bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative opioid withdrawal signs in rats: effects exerted by clothiapine administration
Authors: Pinelli A , Trivulzio S , Ciapponi PM
Published: August 2009

Summary— An opioid withdrawal syndrome, which causes alteration of several physiological signs, was induced in rats by repeated morphine administration and final naloxone injection. The aim of this study was prevention of the altered physiological profiles by utilising clothiapine, which is capable of affecting fecal and urinary excretion, rectal temperature, pain threshold levels and salivatory behaviour. Morphine was administered in three daily intraperitoneal (ip) injections for 4 days at doses of 9, 16 and 25 mg/kg (d 1), 25, 25 and 50 mg/kg (d 2), 50, 50 and 50 mg/kg (d 3) and 50, 50 and 100 mg/kg (d 4). Naloxone was injected (30 mg/kg) ip 180 min after the last morphine injection. Clothiapine was administered orally 0.7, 2 and 6 mg/kg 2 hours before the naloxone administration. Signs such as fecal and urine excretion, rectal temperature and latency times to thermal stimulus, salivation, jumping and wet dog shakes were affected in different ways by morphine, naloxone, clothiapine and combination of them. Notably the administration of clothiapine in rats receiving morphine and naloxone decreased the intensity of certain withdrawal symptoms, such as altered excretion of feces, temperature values, salivation, jumping and wet dog shakes behaviour, and elevated the nociceptive threshold values. The effects exhibited by clothiapine administration may be explained through its antimuscarinic, antiadrenergic and antidopaminergic activities interfering with the mechanisms involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of the acute phase of opioid withdrawal in heroin addicts.
Effect of MET‐88, a γ‐butyrobetaine hydroxylase inhibitor, on myocardial derangements induced by hydrogen peroxide in the isolated perfused rat heart
Authors: Akahira M , Hara A , Abiko Y
Published: August 2009

Summary—The effect of MET‐88 (3‐(2,2,2‐trimethylhydrazinium) propionate dihydrate), a γ‐butyrobetaine (γ‐BB) hydroxylase inhibitor, on the hydrogen peroxide (H2O2)‐induced mechanical and metabolic derangements was studied in the isolated rat heart, which was perfused aerobically by the Langendorff s technique at a constant flow rate and driven electrically. In the first series of experiments, MET‐88 (100 mg/kg/d) was orally administered to rats for 10 days prior to isolation of the heart. In the second series of experiments, MET‐88 or γ‐BB was directly infused to the isolated perfused heart. In both series of experiments, H2O2(600 μM) decreased the left ventricular developed pressure (mechanical dysfunction) and the tissue levels of high‐energy phosphates (metabolic derangement). In the first series of experiments, oral pretreatment with MET‐88 attenuated the H2O2‐induced metabolic derangement with a marked increase in the myocardial level of γ‐BB, while it did not attenuate the H2O2‐induced mechanical dysfunction. In the second series of experiments, MET‐88 (1 mM) did not attenuate the H2O2‐induced metabolic derangement, whereas γ‐BB (500 μM or 1 mM) attenuated it. Nevertheless, γ‐BB did not modify the energy metabolism of H2O2‐untreated heart (normal heart). These results suggest that oral pretreatment with MET‐88 protects the energy metabolism against the H2O2‐induced derangement and that the beneficial effect of the oral pretreatment with MET‐88 may be mediated by γ‐BB that has accumulated in the myocardium because of inhibition of γ‐BB hydroxylase.
Standardization of terminology in meta‐analysis: a proposal for working definitions
Authors: Nony P , Cucherat M , Haugh MC , Boissel JP
Published: August 2009

Summary— In this paper we present a brief overview of the growing concern to standardize definitions and terminology in meta‐analysis. This tool has become inescapable in both drug research and therapeutic evaluation. The performed and published meta‐analyses are increasing, as well as the variation in the meaning of the terms used in meta‐analysis. In the second part of the paper we propose glossary of the most common terms used in reports of meta‐analyses. The glossary has been written by only one group of scientists, the definitions are therefore proposed to the scientific community as working definitions, to be subject to reactions from leaders in meta‐analysis.
Adenosine reduces airway excitatory non‐cholinergic (e‐NC) contraction through both A1 and A2 adenosine receptor activation in the guinea pig
Authors: Lagente V , Barlinski J , Cano E , Frossard N
Published: August 2009

Summary— The influence of adenosine and selective A1 and A2 agonists and antagonists was investigated on the cholinergic and the excitatory non‐cholinergic (e‐NC) contractions induced by electrical field stimulation in the guinea‐pig bronchi. Adenosine (10 nM‐1 mM) induced a concentration‐dependent inhibition of the e‐NC contraction (EC50 = 90 ± 14 μM), whereas the cholinergic peak was only slightly affected. Preincubation of the tissue with the adenosine uptake blocker dipyridamole (10 μM) significantly shifted the concentration‐inhibition curve to adenosine to the left (EC50 = 10 ± 1 μM), suggesting an interaction with extracellular adenosine receptors of A1 and/or A2 subtype. To characterize the receptor type involved in this effect, selective adenosine derivatives were studied. The agonist to both A1 and A2 adenosine receptors, 5′‐N‐ethylcarboxamidoadenosine (NECA) was more potent than the selective A1 agonist, (‐)‐R‐6‐phenylisopropyladenosine (R‐PIA), in inhibiting the e‐NC contraction (EC50 = 0.10 ± 0.04 and 0.60 ±0.12 μM, respectively, with a maximal inhibition of 70 and 45%, respectively). The concentration‐response curve to NECA was shifted to the right by the A2 receptor selective antagonist 3,7‐dimethyl‐1‐propargylxanthine (DMPX) (10 μM) (EC50 = 1.4 ± 0.5 μ) as well as by the specific A1 receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) (10 μM) (EC50 = 0.7 ± 0.3 μM). The inhibitory effect induced by the association of both antagonists, DPCPX and DMPX, was considerably potentiated (EC50 > 22 ± 2.5 μM). The effect of R‐PIA was also shifted to the right by DPCPX (EC50 = 8.2 ± 1.6 μM) but was not modified by DMPX. The contractile response to exogenous substance P was unaffected by NECA pretreatment (0.3 μM). Altogether, these results suggest that adenosine‐induced inhibition of e‐NC contraction of guinea‐pig bronchi is mediated through activation of both A1 and A2 adenosine receptors linked to inhibition of the release of neuropeptides from C‐fibre nerve endings.
Effects of NKH477, a forskolin derivative, and dibutyryl‐cyclic AMP on adrenal catecholamine release in response to splanchnic nerve stimulation, acetylcholine, DMPP and muscarine in anesthetized dogs
Authors: Koshika T , Nagayama T , Iizuka Y , Kimura T , Satoh S
Published: August 2009

