 53% (10/19) of those having a score ≥0.60 (p = 0.002, Fisher exact test). Also, the studies able to identify the presence of a therapeutic window during haloperidol treatment were those having sample sizes >20 (p = 0.06) and those whose patients were treated with fixed doses (p = 0.02). The diagnosis of schizophrenia in the studies seems not to be an exclusive condition, as compared with those also including schizophreniform and schizoaffective disorders (p = 0.12). Our qualitative analysis of haloperidol blood level publications seem to indicate that an upper limit may exist for haloperidol efficacy; values above this limit seem not to provide any supplementary clinical improvement and may even reduce therapeutic effect.
The “optional cross‐over design” for randomized controlled trials
Authors: Ernst E. , Resch KL
Published: August 2009

Summary— In order to facilitate the performance of randomized controlled trials (RCT) in situations where no “hard” endpoints can be identified and the patient's subjective impressions about success of failure of a given treatment are paramount, the “optional crossover design” is suggested. In this design, patients are randomised to receive either active medication or placebo during phase I. At its end the patient may choose to change to the other treatment arm, if therapy was felt to be unsuccessful (= optional cross‐over). In phase II, treatment continues as in phase I except for those patients who have chosen the “optional cross‐over”. Further cross‐over points may ensue depending on the particularities of the situation, however, two such options may be adequate for most studies. At the end of the trial period, the numbers of patients in each treatment arm are counted and evaluated statistically. If an optimally successful remedy is being tested, close to 100% of the study population could finish up in the active treatment arm. If, as in most instances, the remedy is not optimally successful, this percentage will be proportionally less. If an ineffective remedy is being tested, the distribution of the total sample within the two treatment arms approaches 50:50%. The “optional cross‐over design” seems suited for RCT in areas where the complex, unmeasurable and subjective experience of the patient are considered to represent adequate endpoints.