bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the potentiating effects of nicorandil and its denitrated metabolite (SG‐86) on the adenosine‐induced vasodepression in rats
Authors: Sakai K , Saito K
Published: August 2009

Summary—The potentiating activity of SG‐86[N‐(2‐hydroxyethyl)nicotinamide], a denitrated metabolite of nicorandil, on the adenosine‐induced vasodepression was compared with that of nicorandil in anesthetized rats. Single bolus iv adenosine (3–100 μg/kg) produced dose‐dependent reductions of blood pressure, accompanied by slight decreases (except for 100 μg/kg) in heart rate. The adenosine‐induced vasodepression was significantly enhanced during iv infusion of either SG‐86 (100 μg/kg per min) as well as nicorandil (10 μg/kg per min). The enhancement of adenosine action by them did not occur in the presence of glibenclamide (20 mg/kg iv). Single bolus iv injections of SG‐86 (0.3–30 mg/kg), except for 30 mg/kg, which caused a glibenclamide‐sensitive decrease by about 5–10 mm Hg in mean arterial blood pressure, had no effects on blood pressure and heart rate, whereas those of nicorandil (30–300 μg/kg) elicited overt reduction of blood pressure, accompanied by decreases in heart rate. The present results revealed that SG‐86, like nicorandil, significantly enhanced the vasodepressor response to adenosine, probably in part through KATPchannel activation, and that the activity of SG‐86 was about 10 times less potent than that of nicorandil.
Platelet and brain α2‐adrenoceptors and cardiovascular sensitivity to agonists in dogs suffering from endotoxic shock
Authors: Hikasa Y , Fukui H , Sato Y , Ogasawara S , Matsuda H
Published: August 2009

Summary—We examined the changes in α2‐adrenoceptor binding on platelet and brain membranes of dogs treated with a non‐lethal dose of endotoxin (0.1 mg/kg intravenously), and the α2‐adrenoceptor mediated cardiovascular effects during endotoxin shock. At 2 h, 24 h, and 7 days after endotoxin administration, the number of binding sites (Bmax) of [3H]yohimbine binding decreased and equilibrium dissociation constants (Kd) increased in platelets, whereas bothBmaxandKddecreased in either cerebral cortex or medulla oblongata. After 30 days of endotoxin administration, there were no significant differences inBmaxorKdbetween the treated and untreated animals in both platelets and brain tissues. Significant positive correlations were observed forBmaxvalues between platelets and brain tissues, although negative correlations forKdvalues between platelets and brain were not significant. Significant negative correlations were also observed between plasma catecholamine concentrations and platelet α2‐adrenoceptor number, and between plasma noradrenaline and medulla α2‐adrenoceptor number. Pretreatment withE coliendotoxin diminished cardiovascular effects such as bradycardia, hypotension, and increase in systemic vascular resistance induced by either iv clonidine or xylazine. This suggests that α‐adrenoceptor activity is impaired in the central nervous system as well as in the peripheral vascular system during endotoxin shock. Therefore, platelets may in part represent a good model which reflects the α2‐adrenoceptor changes in the central nervous system and peripheral vascular system during and after endotoxin shock.
Effect of rebamipide on the glycosaminoglycan content of the ulcerated rat stomach
Authors: Song D‐U , Ryu M‐H , Chay K‐O , Jung Y‐D , Yang S‐Y , Cha S‐H , Lee M‐W , Ahn B‐W
Published: August 2009

Summary—To elucidate the mechanism of the anti‐ulcer effect of rebamipide (2‐(4‐chlorobenzoylamino)‐3‐[2‐(1H)‐quinolinon‐4‐yl] propionic acid), changes in glycosaminoglycan (GAG), uronic acid and hexosamine contents of stomach tissue were examined in rats treated with the ulcer‐inducing agents and/or rebamipide. Uronic acid and hexosamine contents in acid hydrolysates of stomach tissue were increased after diethyldithiocarbamate (DDC, 800 mg/kg, sc) or histamine (300 mg/kg, ip) treatment, and similar changes in the GAG, uronic acid, and hexosamine levels were observed in stomach tissue extracts. Pretreatment with rebamipide (60 mg/kg, ip) resulted in an additional increase in the contents of the above components after DDC or histamine treatment. However, rebamipide treatment alone did not increase the gastric contents of GAG and GAG components in normal rats. Gel filtration chromatography of extracted GAGs suggested that DDC, histamine and rebamipide treatments do not cause a change in the aggregated forms of gastric GAGs. These results suggest that rebamipide stimulates the GAG synthesis in the ulcerated stomach and that this effect may contribute to the healing process of gastric ulcer.
Cytochrome P450 2E1 activity in diabetic and obese patients as assessed by chlorzoxazone hydroxylation
Authors: Lucas D , Farez C , Bardou LG , Vaisse J , Attali JR , Valensi P
Published: August 2009