Summary—The effects of NKH477, a water‐soluble forskolin derivative, and dibutyryl‐cyclic adenosine monophosphate (dbcAMP) on the release of adrenal catecholamines (CAs) in response to splanchnic nerve stimulation (SNS), acetylcholine (ACh), the nicotinic receptor stimulant 1,1‐dimethyl‐4‐phenyl‐piperazinium iodide (DMPP) and muscarine were examined in anesthetized dogs. NKH477, dbcAMP and the cholinergic agonists were infused and injected, respectively, into the adrenal gland intra‐arterially. SNS (3 Hz) or injections of ACh (3 μg), DMPP (2 μg) and muscarine (2 μg) produced increases in CA output determined from adrenal venous blood. Both NKH477 infusion (0.3, 1 and 3 μg/min) and dbcAMP infusion (0.1, 0.3 and 1 mg/min) caused dose‐dependent enhancement of the SNS‐, ACh‐ and DMPP‐induced increases in CA output, whereas they failed to affect the muscarine‐induced increases in CA output. Neither NKH477 nor dbcAMP affected basal CA output. Cyclic AMP (cAMP) overflow determined from adrenal venous blood increased during NKH477 infusion. These results indicate that NKH477 and dbcAMP have facilitatory effects on adrenal CA release mediated by nicotinic receptors, but not by muscarinic receptors in the dog, and suggest the selective action of cAMP on nicotinic mechanism.
Effect of nitric oxide donors on endogenous dopamine release from rat striatal slices
Authors: Büyükuysal R Levent
Published: August 2009

Summary— Sodium nitroprusside (SNP) significantly decreased basal dopamine (DA) release when rat striatal slices were incubated in a physiological medium deficient in antioxidants. Depolarization‐induced DA release (KCl 25 mM), which was accompanied with a 85% decline in tissue DA levels, was also inhibited by SNP and hydroxylamine (HA). Contrary to these findings, SNP did not protect the slices against depolarization‐induced DA depletion. With HA, moreover, tissue DA levels were found to be depleted more than the control levels, indicating that DA, which is released from or stored in the slices, might be converted to an undetectable product under these conditions. Supporting this conclusion, incubation of the DA standards with SNP caused a dose‐dependent loss in DA levels, an effect that was reversed partially by oxyhemoglobin and inhibited completely by antioxidants. Consistently, both SNP and HA, but not L‐arginine, significantly increased basal DA release when striatal slices were incubated in antioxidants‐containing medium. These results indicate that nitric oxide (NO), which is generated from SNP and HA by different mechanisms, stimulates DA release from rat striatal slices. Observation of this effect, however, requires the presence of antioxidants in the medium.
Comparative effects of adenosine‐5′‐triphosphate and related analogues on insulin secretion from the rat pancreas
Authors: Chapal J , Hillaire‐Buys D , Bertrand G , Pujalte D , Petit P , Loubatieres‐Mariani MM
Published: August 2009

Summary— Adenosine tri‐ and diphosphate (ATP and ADP) and their structural analogues stimulate insulin secretion from the isolated perfused rat pancreas, an effect mediated by P2Y‐purinoceptor activation. Concerning the base moiety of the nucleotide, it was previously shown that purine but not pyrimidine nucleoside triphosphates were active and that substitution on purine C2 with the 2‐methylthio group greatly enhanced the potency. In this study, we further analyze the consequences of ribose and polyphosphate chain modifications. Modifications in 2′ and 3′ position on the ribose led to a decrease in insulin response when bulky substitutions were made: indeed, 2′‐deoxy ATP was similar in activity to ATP, whereas arylazido‐aminopropionyl ATP (ANAPP3) was weakly effective and trinitrophenyl ATP (TNP‐ATP) was inactive. Substitution on the /phosphorus of the triphosphate chain led to a decrease (y‐anilide ATP) or no change (y‐azido ATP) in potency; the replacement of the bridging oxygen between β and /phosphorus by a peroxide group did not significantly change the activity, whereas substitution by a methylene group completely abolished stimulation of insulin secretion. As for the phosphorothioate analogues, adenosine‐5′‐0‐(3‐thiotriphosphate) (ATP)S) induced an insulin response similar to that produced by ATP, whereas adenosine‐5′‐0‐(2‐thiodiphosphate) (ADP/JS) was about 100‐fold more potent than ATP, as previously shown. In conclusion, two structural features seem to have a strategic importance for increasing the insulin secretory activity of ATP analogues: substitution at the C2 position on the adenine ring of ATP and modifications of the polyphosphate chain at the level of the β phosphorus.
Lack of insulin resistance in the Lyon hypertensive rat
Authors: Boulanger M , Duhault J , Broux O , Bataillard A , Sassard J
Published: August 2009

Summary— Genetically hypertensive rats (LH) of the Lyon strain, compared to their normo‐tensive (LN) controls associate, in a unique manner, high blood pressure with increases in body weight and in plasma lipids and insulin/glucose ratio. The present work investigated the development of insulin resistance with age in this model. At the age of 22 and 52 weeks, LH and LN fasted male rats were submitted to an intravenous glucose tolerance test, allowing measurement of the elimination rate of the glucose and the area under the curve of the insulin response. Insulin sensitivity was calculated as the ratio of these two parameters. It was observed that insulin sensitivity coefficient decreased with age in all the animals and that LH rats did not significantly differ from LN controls (from 62.6 ± 3.3 and 69.1 ± 4 at 22 weeks to 42.1 ± 4.4 and 49.5 ± 12.8 at 52 weeks for LH and LN rats, respectively). It is concluded that 1) elevated plasma insulin/glucose ratio does not mean insulin resistance and 2) hypertension can develop without being associated, even in aged rats, to a true insulin resistance.
In vitro and in vivo vasodilating effects of KRN4884, Ki1769 and Ki3005, pyridinecarboxamidine derivatives
Authors: Izumi H , Kawahara J , Takeuchi A , Izawa T , Ogawa N
Published: August 2009

Summary—The vasodilating potencies and mechanism of action of a novel pyridinecarboxamidine derivative, KRN4884 (5‐amino‐N‐(2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] were compared with those of Ki 1769 [N‐cyano‐N'‐(2‐phenylethyl)‐3‐pyridinecarboxamidine] and Ki3005 [N‐[2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] in rat isolated aortas and in anesthetized normotensive rats. In vitro, KRN4884 (10‐10‐10‐6M), Ki3005 (10‐10‐10‐6M) and Ki30O5 (10‐10‐10‐6M) produced concentration‐dependent relaxations. KRN4884 was about 100‐ and 10‐fold more potent than KU769 and Ki3005, respectively. The relaxant effects of these compounds were antagonized by glibenclamide. In vivo, KRN4884 (1–10 μg/kg, intravenously [iv]), KM769 (10–100 μg/kg, iv) and Ki3005 (3–30 μg/kg, iv) produced dose‐dependent decreases in mean blood pressure with slight increases in heart rate. At 10 μg/kg, iv, the hypotensive effect of KRN4884 was about the same as that of Ki3005 and about 5‐fold more pronounced than that of Ki 1769.

The hypotensive action remained for a longer period after KRN4884 administration. In rats pre‐treated with glibenclamide (20 mg/kg, iv), the hypotensive effect of KRN4884 was abolished. These results suggest that the effect of KRN4884 in vitro and in vivo is based on its K channel opening action and that the in vitro vasorelaxant effect of these compounds in aortic rings does not predict their relative hypotensive effect in vivo.
Pharmacological characterization of the contractile effects of galanin(l‐29)‐NH2, galantide and galanin(l‐14)‐(α‐aminobutyric acid8)scyliorhinin‐I in the rat gastric fundus†
Authors: Korolkiewicz R , Sliwinski W , Konstanski Z , Rekowski P , Halama‐Borowiec A , Szyk A , Emerich J , Korolkiewicz KZ
Published: August 2009

Summary— Porcine galanin (l‐29)‐NH2, galantide (M15) and galanin (l‐14)‐(a‐aminobutyric acid8)‐scyliorhinin‐I used in concentrations of 300, 1,000 and 3,000 nM respectively caused contractions of rat fundus strips. The contractile responses to galanin(1–29)‐NH2 were not modified by atropine (10 μM), guanethidine (10 μM), naloxone (1 μ), a mixture of propranolol (10 μM) and phentolamine (10 μM), indomethacin (10 μM), a mixture of mepyramine (10 μM) and Cimetidine (10 μM), saralasin (10 μM), and spantide (100 μM). The effects of M15 and galanin(l‐14)‐(a‐aminobutyric acid8)‐scyliorhinin‐l were significantly decreased by atropine for 36 and 18% and by spantide for 37 and 26% respectively. Indomethacin inhibited the muscle response to M15 without influence on the galanin (l‐14)‐(a‐aminobutyric acid8)‐scyliorhinin‐I‐induced action. These results support findings that galanin (l‐29)‐NH2 contracts rat gastric fundus strips by stimulating specific receptors localized on the surface of smooth muscle cells. M15 and galanin(l‐14)‐(a‐aminobutyric acid8)‐scyliorhinin‐I seem to contract smooth muscles not only by acting at galanin receptors, but by interacting with muscarinic or tachykinin receptors or modulating the release of acetylcholine and substance P. Diltiazem (EC50 825 nM), dantrolene (EC50 30.2 μM) and the phospholipase C inhibitors U‐73122 (EC50 549 μM) and U‐73343 (EC50 751 fjM) lowered the contraction to galanin(l‐29)‐NH2 in a concentration‐dependent manner. These observations imply that though the extracellular Ca2+ influx plays a major role in the action of galanin(l‐29)‐NH2, the release of Ca2+ ions from the intracellular stores contributes to the response of smooth muscles to galanin(l‐29) NH2. Norepinephrine (30, 60, 100 and 300 nM) concentration‐dependently reduced the Emax to galanin (l‐29)‐NH2 and reduced the slopes of the concentration‐contraction curves, without a notable change in EC50. Pertussis toxin pre‐treatment (10 and 30 mg/kg intravenous[iv]), 120 h before the experiment, notably increased the maximal response of the rat gastric fundus to galanin(l‐29)‐NH2, without a significant change in the properties of the concentration‐contraction curves (EC50, slopes). The observations may suggest that pertussis toxin‐sensitive GTP‐binding proteins are involved in the modulation of the excitatory effects of galanin(l‐29)‐NH2 in the rat gastric fundus.
Introduction
Authors: Bousquet P
Published: August 2009

Ce numéro supplémentaire de Fundamental and Clinical Pharmacology contient les résumés des communications présentées au symposium « Mécanismes nerveux de l'hypertension » (Strasbourg, 21 juin 1996)

Ce symposium correspondait à une réunion satellite du 16e Congrès Scientifique de la Société Internationale d'Hypertension qui s'est tenu à Glasgow (Royaume‐Uni) quelques jours plus tard.