Summary—Cytochrome P450 2E1 (CYP2E1) is a phase I detoxification enzyme, which is induced by chronic alcohol consumption. It is involved in the activation of numerous carcinogens and in the production of free radicals. As it has previously been shown to be induced in diabetic and obese rats, the aim of this study was to investigate its induction level in poorly‐controlled diabetics and in obese patients (Body Mass Index > 30 kg/m2). CYP2E1 activity was determined in 35 diabetic and 17 obese patients by using the in vivo chlorzoxazone hydroxylation test. Even though the glucidic parameters were highly disturbed (mean fasting glycemia > 7.9 mmol/L, post prandial glycemia > 12.2 mmol/L and fructosamine > 326 μmol/L), CYP2E1 activity was not enhanced either in insulin‐dependent diabetics (IDDs,n= 7) nor in non‐obese non‐insulin‐dependent diabetics (NTTDDs,n= 15) when compared to controls (n= 42) (0.21 ± 0.03, 0.33 ± 0.03 and 0.30 ± 0.02, respectively, mean ± SEM). However, this activity was lower in IDDs when compared to NIDDs (P< 0.05). In obese patients, with (n= 13) or without (n= 17) NIDD mellitus, CYP2E1 activity was increased by a mean of 40% when compared to controls. In addition, positive correlations were found in all subjects (controls or patients,n= 74) between CYP2E1 activity and serum cholesterol (r= 0.42,P< 0.0001), triglycerides (r= 0.44,P< 0.0001) and BMI (r= 0.36,P< 0.001). Accordingly, subjects with cholesterol and/or triglyceride serum levels above 6.4 and 1.8 mmol/L, respectively, displayed a mean increase of 40% of their CYP2E1 activity vs subjects within the above values. It is believed that individuals with increased CYP2E1 activity are more susceptible to the adverse effects of CYP2E1‐mediated activation of toxins and carcinogens.
Interests of the ‘artifical stomach’ techniques to study antacid formulations: Comparison with in vivo evaluation
Authors: Vatier J , Célice‐Pingaud C , Farinotti R
Published: August 2009

Summary—In this overview, the methods for assessing antacid activity in vitro are surveyed, and the problems of their comparison with in vivo methods of evaluation are discussed. In vitro assessment is based on two types of method: static and dynamic. The static method of titration, with end‐of‐titration pH values ranging between 3.0 and 1.0, has been used to quantify the number of sites capable of binding H+ions at each end‐of‐titration pH, and to identify certain chemical mechanisms involved in this binding; in other words, this approach provides the pharmacological characteristics of the drugs tested. In contrast, it does not take into account physiological factors modulating antacid activity, such as gastroduodenal fluxes (including gastric emptying), drug adherence to the mucosa, and acid secretion. The dynamic method was initially based on an artificial stomach model, which has gradually been upgraded to a computer‐controlled artificial stomach‐duodenum model. This model overcomes certain weaknesses of the static method by simulating flux and pH conditions in the gastroduodenal tract, by taking into account interactions with the gastric mucosa and thereby reproducing the in vivo medium encountered by antacids. It is therefore capable of reflecting the characteristics of antacids, namely their effect on gastric pH and resistance to acidification, at the same time helping to identify the underlying chemicophysical mechanisms. In vivo, the antacid effect can be assessed qualitatively by means of pH‐meter studies in healthy volunteers, both in baseline conditions and during secretory stimulation, and also quantitatively by methods based on intragastric titration in response to a liquid meal (IGT). pH‐meter studies in baseline conditions come up against the variability of the basal pH and antacid homogenization with gastric contents, which results in a wide range of individual values. This variability is found in pH‐meter studies during pentagastrin infusion and, to a lesser degree, in response to a meal. Close correlations have, however, been established between results obtained with the artificial stomach model and in healthy volunteers submitted to pH‐metric or IGT studies, with several antacids. It seems that the artificial stomach method is sufficiently reproducible to make it the method of choice for investigating the antacid activity of all drugs aimed at treating acid hypersecretion disorders. In contrast, in vivo studies may be warranted for precise therapeutic indications, such as treatment of duodenal ulcer or gastro‐esophageal reflux, in which the therapeutic effect is judged on the basis of an improvement in symptoms and endoscopic criteria, without the need to demonstrate the antacid effect itself.
Renal artery vasomotion: In vivo assessment in the pig with intravascular Doppler
Authors: Beregi J‐P , Lahoche A , Willoteaux S , McFadden E , Bordet R , Gautier C , Etchrivi T
Published: August 2009

Summary— Intravascular Doppler is widely used for experimental studies in the coronary circulation. We designed this study to assess baseline bloodflow and arteriolar resistance in the porcine renal circulation and to study the vasomotor responses of vasoactive drugs. In anesthesized piglets (n = 15), renal arterial diameter was measured with quantitative angiography and blood flow velocity with a Doppler wire (Cardiometrics). Bloodflow and resistances were calculated at baseline and after injection of vasoactive drugs (isosorbide dinitrate, papaverine). This allowed us to determine the renal bloodflow reserve (the capacity of the kidney to augment basal bloodflow). Injection of isosorbide dinitrate was associated with an increase in average peak velocity of 64% (P < 0.01) and a small (from 4.5 to 4.74, P < 0.01) but significant increase in renal artery diameter, resulting in an increase in bloodflow of 82% (P < 0.01) and a decrease in arteriolar resistance of 46% (P < 0.01). Bloodflow returned to baseline (4.76 ± 1.48 mL/s) approximately 5 min after isosorbide injection. Average Peak Velocity increased almost twofold after papaverine injection (60 ± 10 to 108 ± 24 cm/sec, P < 0.01). There was a significant (P < 0.01) increase in arterial bloodflow of 96% in the right and 79% in the left renal artery after injection of papaverine with a corresponding significant (P < 0.01) decrease in arteriolar resistance of 49% in the right and 44% in the left renal artery. Using a combination of quantitative angiography and intravascular Doppler allows easy measurement of baseline renal blood flow and of the effects of vasodilator drugs on bloodflow and resistance. The results show that a vasodilatator reserve exists in the renal circulation but is less marked than that reported in the coronary circulation.
Endogenous central cholinergic systems and baroreflex modulation in the conscious dog
Authors: Lazartigues E , Tran MA , Brefel‐Courbon C , Montastruc JL , Rascol O
Published: August 2009

Summary—Intracisternal atropine and mecamylamine failed to modify baroreflex sensitivity in dogs, suggesting a lack of cholinergic neurons integrated in baroreflex pathways. Conversely, neostigmine lowered baroreflex sensitivity suggesting a putative cholinergic modulation.
Histamine H3‐receptor stimulation is unable to modulate noradrenaline release by the isolated rat heart during ischaemia‐reperfusion
Authors: Mazenot Catherine , Durand Andrée , Ribuot Christophe , Demenge Pierre , Godin‐Ribuot Diane
Published: August 2009