Cette manifestation concernait les principaux aspects fondamentaux et cliniques de la régulation nerveuse du tonus vasomoteur et de ses dysfonctionnements. Le programme s'est déroulé sur une journée.

Les deux premières sessions ont été consacrées à des présentations générales et à des exposés de travaux récents portant sur les structures cérébrales, les neurotransmetteurs et les voies impliquées dans le contrôle de la pression artérielle. Une troisième session a été consacrée aux neurohormones, avec un point particulier sur les modèles transgéniques. La quatrième session a porté sur le baroréflexe et la variabilité tensionnelle. La dernière session a abordé les aspects cliniques de l'implication du système nerveux sympathique dans l'hypertension.

Cette journée a été émaillée de discussions très intéressantes.

Je remercie tous les participants et les présidents de séance qui ont rendu ce symposium très agréable et intéressant. Je suis reconnaissant à Biopharma (du Groupe de Recherche Servier, France) pour son aide généreuse qui a permis que ce symposium se tienne dans des conditions fécondes et contribue ainsi à son succès. Je remercie également l'Institut National de la Santé et de la Recherche Médicale (France) pour son soutien.
Enhancement of the vasodepressor response to adenosine by nicorandil in rats: comparison with cromakalim
Authors: Saito K , Sakai K
Published: August 2009

Summary— The effect of nicorandil on systemic blood pressure (SBP) and heart rate (HR) responses to adenosine was compared with that of cromakalim, an adenosine triphosphate (ATP)‐sensitive K+ channel opener, in anesthetized rats. Intravenous (iv) adenosine in doses of 1–100 μg/kg elicited dose‐dependent decreases in SBP, accompanied by decreases in HR. Potentiation of adenosine action by iv infusion of either nicorandil (10 or 30g/kg per min) or cromakalim (0.1 μg/kg per min) occurred in all of the animals tested. After iv treatment with glibenclamide (20 mg/kg), an ATP‐sensitive K+ channel blocker, not only adenosine action but also the enhancement of adenosine action by nicorandil and cromakalim were significantly attenuated. The present result indicates that the enhancement of the adenosine action by nicorandil and cromakalim appears to occur at least partly through ATP‐sensitive K+ channel activation.
Regional differences in the vasorelaxant effects of nicorandil and amlodipine on isolated porcine coronary arteries
Authors: Tankó LB , Mikkelsen EO , Frøbert O , Bagger JP
Published: August 2009

Summary— The vasorelaxant effects of nicorandil, a K+‐channel opener, and amlodipine, a dihydropyridine‐type Ca2+‐channel blocker, were investigated on partially and maximally K+‐depolarized ring preparations from the porcine left anterior descending coronary artery. By comparing vascular responses in the proximal and distal parts of the epicardial segment, the scope of the study was to evaluate regional differences in the action of nicorandil and amlodipine. Nicorandil (10 7‐ 10‐4 M) shifted the K+ concentration‐response curves to the right and depressed the maximal contractile responses in a concentration‐dependent manner, consistent with K+‐channel opening and secondary non‐K+‐channel opening mechanisms of action. Nicorandil had a significantly more potent relaxant effect in the proximal compared to the distal arterial rings contracted with 85 mM K+. Pretreatment with methylene blue (10‐5 M) did not significantly influence the regional difference in the action of nicorandil. Amlodipine (109‐ 10‐6 M) had a significantly more potent and effective inhibitory and relaxant effect than nicorandil under the same conditions. In contrast to nicorandil, the effect of amlodipine was more prominent in the distal compared to the proximal vessel rings. The cumulative addition of extracellular Ca2+ exhibited a more potent contractile response in the distal rather than in the proximal rings. Nicorandil totally and amlodipine partly eliminated the contractile responses to the lowest concentration of Ca2+. The inhibitory effect of amlodipine on the contractile responses to higher Ca2+ concentrations was more pronounced than that of nicorandil. The results show that there are regional differences in the responsiveness of porcine coronary arteries to Ca2+, nicorandil and amlodipine. Our findings indicate that the regional difference in nicorandil‐induced vasodilation was caused neither by the K+‐channel opening nor by the nitrate‐like mechanism of action, but could be due to a direct Ca2+‐influx blocking effect of the drug.
The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist
Authors: Hong KW , Kim CD , Lee SH , Yoo S‐E
Published: August 2009

Summary— KR31080 (2‐butyl‐5‐methyl‐6‐(1‐oxopyridin‐2‐yl)‐3‐[[2′‐(1H‐tetrazol‐5‐yl) biphenyl‐4‐yl]methyl]‐3H‐imidazo[4,5‐b] pyridine) is a potent inhibitor of angiotensin type 1 (AT1) receptors in rabbit aorta and human recombinant AT1 receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration‐response curves to angiotensin II (All) with decreased maximal response (pD'2 = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [125I]AII binding to rabbit aortic membranes (AT, receptors) and [125I][Sar1, Ile8]AII binding to human recombinant AT1 receptors in a concentration‐dependent manner with IC50 values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [125I)AII binding to bovine cerebellum membranes (ÀT2 receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT1 receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT1 selective angiotensin receptor antagonist which exerts a competitive antagonism in the [125I]AII binding assay and insurmountable AT1 receptor antagonism in the functional study.
Sparfloxacin but not levofloxacin or ofloxacin prolongs cardiac repolarization in rabbit Purkinje fibers
Authors: Adamantidis MM , Dumotier BM , Caron JF , Bordet R
Published: August 2009

Summary—Sparfloxacin, a fluoroquinolone antibacterial, has been reported to prolong cardiac repolarization in some patients. In this study, we have investigated the in vitro cardiac electrophysiological effects of two other fluoroquinolones, levofloxacin and ofloxacin, and compared them with those exerted by Sparfloxacin. Cardiac action potentials have been recorded from rabbit Purkinje fibers using conventional glass microelectrodes. The influence of a sudden decrease in stimulation rate on repolarization is examined. It is found that ofloxacin and levofloxacin (1–100 μM) do not alter the action potential parameters even at a concentration as high as 100 μM. The stimulation rate is without effect on repolarization. On the contrary, Sparfloxacin (1–100 μM) lengthens concentration‐dependently the duration of action potential, this effect being significant from the concentration of 10 μM. A non significant decrease in maximal rate of rise of phase 0 depolarization was observed at the concentration of 100 μTM. Under low stimulation rate, the sparfloxacin‐induced prolonging effect was magnified and early afterdepolarizations occurred in one of seven fibers from the concentration of 30 μM and in four other fibers at the concentration of 100 μM. These results suggest that levofloxacin and ofloxacin had no effect on cardiac cellular electrophysiology whereas Sparfloxacin exerts pure class III electrophysiological effects, which can explain the prolongation of QT interval observed clinically in some patients and might become arrhythmogenic in the presence of other predisposing factors.
Positive chronotropic activity of bradykinin in the pithed normotensive rat
Authors: Loro JF , Zhang J , Pfaffendorf M , van Zwieten PA
Published: August 2009

Summary— The positive chronotropic effect of bradykinin was investigated in the pithed rat preparation. Cumulative treatment with bradykinin (0.20 nmol/kg‐6.59 μmol/kg, intravenous [iv]) caused a dose‐dependent increase in heart rate (HR) by a maximum of 80 ± 3.3 beats min‐1. In contrast, the active metabolite of bradykinin and selective bradykinin B1‐ receptor agonist, [des‐Arg9]‐bradykinin did not influence the spontaneous frequency of beating. Propranolol alone reduced the bradykinin‐induced increase in HR and a combination of propranolol with prazosin abolished the chronotropic effect of bradykinin. The selective bradykinin B2 receptor antagonist, Hoe 140, dose‐dependently shifted the dose‐response curves of bradykinin to the right, whereas the bradykinin B1 receptor antagonist, des‐Arg10‐[Leu9]‐kallidin proved ineffective. From our experiments it may be concluded that bradykinin induces tachycardia in the pithed rat primarily by stimulating the sympathetic ganglia leading to the release of noradrenaline, which subsequently activates cardiac β1‐adrenoceptors. The bradykinin‐induced chronotropic effect is mediated by bradykinin B2‐receptors, whereas B1‐receptors appear not to be involved.
Receptors involved in the positive inotropic action induced by dopamine on the ventricle of a 7‐day‐old chick embryo heart
Authors: Ouedraogo L , Magnon M , Sawadogo L , Tricoche R
Published: August 2009

Summary—Earlier experiments only revealed involvement of sympathetic pre‐synaptic dopaminergic receptors in dopamine induced inotropism in myocardium. We therefore used electrically stimulated (1 Hz) isolated 7‐day‐old chick embryo heart ventricles, thought to be devoid of functional sympathetic nerves, to re‐investigate post‐synaptic receptors involvement and particularly that of dopaminergic receptors in the positive inotropic effect of dopamine. The results snowed that noradrenaline, isoprenaline and dopamine produced a positive inotropic effect with a similar efficacy and with an order of potency as follows: Isoprenaline = Noradrenaline > Dopamine. Tyramine induced no significant modification of the “initial tension” indicating that functional sympathetic innervation and/or releasable endogenous catecholamines were not demonstrable in the 7‐day‐old chick embryo heart ventricle. Propranolol (1 μM) competitively antagonized the positive inotropic response to isoprenaline, noradrenaline and dopamine, meanwhile phentolamine (3 μM) failed to significantly modify the effects of both noradrenaline and dopamine, indicating that these catecholamines induced their positive inotropic effectsviastimulation of β‐adrenoceptors; involvement of α‐adrenergic receptors stimulation was not demonstrable in these effects. Moreover, haloperidol (2 μM) antagonized the positive inotropic response to dopamine but had not any significant effect on the response to isoprenaline. The combined application of both propranolol and haloperidol antagonized the positive inotropic response to dopamine to a greater extent than when these two antagonists were given alone. Consequently, post‐synaptic dopaminergic receptors were also involved in the positive inotropic effect of dopamine. Furthermore, in preparations in which sodium channels were inactivated by high potassium physiological salt solution, high concentrations of dopamine (0.1 mM to 1 mM) induced a slow developing electrical and positive inotropic responses which were also inhibited by propranolol and haloperidol, but not by phentolamine. These latter results indicated that like β‐adrenergic stimulation, the slow inward calcium current activated by stimulation of adenylate cyclase, was at least in part involved in the positive inotropic response to dopamine. In conclusion, dopamine induced its positive inotropism via stimulation of post‐synaptic β‐adrenergic and dopaminergic receptors. The contribution of dopaminergic receptors in this positive inotropic effect might be of the DA‐2 receptors since haloperidol used had been reported to be more DA‐2 than DA‐1 antagonist. These DA‐2 receptors subtypes would mediate activation of adenylate cyclase.
Potentiating effects of nicorandil on the adenosine A2 receptor‐mediated vasodepression in rats: potential role for KATP channels
Authors: Saito K , Sakai K
Published: August 2009