Abstract—The aim of this study was to evaluate the ability of H3‐histaminergic prejunctional receptors to modulate the noradrenaline release induced by myocardial ischaemia in the rat, and the effects of an eventual modulation on haemodynamic, biochemical and electrophysiological parameters. Isolated rat hearts were perfused according to the Langendorff technique. Control hearts (n= 13) were not treated; two groups were treated with the H3‐agonist R‐α‐methyl‐histamine at 0.3 μM (n= 14) and 1 μM (n= 11) and one group, used as positive control, was treated with the selective α2‐agonist Mivazerol at 0.5 μM (n= 14) added to the perfusion medium. Noradrenaline, lactate and transaminase output in the coronary effluent, as well as various haemodynamic and electrophysiological parameters, were measured during global and total ischaemia (30 min) and reperfusion (30 min). α2‐receptor stimulation increased ischaemia‐induced noradrenaline release during reperfusion (195 ± 13 vs. 145 ± 12 pmol·g−1in control group,P< 0.05). In contrast, R‐α‐methyl‐histamine, at both doses, did not significantly modify these parameters. Both treatments did not affect ischaemia‐ and reperfusion‐induced haemodynamic (decrease in heart rate or in left ventricular developed pressure), biochemical (lactate and GOT release) and electrophysiological (arrhythmias or increase in action potential duration) alterations. Unlike other species, the rat appears to be insensitive to H3‐histaminergic receptor modulation of ischaemia‐induced noradrenaline release, although a modulation can be seen with other prejunctional receptor agonists.
Intra‐individual variability and influence of urine collection period on dextromethorphan metabolic ratios in healthy subjects
Authors: Chládek Jaroslav , Zimová Gabriela , Martínková Jirina , Tůma Ivan
Published: August 2009

Abstract— The aim of the study was to evaluate intra‐individual variability in metabolic ratios (MRs) of dextromethorphan (DM) in healthy volunteers and to compare the MRs in urine collected 0–4, 0–8 and 0–24 h post‐dose. Urinary molar ratios of DM to dextrorphan (MR1) and of DM to methoxymorphinan (MR2) were obtained after a single oral 27.5 mg dose of DM hydrobromide to ten healthy male and four female Caucasians (ten extensive metabolizers (EM) and four poor metabolizers (PM) of DM) to probe activities of CYP2D6 and CYP3A, respectively. Seven EM and one PM received DM on three additional occasions within 2 months. For the seven EM, the intra‐individual variability (CVW) in the MRs obtained in the three urine collections ranged from 11 to 93% (MR1) and from 8 to 77% (MR2). The mean CVW estimated separately for the 4, 8 and 24 h urines by two‐way analysis of variance reached 58, 57 and 44% for the MR1 and 50, 42 and 31% for the MR2, respectively. For all 14 subjects, the log‐transformed ratios (MR1) obtained in the 24 h urines were highly correlated with those in either the 8 h (rs = 0.967, P <0.0001) or 4 h urines (rs = 0.946, P <0.0001). Correlation between the log‐transformed MR2s were weaker (24 h vs. 8 h: rs = 0.829, P <0.0001, 24 h vs. 4 h: rs = 0.831, P <0.0001). The MRIs in 4 h and 8 h urines were only 2 and 9% less than those in 24 h urines (median differences) and varied from 48 and 47% below to 85 and 55% above (95% –CI for the differences). However, the MR2s in the 4 h and 8 h urines were shifted towards higher values by 49 and 23% and the corresponding 95% –CI limits were: 16–164% (4 h vs. 24 h) and 30–119% (8 h vs. 24 h). In conclusion, MR1 values in the 4 h urine collection agree well with those in longer collections and their use in epidemiological studies can be recommended. The intra‐individual variability of approximately 50% in the MR1 has to be taken into account in clinical studies with within‐subject design. Accurate determination of the MR2 requires at least a 24 h period of urine collection.
Influence of losartan and nicardipine on the contractile responses of human subcutaneous arteries and veins to angiotensin II
Authors: Baan Jan , Pfaffendorf Martin , van der Wal Allard C. , Chang Peter C. , van Zwieten Pieter A.
Published: August 2009

Abstract—In the human forearm vascular bed, the arterial constrictor effects of angiotensin II were found to be caused by an AT1‐receptor mediated calcium influx, while the venous constrictor effects appeared to be independent of L‐type calcium channels. In this study, we investigated the influences of the AT1‐receptor antagonist losartan and the calcium channel blocker nicardipine on the angiotensin II‐induced constriction of small isolated subcutaneous arteries and veins obtained from human mammary tissue. Subcutaneous arteries and veins were isolated from mammary tissue from 9 healthy women who underwent breast reduction surgery. Effects of angiotensin II (0.3 nM to 1 mM), losartan (0.1 mM) and nicardipine (0.1 mM) were investigated in a myograph set up. Identification of arteries and veins was confirmed histologically after the experiments. Drug effects were expressed relatively to the potassium‐induced contraction. Angiotensin II concentration‐dependently contracted arteries and veins by maximally 1.66 ± 0.31 N/m and 0.43 ± 0.08 N/m, respectively (P< 0.05). In arteries the angiotensin II were subject to a mild degree of tachyphylaxis: the Emaxof the repetitive concentration‐response curve (CRC) was reduced from 105 ± 4% of the potassium‐induced contraction to 84 ± 6% (P< 0.05); the EC50 value was unchanged (P> 0.05). In veins no tachyphylaxis was observed. Losartan caused a rightward shift of the CRC of angiotensin II in arteries and veins (P< 0.05), and reduced the Emaxin arteries from 105 ± 4 to 85 ± 9% (P< 0.05), but did not change the Emaxin veins. Nicardipine significantly decreased the Emaxin arteries and veins (to residual values of 10 ± 2 and 20 ± 4%, respectively, of the control values). In conclusion, the angiotensin II‐induced constriction of human arteries and veins isolated from mammary tissue are AT1‐receptor mediated and inhibited by losartan. The nearly complete inhibition by nicardipine indicates that the constrictor effects in both types of vessels are dependent on L‐type calcium channels.
Selective blockade by nicergoline of vascular responses elicited by stimulation of alpha1A‐adrenoceptor subtype in the rat
Authors: Alvarez‐Guerra Miriam , Bertholom Nadine , Garay Ricardo Pablo
Published: August 2009

Abstract—The alpha1‐adrenergic blocking activity of nicergoline was re‐examined in rats, with a particular emphasis on alpha1‐adrenoceptor subtypes. In pithed rats, nicergoline and prazosin infused at a single small dose (0.5 μg/kg/min i.v.) produced a substantial and identical shift to the right of the control dose pressor response curve to the specific alpha1‐agonist cirazoline (ED50= 4.0 ± 0.1, 4.0 ± 0.1 and 0.9 ± 0.01 μg/kg i.v. for nicergoline, prazosin and vehicle respectively). In the isolated perfused mesenteric vascular bed, nicergoline strongly inhibited the pressor responses elicited by cirazoline, with approximately 40‐fold higher potency (pA2= 11.1 ± 0.3) than prazosin (pA2= 9.5 ± 0.3). Conversely, nicergoline was 20‐fold less potent than prazosin to antagonize the contractile effects of cirazoline in isolated endothelium‐denuded aorta (pA2= 8.6 ± 0.2 and 9.9 ± 0.2 for nicergoline and prazosin respectively). Pretreatment of mesenteric vascular beds with chloroethylclonidine did not significantly modify nicergoline antagonistic potency (pA2= 10.6 ± 0.2). Nicergoline displaced [3H]‐prazosin bound to rat forebrain membranes pretreated with chloroethylclonidine (pK1= 9.9 ± 0.2) at concentrations 60‐fold lower than in rat liver membranes (pK1= 8.1 ± 0.2). Finally, of the nicergoline metabolites studied, lumilysergol acted as a modest alpha1antagonist (bromonicotinic acid was devoid of alpha1antagonist activity). In conclusion, nicergoline is a potent and selective alpha1A‐adrenoceptor subtype antagonist, an alpha1‐adrenoceptor subtype which is mainly represented in resistance arteries.
A GppNHp‐insensitivity factor modulates the activation of β‐adrenoceptor‐coupled Gsprotein in rat cortex and cerebellum
Authors: Garnier Vincent , Zini Roland , Tillement Jean‐Paul
Published: August 2009

Abstract—The effect known as the GTP‐shift refers to the complete conversion of receptors from the high‐ to the low agonist‐affinity state in the presence of an excess of GTP or one of its analogs. 5′‐Guanylylimidodiphosphate (GppNHp) was able to fully suppress the high (‐)‐isoproterenol‐affinity of β‐adrenoceptors ((βAR) in cultured rat brain astrocytes. In contrast, a proportion of βAR in rat cortex and cerebellum synaptosomes was found to be insensitive to this GTP analog. This GppNHp‐insensitivity was due to a membrane‐associated factor, presumably interacting with Gsproteins and not present in a functional form in cultured astrocytes. Here we assessed the effect of this factor on the βAR‐mediated activation of Gsproteins. The removal of the GppNHp‐insensitivity factor from the synaptosomes was achieved using 3‐[(3‐cholamidopropyl)dimethylammonio]‐1‐propanesulfonate (CHAPS), a mild detergent. The activation of Gsproteins was monitored by the binding of another non‐hydrolysable GTP‐analog, guanylyl 5′‐[γ‐[35S]thio]‐triphosphate ([35S]GTPγS). The βAR‐Gsprotein coupling was at least twofold less efficient in synaptosomes relative to cultured astrocytes. The CHAPS treatment induced a twofold increase in the coupling efficiency in cortex and cerebellum synaptosomes, but had no effect in cultured astrocytes. It undoubtedly indicated the inhibitory effect of the GppNHp‐insensitivity factor on the activation of Gsproteins in the synaptosomes. Using CHAPS‐soluble material extracted from synaptosomes, it was possible to reconstitute the GppNHp‐insensitivity of CHAPS‐treated membranes or even to induce it in cultured astrocytes. This effect correlated with the amount of CHAPS‐soluble material according to a sigmoid curve, but it was abolished by the heat of CHAPS‐soluble material. Successful crossed reconstitutions of the GppNHp‐insensitivity suggest that the GppNHp‐insensitivity factor is the same regardless of its originating area, and that it might play a general role in the central nervous system. Further investigations should help to identify the GppNHp‐insensitivity factor.
Peripheral cardiovascular actions of SR 58611 A, a beta 3‐adrenoceptor agonist, in the dog: lack of central effect
Authors: Montastruc Jean‐Louis , Verwaerde Patrick , Pelat Michel , Galitzky Jean , Langin Dominique , Lafontan Max , Berlan Michel
Published: August 2009