Summary— The effects of nicorandil on systemic blood pressure (SBP) and heart rate (HR) responses to adenosine were compared with those to N6‐cyclopentyladenosine (CPA), a selective adenosine A, receptor agonist, and 5′‐(N‐cyclopropyl)‐carboxamidoadenosine (CPCA), a selective adenosine A2 receptor agonist, in anesthetized rats. When injected intravenously (iv), single bolus doses of CPCA (0.01–1.0 μg/kg), like adenosine (30 μg/kg), elicited dose‐dependent decreases in SBP scarcely affecting HR, while CPA (0.03–1.0 μg/kg) produced only reduction of HR without influencing SBP. The enhancement of the vasodepressor response to CPCA, like adenosine, was induced by the iv infusion of either nicorandil (10 μg/kg per min) or cromakalim (0.1 μg/kg per min), but the response to CPA in HR remained unmodified during the infusion of nicorandil as well as cromakalim. After iv treatment with glibenclamide (20 mg/kg), an adenosine triphosphate (ATP)‐sensitive K+ channel blocker, or 3,7‐dimethyl‐1‐propargylxanthine (DMPX) (1 mg/kg), a selective antagonist of adenosine A2 receptor, not only CPCA action but also the enhancement of CPCA action by nicorandil and cromakalim were significantly attenuated. Similar results were obtained in the case of single bolus iv adenosine. The present result indicates that the augmentation of the adenosine action by nicorandil appears to be mediated by activation of ATP‐sensitive K+ channels, closely linked with stimulation on A2 receptors by adenosine.
Contractile responses evoked by dihydroergotamine, naratriptan and sumatriptan in the canine isolated coronary artery
Authors: Valentin JP , Bonnafous R , John GW
Published: August 2009

Summary—Contractile responses evoked by the 5‐HT1B/Dreceptor agonists, dihydroergotamine, naratriptan and sumatriptan, were compared in canine isolated coronary artery rings before and after endothelial dysfunction as obtained by inhibition of nitric oxide synthase with Nω‐nitro‐L‐arginine methyl ester (L‐NAME; 10 μM). The three agonists contracted rings in the potency order of dihydroergotamine (geometric mean pD2value with 95% confidence limits in parentheses: 6.9 [5.3–7.9] and 7.0 [5.4–7.3] in the absence and presence of nitric oxide synthase (NOS) inhibition [I], respectively) ≥ naratriptan (6.8 [5.7–7.3] and 6.4 [5.7–6.6]) > sumatriptan (4.8 [3.6–5.6] and 5.0 [3.6–5.6]) independently of the presence or absence of L‐NAME. In absence of L‐NAME, efficacy, as assessed by the mean maximal contractile response (Emax), tended to be greater, although not significantly, for sumatriptan and naratriptan compared to dihydroergotamine. L‐NAME per se markedly increased developed tension (43.0 ± 4.6 mN;n= 50) and potentiated maximal responses (0.6 ± 0.2 and 10.7 ± 2.4 mN for dihydroergotamine in the absence and presence of L‐NAME respectively; 1.7 ± 0.6 and 18.7 ± 3.7 mN for naratriptan; 2.5 ± 0.6 and 21.3 ± 3.8 mN for sumatriptan;P< 0.01 in each case). Emax values of sumatriptan and naratriptan were greater than those produced by dihydroergotamine in the presence of L‐NAME but remained lower than the sub‐maximal contractile responses evoked by the thromboxane A2analogue, U‐46619 (ie, 32.4 ± 5.2 mN in the absence of L‐NAME;n= 50), or L‐NAME per se. In conclusion, 5‐HT1B/Dreceptor agonist efficacies in contracting coronary arteries are relatively low under basal conditions and are potentiated in the presence of a dysfunctional endothelium, whereas agonist potencies remain unaffected.
Evidence for a role for bulbospinal pathways in the spinal antinociceptive effect of systemically administered vapreotide in normal rats
Authors: Berger V , Alloui A , Kemeny J‐L , Dubray C , Eschalier A , Lavarenne J
Published: August 2009

Summary—Numerous neurotransmitters are involved in nociceptive transmission or regulation. Several reports have shown the analgesic effects of somatostatin and its analogues. Somatostatin, when given intrathecally, markedly reduced pain in cancer patients. Somatostatin analogues that possess a longer half‐life time are more convenient for therapeutic use. Vapreotide, a somatostatin analogue, was shown to induce a long‐lasting antinociceptive effect in rats. We studied the site and the mechanism of action of vapreotide in rats using the paw pressure test. Intrathecal administration of vapreotide induced no antinociception. Systemically administered vapreotide‐induced antinociception was inhibited by several intrathecal (it) administered antagonists (yohimbine, naloxone and to a lesser degree tropisetron). These results show a lack of spinal effect and suggest a supraspinal site of action with an involvement of noradrenergic and to a lesser degree serotonergic bulbospinal pathways. In addition, spinal opioid receptors also seem to be involved.
Effects of reduced glutathione and n‐acetylcysteine on lidocaine metabolism in cimetidine treated rats
Authors: Testa R , Ghia M , Mattioli F , Borzone S , Caglieris S , Mereto E , Giannini E , Risso D
Published: August 2009

Summary—The aim of this work was to evaluate the effects of exogenous glutathione (GSH) and N‐acetylcysteine (NAC) on the formation of monoethylglycinexylidide (MEGX) from lidocaine in rats with and without the administration of cimetidine. GSH and NAC were administered intraperitoneally (ip) (1 mmol/kg) 1 hour before treatment with cimetidine (0.5 mmol/kg) or saline, and 1 hr later all rats were injected ip with lidocaine (1 mg/kg). Blood samples were drawn 30 min after the lidocaine injection. MEGX and lidocaine serum concentrations were determined by means of fluorescence polarization immuno‐assay using the TDX system. Cimetidine produced a decrease in MEGX levels (from 210 ± 18 to 164 ± 13 ng/mL) and a parallel increase in lidocaine levels (from 73 ± 22 to 172 ± 47 ng/mL), consistent with cytochrome P‐450 3A inhibition. Both GSH and NAC produced a significant decrease in MEGX levels (151 ± 16 and 139 ± 14 ng/mL, respectively), but no significant increase in lidocaine levels were found. As compared to the cimetidine group, pre‐treatment using either GSH or NAC with Cimetidine produced a marked decrease in lidocaine levels (37 ± 27 and 63 ± 28 ng/mL, respectively) and no modification of MEGX levels (155 ± 12 and 165 ± 22 ng/mL, respectively). These results suggest that GSH and NAC might accelerate the lidocaine metabolism while counteracting the inhibitory effect of Cimetidine.
Tissue injury by reactive oxygen species and the protective effects of flavonoids
Authors: de Groot H , Rauen U
Published: August 2009