Abstract—In order to investigate the putative role of beta3‐adrenoceptors in central and peripheral cardiovascular regulations, the effects of intracisternal (i.c.) and intravenous (i.v.) injections of SR 58611 A (10, 50, 100 and 200 nmol kg−1), a selective beta3‐adrenoceptor agonist, were investigated in chloralose anaesthetized dogs. In normal dogs, i.v. SR 58611 A (100 and 200 nmol kg−1) induced a dose‐dependent increase in heart rate with no change in blood pressure. After i.c. injection, SR 58611 A failed to modify blood pressure and heart rate (except at the highest dose 200 nmol kg−1which induced a positive chronotropic effect). The positive chronotropic effect of SR 58611 A (200 nmol kg−1) appeared earlier and was significantly more pronounced after i.v. than i.c. administration. The positive chronotropic effect of i.v. SR 58611 A (200 nmol kg−1) was reduced by pretreatment with beta‐adrenoceptor antagonists [propranolol, nadolol, bupranolol or the beta3‐adrenoceptor selective antagonist, SR 59230 A (2 mg kg−1i.v.)] and suppressed after sinoaortic denervation (i.e. after removal of vagal tone to the heart). These experiments do not show evidence for a primary central cardiovascular effect of SR 58611 A. The positive chronotropic effect of i.v. SR 58611 A is mainly of peripheral origin and can be attributed to a baroreceptor‐mediated reflex due to the beta3‐adrenoceptor mediated vasodilation with an increase in sympathetic tone and a reduction in vagal tone to the heart.
Effects of tramadol on experimental inflammation
Authors: Bianchi Mauro , Rossoni Giuseppe , Sacerdote Paola , Panerai Alberto E.
Published: August 2009

Abstract—We examined the ability of the analgesic drug tramadol to affect the development of inflammation in rats. The acute administration of tramadol significantly reduced the edema and the hyperalgesia induced by yeast injection in the paw. Moreover, in the subcutaneous carrageenin‐induced inflammation, tramadol reduced the amount of the exudate, as well as the prostaglandin (PG)E2‐like bio‐ and immuno‐activity in the exudate; on the contrary, leukotriene (LT)B4concentrations in the exudate were not changed. However, tramadol did not affect the ability of macrophages to migrate towards the chemotactic peptide N‐formyl‐L‐methionil‐L‐leucyl‐L‐phenylalanine (FMLP). Our results suggest that tramadol is able to inhibit the development of different types of inflammation in the rat without affecting immune mechanisms, and contribute to explain the efficacy of this drug in the treatment of inflammatory pain.
Renal effects of cP450 arachidonate metabolites in the Lyon hypertensive rat
Authors: Monneret Guillaume , Sassard Jean , Benzoni Daniel
Published: August 2009

Abstract—This study is aimed at evaluating the influence of the cytochrome P450 arachidonate metabolites on the renal alterations exhibited by the Lyon hypertensive (LH) rat. To that purpose, kidneys were isolated from LH rats and their normotensive (LN) controls and single‐pass perfused at different pressure levels before (control conditions) and after cytochrome P450 inhibition by 7‐ethoxyresorufin (7‐ER, 1 μM). In control conditions, LH kidneys differed from LN ones by an increased preglomerular resistance and a blunted pressure natriuresis. 7‐ER, which did not affect the function of LN kidneys, decreased the vascular resistance of LH kidneys, increased their glomerular filtration rate but had no effect on their pressure natriuresis. These results indicate that the renal cytochrome P450 arachidonate metabolism differs between LN and LH rats and is presumably involved in the functional alterations exhibited by LH kidneys.
Trandolapril treatment at low dose improves mechanical and functional properties in perfused coronary arteries of spontaneously hypertensive rat
Authors: Pourageaud Fabrice , Hamon Gilles , Freslon Jean‐Louis
Published: August 2009

Abstract— The ex‐vivo effects of a 1‐month treatment period with trandolapril at a low dose (0.3 mg/kg/day) were assessed on the mechanical and functional alterations observed in SHR coronary arteries. The in‐vitro intrinsic elastic properties of the wall in treated SHR coronary arteries were determined in comparison to those of SHR rats. In preconstricted preparations, agonist‐ and flow‐induced dilatations were investigated in arteries of both groups. Arterial segments were cannulated at both ends using an arteriograph system. Internal diameter and wall thickness were continuously monitored while intraluminal pressure and flow were controlled. Wall thickness was reduced in arteries of treated rats compared to those in control SHR (mm): 52 ± 2 vs. 41 ± 2, P < 0.001, respectively. Arterial stiffness, expressed by the incremental elastic modulus‐stress relationship, was significantly lower in arteries of treated compared to control SHRs. In preconstricted preparations, dilatations induced by bradykinin were significantly greater in treated SHR compared to control SHR arteries whereas dilatations induced by acetylcholine were slightly but not significantly increased. On the other hand, starting flow at the plateau of 5‐HT‐induced constriction led to dilatations which were not significantly different in the treated compared to the control group. The maximal dilatation induced by flow in arteries of treated rats was obtained for the same value of shear stress compared to that determined in preparations of control SHRs: (dyn/cm2) 63 ± 3 vs. 61 ± 2, respectively, NS. These results show that together with hypertrophy, the abnormal mechanical properties observed in the coronary arterial wall of SHR were improved by a low dose of trandolapril treatment. However, differential effects of trandolapril treatment were observed on agonist and flow‐induced dilatations. Although flow‐induced dilatation seemed to remain unaffected, acetylcholine‐induced dilatation was slightly improved and bradykinin‐induced dilatation was markedly increased by trandolapril treatment.
Effects of K+‐channel blockers on A1‐adenosine receptor‐mediated negative inotropy and chronotropy of guinea‐pig isolated left and right atria
Authors: Ford William R. , Broadley Kenneth J.
Published: August 2009

Abstract—Adenosine has previously been shown to stimulate K+‐efflux and to block L‐type calcium channels in atrial myocytes. The aim of the present study was to evaluate the contribution of K+‐channels in the development of the negative inotropic and chronotropic responses to adenosine agonists in guinea‐pig left and right atria, respectively. Tetraethylammonium (TEA) potentiated the negative inotropic and chronotropic responses to R‐(‐)‐N6‐(2‐phenyl‐isopropyl)‐adenosine (R‐PIA). seen as leftward shifts of the concentration‐response curves. Glibenclamide had no effect on the negative inotropic response to R‐PIA but increased the rate of onset of the negative chronotropic response in right atria. 4‐Aminopyridine (4‐AP, 10 mM), potentiated the left atrial inotropic responses to R‐PIA, seen as a leftward shift of the concentration‐response curve, but slowed the speed of onset of the response to a single concentration (10−6M) of R‐PIA. This reduction in speed of onset of the response can explain the differences in effects of 4‐AP on concentration‐response curves reported here and previously. In the right atria, 4‐AP (10 mM) inhibited the negative chronotropic responses to R‐PIA. seen as a rightward shift of the concentration‐response curve and reduction of the maximum response. 4‐AP also slowed the onset of the right atrial rate response to R‐PIA. These results support the theory that K+‐efflux plays only a minor role in the negative inotropic responses of guinea‐pig left atria to R‐PIA. This apparently controls the speed of onset of the response. The negative chronotropic response of guinea‐pig right atria to R‐PIA appears to be much more dependent upon K+‐efflux than for the negative inotropic response of the left atria.
Effects of 50mg amisulpride on EEG, psychomotor and cognitive functions in healthy sleep‐deprived subjects
Authors: Patat Alain , Rosenzweig Pierre , Miget Nathalie , Allain Hervé , Gandon Jean‐Marc
Published: August 2009

Abstract— Amisulpride, a substituted benzamide, binds selectively to the dopamine D2‐ and D3‐receptors. It has higher affinity for limbic compared to striatal dopamine receptors in vivo. At low doses, amisulpride facilitates dopamine transmission via a selective blockade of presynaptic D2‐ and D3‐receptors. Amisulpride is an active antipsychotic compound effective at low doses for negative symptoms and at high doses for positive symptoms of schizophrenia. The CNS profile of multiple doses of a low dosage regimen of amisulpride (50 mg once daily for 4 days) was assessed in a randomised, double‐blind, 3‐way crossover, placebo‐controlled study carried out in 12 young sleep‐deprived (for 36 h) subjects, using EEG and various measures of psychomotor and cognitive functions. Caffeine slow release (600 mg) was used as a positive reference. Multiple doses of 50 mg amisulpride once daily were devoid of any detrimental effects on EEG and psychomotor performance and cognitive function after total sleep deprivation. In addition, 50mg amisulpride partially antagonized the deleterious effects of sleep deprivation on EEG and subjective sedation as shown by trends, and a significant increase in EEG relative beta power and a decrease in subjective sedation. These effects were more pronounced at the end of sleep deprivation, suggesting possible alerting effects of amisulpride at this dose level. Caffeine significantly antagonized the detrimental effects of sleep deprivation on vigilance (increase in EEG beta waves, speed of reaction, sustained attention and reduction in subjective sedation). In conclusion, the present results demonstrate that 50 mg amisulpride is devoid of detrimental effects on EEG, psychomotor and cognitive performance after sleep deprivation, a situation well‐known to amplify such effects if they exist. Moreover, some data suggest possible alerting effects of this low dosage regimen of amisulpride.
Thrombotic risk associated with the use of iodinated contrast media in interventional cardiology: pathophysiology and clinical aspects
Authors: Idée Jean‐Marc , Corot Claire
Published: August 2009

Abstract— A review of the current knowledge of the anti‐thrombotic properties of iodinated contrast media (CM) has been conducted. CM are classified according to their chemical structure, either ionic or non‐ionic (monomeric or dimeric). Numerous in vitro and in vivo data show that, although all CM have anti‐coagulant properties, ionic molecules are more potent than non‐ionic and, furthermore, do not activate resting platelets, unlike non‐ionic agents. These properties may lead to a decrease in thrombus formation during interventional procedures. Several clinical trials have shown that CM may play a role in the occurrence of acute thrombotic complications but also in delayed ischaemic events during interventional procedures. A recent meta‐analysis showed that, compared to non‐ionic monomers, ionic low‐osmolar CM reduce the rate of coronary artery abrupt closure, but no significant difference was found with respect to ischaemic complications. Ionic CM lead to a lower deposit of thrombotic materials on catheters and guide‐wires. To date, clinical data comparing ionic CM and non‐ionic dimers are scarce, significantly heterogeneous and, unlike experimental data, they do not show differences between both classes of CM. Further studies are required to better understand the precise mechanisms of such interactions and to analyse the effect of CM when new antiplatelet agents or new procedures (stenting) are used, to comply with new clinical strategies.
Ketanserin inhibits digoxin‐induced arrhythmias in the anaesthetized guinea‐pig
Authors: Kalyoncu Nuri Ihsan , Ozyavuz Rasin
Published: August 2009

Abstract— Digoxin inhibits the membrane‐bound ATPase enzyme, resulting in a rise in intracellular sodium and activated outward potassium current, predisposing to arrhythmias. In this study, the effect of ketanserin, thought to block outward potassium currents, was investigated on digoxin‐induced arrhythmias. Twenty‐four guinea‐pigs were studied in four groups (control, ketanserin 0.5 mg/kg, ketanserin 1 mg/kg, ketanserin 2 mg/kg). Under pentobarbital anaesthesia (40 mg/kg), 15 min after injection of saline or ketanserin, digoxin (0.6 mg/kg) was administered through the jugular vein. Carotid artery blood pressure and electrocardiogram (ECG) were recorded. The time for the onset of the first arrhythmia and incidence of ventricular tachycardia (VT), ventricular fibrillation (VF), and premature ventricular contraction (PVC) were determined. Arrhythmias were scored according to the MacLeod scale. Ketanserin produced minor haemodynamic effects and lacked, by itself, arrhythmogenic effects at the doses studied. However, it increased the time for the onset of the first digoxin‐induced arrhythmia and decreased the incidence of VT, VF and PVC. We conclude that ketanserin inhibits digoxin‐induced arrhythmias in guinea‐pigs.
Presynaptic dopamine receptors involved in the inhibition of noradrenaline and dopamine release in the human gastric and uterine arteries
Authors: Morgadinho Maria T. , Ribeiro Carlos A. Fontes , Macedo Tice R.A.
Published: August 2009