Summary— Reactive oxygen species contribute decisively to a great variety of diseases. Flavonoids are benzo‐γ‐pyrone derivatives of plant origin found in various fruits and vegetables but also in tea and in red wine. Some of the flavonoids, such as quercetin and silibinin, can effectively protect cells and tissues against the deleterious effects of reactive oxygen species. Their antioxidant activity results from scavenging of free radicals and other oxidizing intermediates, from the chelation of iron or copper ions and from inhibition of oxidases. For their free radical scavenging properties, scavenging of lipid‐ and protein‐derived radicals is presumably of special importance. A non‐radical reactive oxygen species effectively trapped by flavonoids is hypochlorous acid. In general, the antioxidative properties of flavonoids are favoured by a high degree of OH substitution. On the other hand, inhibition of enzymatic functions other than oxidases, eg, inhibition of lipoxygenase and thus prevention of the formation of leukotrienes, may also participate in the cell and tissue protective properties of flavonoids.
YM022, a highly potent and selective CCKBantagonist inhibiting gastric acid secretion in the rat, the cat and isolated rabbit glands
Authors: Attoub S , Moizo L , Laigneau JP , Alchepo B , Lewin MJM , Bado A
Published: August 2009

Summary—We investigated the effects of the novel CCKB/gastrin antagonist YM022 on gastric acid secretion in vivo and in vitro, compared to CI‐988 and L365.260 as reference antagonists. In the anaesthetized rat, pentagastrin‐induced stimulation of gastric acid secretion was dose‐dependently and up to 100% inhibited by iv administration of YM022 with an ID50of 0.009 ± 0.0006 μmol/kg h in comparison to 0.6 ± 0.03 and 3.40 ± 0.05 μmol/kg h for CI‐988 and L‐365,260, respectively. In the gastric fistula cat, iv administration of YM022 produced a similar inhibitory effect with an ID50of 0.02 μmol/kg in comparison to 1.6 and 2.5 μmol/kg for CI‐988 and L‐365,260, respectively. Furthermore, bolus injection of 0.6 μmol/kg YM022 produced 100% inhibition within 30 min and 85% inhibition was still observed after 3 h. In the isolated rabbit gastric glands, CCK8‐stimulated14C‐aminopyrine uptake was inhibited according to the following rank order of potency: YM022 (IC50= 0.0012 μM) ≫ CI‐988 (IC50= 0.2 μM) ≫ L365.260 (IC50= 2.8 μM). Unlike with L365.260, no influence of CI‐988 and YM022 on histamine‐stimulated acid output was shown in this study. Thus, YM022 is a highly potent and selective gastric CCK8/gastrin receptor antagonist and has a long‐lasting inhibitory effect on gastric acid secretion.
Beneficial hemodynamic effects of nicorandil in a canine model of acute congestive heart failure: Comparison with nitroglycerin and cromakalim
Authors: Noguchi K , Matsuzaki T , Ojiri Y , Koyama T , Nakasone J , Sakanashi M
Published: August 2009

Summary— Comparative hemodynamic effects of nicorandil (NCR), nitroglycerin (NTG) and cromakalim (CRM) were examined in a canine model of acute congestive heart failure (CHF). CHF was produced by injections of saponin into coronary arteries of anesthetized dogs followed by volume loading and continuous iv infusion of methoxamine. After the treatment, aortic blood flow (AoF), left ventricular dP/dt and myocardial segment shortening (SS) markedly decreased, while the left ventricular end‐diastolic pressure (LVEDP), the right atrial pressure (RAP) and the systemic vascular resistance (SVR) increased. NCR (n = 6), NTG (n = 6) and CRM (n = 8), which were administered iv after production of CHF, caused a comparable reduction in LVEDP. NCR and CRM profoundly increased AoF and SS but NTG did only slightly. On the other hand, NTG and NCR but not CRM significantly reduced RAP. Intracoronary NCR (n = 8) exerted no or similar effects on SS as well as systemic hemodynamic indices to those observed with iv NCR despite distinct coronary vasodilation. These results indicate that NCR may exert beneficial hemodynamic effects in an experimental CHF mainly due to lessening both afterload and preload rather than the coronary vasodilating effect.
Inhibitory effects of tacrine and physostigmine on catecholamine secretion and membrane currents in guinea‐pig adrenal chromaffin cells
Authors: Sugawara T , Kitamura N , Ohta T , Ito S , Nakazato Y
Published: August 2009

Summary—The effects of tacrine and physostigmine on catecholamine secretion induced by veratridine and high K+, and on voltage‐dependent Na+and Ca2+currents, were investigated in guinea‐pig adrenal chromaffin cells. In perfused adrenal glands, tacrine (100 μM) caused an inhibition of veratridine‐induced catecholamine secretion, but physostigmine (100 μM) did not. In dispersed cells, both tacrine (1 μM‐1 mM) and physostigmine (1 μM‐1 mM) decreased catecholamine secretion induced by veratridine in a dose‐dependent manner. The inhibitory effect of tacrine was much greater than that of physostigmine. Tacrine alone at a high concentration (such as 1 mM) caused a substantial increase in catecholamine secretion by itself and completely abolished the veratridine‐induced secretory response in dispersed cells. High‐concentration physostigmine showed a similar effect, but to a much lesser extent. The high K+(46.2 mM)‐evoked catecholamine secretion from dispersed cells was not affected by tacrine (1–100 μM) or physostigmine (1 μM‐1 mM). In fura‐2 loaded cells, tacrine (100 μM) almost abolished [Ca2+]i rise induced by veratridine, but only slightly reduced that evoked by high K+. In voltage‐clamped cells, tacrine (300 μM) depressed the voltage‐dependent Na+and Ca2+currents by about 93% and 69%, and physostigmine (300 μM) depressed them by about 30% and 17%, respectively. These results suggest that tacrine decreases the veratridine‐induced catecholamine secretion primarily by inhibiting the voltage‐dependent Na+channels rather than the Ca2+channels. Physostigmine acts in a manner similar to tacrine, but its potency is much lower than that of tacrine.
Organisation of a clinical trial unit — a proposal
Authors: Gluud C , Sørensen TIA
Published: August 2009