Abstract—Electrical stimulation‐induced depolarization releases both dopamine (DA) and noradrenaline (NA) from sympathetic neurones of the human gastric and uterine arteries. The overflow of catecholamines elicited by electrical stimulation was measured by using high performance liquid chromatography with electrochemical detection. The addition of yohimbine (0.01–10 μM), an α2‐adrenoceptor antagonist, to the perfusion fluid increased, in a concentration‐dependent manner, the electrically‐evoked DA and NA overflow from gastric and uterine arteries. In the presence of sulpiride (0.1–10 μM), a dopamine D2‐type receptor antagonist, the overflow of both amines was found to be increased in the uterine artery, but not in the gastric artery. Apomorphine (0.1–10 μM), a dopamine receptor agonist, produced a dose‐dependent inhibition in the amount of DA and NA released from gastric and uterine arteries. SCH 23390 (0.1–10 μM), a dopamine D1 receptor antagonist, had no effect on the release of both amines in both preparations. The inhibitory effect of apomorphine was blocked by sulpiride in the gastric and uterine arteries but not by SCH 23390. The results presented suggest the existence of dopamine D2‐type receptors in the human gastric and uterine arteries. They seem to have, in each artery, a different physiological importance.
Susceptibility to provoked cerebral infarction is not increased in a rat model of pharmacologically‐induced hypertension despite endothelial dysfunction
Authors: Bordet Régis , Pu Qian , Puisieux François , Deplanque Dominique , Jaboureck Olivier , Leys Didier , Vallet Benoit , Dupuis Bernard
Published: August 2009

Abstract—An increase in susceptibility to provoked stroke has been described in a genetically‐determined rat model of hypertension. We investigated whether the susceptibility to provoked cerebral ischaemia was also increased in a rat model of pharmacologically‐induced hypertension with endothelial dysfunction. Chronic inhibition of nitric oxide synthase induced by Nω‐nitro‐L‐arginine methyl ester (L‐NAME) administration (50 or 75 mg. kg−1day−1) in drinking water for 6 weeks caused a sustained hypertension, comparable in the two groups. Endothelium‐dependent relaxation induced by acetylcholine or A22187 was significantly, and dose‐dependently, impaired in rats receiving L‐NAME, as proven by a decrease in maximal relaxation and increase of EC50, as compared to control. Endothelium‐independent relaxation induced by sodium nitroprusside was not different in the three groups. Aortic media area was significantly, and dose‐dependently, increased following chronic nitric oxide inhibition. Cerebral infarct volumes were not increased in L‐NAME‐treated groups independently of the level of endothelial dysfunction induced by chronic L‐NAME administration. These data demonstrate that susceptibility to cerebral infarction was not increased in a non‐genetically determined hypertension model in spite of the development of endothelial dysfunction and vascular structure alterations.
Emitted doses of salbutamol pressurized metered‐dose inhaler from five different plastic spacer devices
Authors: Dubus Jean‐Christophe , Dolovich Myrna
Published: August 2009

Abstract— In a recent clinical study we have demonstrated that the bronchodilator effect of 200 μg salbutamol (Ventoline®) was spacer device‐dependent in 100 tested asthmatic children, with the Babyhaler® providing greater efficacy for improving peak expiratory flow rate compared to Aeroscopic®, Nebuhaler®, Aerochamber® and Volumatic®. The aim of this present study was to correlate our clinical results to in vitro determinations of the emitted dose (ED) of Ventoline® administered via these five different plastic spacer devices. ED was determined from the mean of single doses collected in unit dose sampling tubes using a constant suction flow of 28.3 L/min. Three pressurized metered‐dose inhalers and three sets of spacer devices were used to obtain a total of 30 measurements per group. Inter‐group results were compared by RM‐ANOVA or Student‐Newman‐Keuls method when indicated. Babyhaler® delivered significantly (P < 0.05) more salbutamol than Nebuhaler®, Aerochamber® and Aeroscopic® (mean ± standard deviation: 63.6 ± 2.9 μg/100 μg actuation for Babyhaler® vs. 59.4 ± 8.6 for Nebuhaler®, 50.8 ± 5.0 for Aerochamber® and 47.5 ± 2.5 for Aeroscopic®). The ED from Volumatic® (61.5 ±7.9 μg/100 μg actuation) was similar to that from the Babyhaler®. The variability in the ED was greatest with the large volume spacers. Despite a greater ED from the Babyhaler®, in vitro results do not fully explain the in vivo results. However, the previously described clinical improvement seen with the Babyhaler® may be due to the quantitatively different aerosol production in a more ‘useful’ size range, as well as the different breathing patterns of the children tested. The results of this present study question the relevance of mouthpiece filter collection studies using a constant sampling in predicting clinical or physiological outcomes.
Are isoprostanes a clinical marker for antioxidant drug investigation?
Authors: Souvignet Claude , Cracowski Jean‐Luc , Stanke‐Labesque Françoise , Bessard Germain
Published: August 2009