Summary— The urgent need for the performance of more, better designed, and better conducted randomised clinical trials is increasingly recognised. Based on structured interviews with leading persons of 43 outstanding organisations and units involved in clinical trials in Europe and North America during 1993, ways of organising and staffing clinical trial units were investigated. The present proposal is based on this experience from which an attempt to extract a composite set of minimal requirements has been made regarding pertinent objectives and aims, organisational aspects, staffing, and estimated costs of establishing a clinical trial unit. The core staff is suggested to consist of two chief physicians, one statistician, one data manager, one project coordinator, and two secretaries. In order to fulfil the minimal requirements for running such a unit, it is calculated that about GBP 450,000 per year is needed to cover investments, core staff, and running costs, but excluding housing costs and costs of randomised clinical trials that do not originate from trial coordination. In return, such a unit should be able to mount and launch 6–7 multicenter randomised clinical trials during a 5 year period, corresponding to a total cost for coordination per trial of about GBP 340,000. However, with a larger staff more studies may be coordinated possibly reducing the cost per trial depending on greater effectiveness in utilisation of the basic facilities.
Moxisylyte: A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in impotence
Authors: Marquer C , Bressolle F
Published: August 2009

Summary— Moxisylyte is a competitive noradrenaline antagonist, acting preferentially on post‐synaptic alpha‐1 adrenoceptors. It was introduced more than thirty years ago for the treatment of cerebro‐vascular disorders and shown more recently effective in the urological field due to its ability to modulate the urethral pressure. Renewal of interest in this drug has been observed in recent years since the demonstration of the possibilities of vasoactive drugs in evaluation and treatment of erectile dysfunctions. Moxisylyte is a prodrug, rapidly transformed into an active metabolite in plasma (Deacetylmoxisylyte or DAM). Elimination of the active metabolite occurs by N‐demethylation, sulpho‐ and glucuroconjugation. The N‐demethylated metabolite is sulphoconjugated only. Urine is the main route of excretion. The metabolites of moxisylyte can be determined in biological fluids by various methods using high‐performance liquid chromatography. Their pharmacokinetics is dependent on the route of administration. By the oral route, the concentrations of the active metabolite are low, and the glucuroconide of DAM predominates over the sulphates. After intravenous and intracavernous injection, the active metabolite is proportionally higher, the two sulphates are equivalent and in larger amounts than the glucuronide. In the treatment of impotence, intracavernous injection of moxisylyte at 10, 20 or 30 mg can induce an erection adequate for intercourse in most of the patients. Compared to inducing agents such as papaverine and prostaglandin El, moxisylyte must be considered as a facilitator of male erection, its interest lying in the low rate of adverse effects, either general or local.
Presynaptic imidazoline receptors mediate inhibition of noradrenaline release from sympathetic nerves in rat blood vessels
Authors: Molderings GJ , Göthert M
Published: August 2009

Summary—In rat vena cava and aorta preincubated with [3H]noradrenaline the involvement of imidazoline receptors in modulation of [3H]noradrenaline release from sympathetic nerves was investigated. In the vena cava, the guanidine 1,3‐di(2‐tolyl)guanidine (DTG) inhibited the electrically evoked [3H]noradrenaline release; the inhibitory effect was more pronounced in the presence than in the absence of the α2‐adrenoceptor antagonist rauwolscine. The concentration‐response curves of BDF 6143 [4‐chloro‐2‐(2‐imidazolin‐2‐ylamino)‐isoindoline], and idazoxan for their facilitatory effect on electrically evoked [3H]noradrenaline release was bell‐shaped; in the presence of rauwolscine, BDF 6143 inhibited the evoked [3H)noradrenaline release, whereas idazoxan did not. After blockade of α2‐autoreceptors by rauwolscine, the electrically evoked [3H]noradrenaline release from vena cava was inhibited not only by DTG and BDF 6143 but also by aganodine, clonidine and cirazoline; the rank order of potency of most of the drugs was similar to that found at the presynaptic imidazoline receptors in the rabbit aorta and pulmonary artery as well as in human atrial appendages. In the presence of rauwolscine, clonidine‐induced inhibition of electrically evoked [3H]noradrenaline release was counteracted by 1 μM of the selective CB1receptor antagonist SR141716A (N‐[piperidin‐1‐yl]‐5‐[4‐chlorophenyl]‐1‐[2,4‐dichlorophenyl]‐4‐methyl‐1H‐pyrazole‐3‐carboxamide). In the aorta, BDF 6143 and cirazoline did not modify [3H]noradrenaline release in the absence of α2‐adrenoceptor blockade; in the presence of rauwolscine, the electrically evoked [3H]noradrenaline release from aorta was inhibited by BDF 6143, cirazoline, aganodine and Clonidine with a rank order of potency similar to that in the vena cava. SR141716A 1 μM antagonized the inhibitory effect of BDF 6143 and Clonidine (in the presence of rauwolscine). In conclusion, noradrenaline release in rat vena cava and aorta is inhibited via presynaptic imidazoline receptors which appear to be related to those previously characterized in rabbit and human cardiovascular tissue.