Abstract—Numerous pathological conditions are suspected to involve free radical production as part of their pathogenic process. Therefore, a pharmacological control of oxidative stress could probably benefit many vascular, inflammatory or degenerative diseases. However, the development of antioxidant drugs and their clinical evaluation are limited by the absence of an accurate, reliable and easy‐to‐handle marker of tissue oxidative events. Isoprostanes (isoPs), a prostaglandin‐related series of metabolites, are emerging as major candidates for clinical measurement of oxidative stress. They are chemically stable products of lipid peroxidation, formed in cellular membranes and subsequently released and excreted in the urine. Many recent clinical studies have reported that urinary and plasma levels of isoPs (in particular the iPF2α‐III isomer also called 8‐epi‐PGF2α) are increased in clinical conditions where oxidative stress is suspected to play a pathogenic role. Moreover, isoPs have been detected in tissue extracts from atherosclerotic plaques and Alzheimer patients brain tissue. Finally, antioxidant treatments such as vitamin E supplementation appear to reduce isoPs levels in biological fluids of treated patients. These preliminary observations argue for a further investigation of isoPs as a practical pharmacodynamic endpoint for the clinical evaluation of antioxidant therapies.
Role of the endothelium on the response to adrenoceptor agonists of rabbit aorta during cooling
Authors: Ataik Esra K. , Şahin Ayşe S. , Kiliç Mehmet , Doğan Necdet
Published: August 2009

Abstract— The role of the endothelium in the effects of cooling on the response to α1‐ and α2‐adrenoceptor agonists of rabbit aorta was studied. The contractions induced by clonidine (10−9‐ 3 × 10−4M) and xylazine (10−7‐ 10−3M) but not phenylephrine (10−9‐ 3 × 10−4M) and methoxamine (10−9‐ 3 × 10−4M) were enhanced in endothelium‐denuded or NG‐nitro‐L arginine methyl esther (l‐NAME) (10−5M) pretreated rabbit aorta. The senstivily, but not the maximal response, of both α1‐ and α2‐adrenoceptor agonists was significantly lower at 28 °C (cooling) than at 37 °C. Endothelium removal did not affect the action of cooling. These results were taken as evidence for the specificity of α2‐adrenoceptor agonists on the production and release of nitric oxide from vascular endothelium. The results suggest that the endothelium seems to have no role in the cooling‐induced responses of both α1‐ and α2‐adrenoceptors.
Angiotensin II receptor blockade unmasks a depressor response to endothelin antagonists in rats
Authors: Richard Vincent , Hogie Manuela , Thuillez Christian
Published: August 2009

Abstract—Endothelin (ET) antagonists do not decrease blood pressure in normal rats. Since angiotensin II (All) and ET both induce smooth muscle cell contraction through the same transduction pathways we designed experiments to assess whether blockade of the renin angiotensin system would unmask a vasodilatory response to ET receptor antagonists in rats. For this purpose, we tested the effect on arterial blood pressure of the mixed ETA‐ETB receptor antagonist bosentan or of the ETA antagonist BQ‐123 in the absence or the presence of the All receptor antagonist losartan. In control conditions bosentan did not affect arterial blood pressure. In contrast, in losartan‐pretreated rats, bosentan induced a marked, dose‐dependent decrease in arterial pressure (% change after bosentan 10 mg/kg: control — 3 ± 3; losartan –32 ± 6; cilazapril –28 ± 3). Similarly, BQ‐123 decreased blood pressure in losartan‐pretreated but not in control rats. Bosentan also increased the hypotensive effect of losartan in conscious, normotensive rats. The hypotensive effect of the combination of bosentan and losartan was not associated with any changes in cardiac output or heart rate, and thus was entirely due to a decrease in total peripheral resistance. We conclude that blockade of angiotensin II, AT1receptors unmasks a vasodilator response to ET antagonists. This suggests that endogenous ET plays an active role in the maintenance of arterial blood pressure in rats which can be unmasked by a concomitant inhibition of the renin angiotensin system.
Attenuation of the acute amnestic effect of ethanol by ifenprodil: comparison with ondansetron and dizocilpine
Authors: Napiórkowska‐Pawlak Dorota , Malinowska Barbara , Pawlak Robert , Buczko Wtodzimierz , Göthert Manfred
Published: August 2009

Abstract—The aim of the present study was to examine the influence of ifenprodil, a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist which also blocks 5‐HT3receptors, on the amnestic effect of ethanol in a passive avoidance task in mice. The anti‐amnestic action of ifenprodil was compared with the effects of the 5‐HT3receptor antagonist ondansetron and the non‐competitive NMDA‐receptor antagonist dizocilpine (MK‐801). Ethanol, 2 g/kg and dizocilpine 0.1 mg/kg significantly impaired the passive avoidance response. In contrast, ifenprodil (0.1–10 mg/kg), ondansetron (0.03‐0.3 mg/kg) and dizocilpine (0.01 and 0.03 mg/kg) did not alter passive avoidance by themselves. Dizocilpine did not diminish the amnestic action of ethanol when administered at doses of 0.03‐0.1 mg/kg. However, the amnestic effect of ethanol was partially restored towards normal by ifenprodil 0.3 mg/kg and by ondansetron 0.03 mg/kg (alone or together with dizocilpine 0.01 mg/kg) but it was not affected by other doses of ifenprodil (0.1, 1 and 10 mg/kg) and ondansetron (0.1 and 0.3 mg/kg). In conclusion, ifenprodil at an appropriate dose reduced ethanol‐induced amnesia in a step‐through passive avoidance task. The results are compatible with the assumption that the anti‐amnestic action of ifenprodil may be (at least partially) due to an antagonism at 5‐HT3receptors.
Imipenem but not meropenem induces convulsions in DBA/2 mice, unrelated to cerebrospinal fluid concentrations
Authors: Dupuis Antoine , Pariat Claudine , Courtois Philippe , Couet William , Bouquet Serge
Published: August 2009

Abstract—Imipenem and meropenem CSF diffusion was comparable in DBA/2 mice but only imipenem induced convulsions, not related to CSF concentration.