European Journal of Pharmacology (v.444, #3)

Risperidone prolongs cardiac action potential through reduction of K+ currents in rabbit myocytes by Pascale Gluais; Michèle Bastide; Jacques Caron; Monique Adamantidis (123-132).
Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1–3 μM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03–0.3 μM) reduced significantly the current density of the delayed rectifier current and at 30 μM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events.
Keywords: Risperidone; Action potential; Transient outward current; Delayed rectifier current; Inward rectifier current; Heart;

We investigated the biochemical and pharmacological properties of a new adenosine A3 receptor antagonist, KF26777 (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride). This compound was characterized using N 6-(4-amino-3-iodobenzyl)adenosine-5′-N-methyluronamide ([125I]AB-MECA) or [35S]guanosine 5′-O-(3-thiotriphosphate) (GTPγS) binding to membranes from human embryonic kidney 293 (HEK293) cells expressing human adenosine A3 receptors. KF26777 showed a K i value of 0.20±0.038 nM for human adenosine A3 receptors labeled with [125I]AB-MECA and possessed 9000-, 2350- and 3100-fold selectivity vs. human adenosine A1, A2A and A2B receptors, respectively. The inhibitory mode of binding was competitive. KF26777 inhibited the binding of [35S]GTPγS stimulated by 1 μM 2-chloro-N 6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (Cl-IB-MECA). The IC50 value was 270±85 nM; the compound had no effect on basal activity. Dexamethasone treatment for HL-60 cells, human promyelocytic leukemia, up-regulated functional adenosine A3 receptors expression, and resulted in the enhanced elevation of intracellular Ca2+ concentration ([Ca2+]i) via the adenosine A3 receptor. KF26777 antagonized this [Ca2+]i mobilization induced by Cl-IB-MECA, with a K B value of 0.42±0.14 nM. These results indicate that KF26777 is a highly potent and selective antagonist of the human adenosine A3 receptor.
Keywords: Adenosine A3 receptor; KF26777 (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride); Binding assay; Ca2+; Guanine nucleotide;

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions. However, these studies led to conflicting results, suggesting that individual differences between rat strains and lines may play an important role. In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to investigate the possible relationship between ethanol sensitivity and the concentrations of extracellular amino acids in the nucleus accumbens. Several groups of HAS and LAS rats were injected with either saline or ethanol (1.0, 2.0 or 3.0 g/kg, i.p.) and the concentrations of amino acids in the nucleus accumbens microdialysates were assayed by electrochemical detection. Acute ethanol induced a dose-dependent increase in extracellular taurine concentrations. However, this increase was significantly reduced at 2.0 and 3.0 g/kg ethanol in HAS rats relative to LAS rats. Since the biological functions of taurine suggest its implication in the reduction of ethanol adverse effects, a higher increase in taurine concentrations may contribute to the lower ethanol sensitivity of LAS rats. Although 2.0 and 3.0 g/kg ethanol did not affect extracellular glutamate concentrations, a significant increase in glutamate was observed after 1.0 g/kg ethanol to HAS rats but not to LAS rats. Such an effect remains unexplained but suggests that discrepancies between the results of previous microdialysate studies may be related to differences in the ethanol sensitivities of various rat strains.
Keywords: Ethanol; Taurine; Glutamate; Microdialysis; Alcohol sensitivity; Alcohol sensitivity;

Repeated imipramine and electroconvulsive shock increase α1A-adrenoceptor mRNA level in rat prefrontal cortex by Irena Nalepa; Grzegorz Kreiner; Marta Kowalska; Marek Sanak; Agnieszka Zelek-Molik; Jerzy Vetulani (151-159).
α1-Adrenoceptors have been implicated in the mechanism of action of antidepressants, but their action on specific receptor subtypes was rarely reported. We compared now the action of two prototypic antidepressant treatments: repeated imipramine and electroconvulsive shock, on the expression of the α1A- and α1B-adrenoceptor mRNAs and on the receptor density in rats. The mRNA expression was assessed by Northern blot in the prefrontal cortex and the hippocampus, the receptor density was measured by [3H]prazosin binding in the total cerebral cortex and hippocampus. In the cortex, both treatments elevated the α1A-adrenoceptor mRNA and the expression of receptor protein. The expression of α1B-adrenoceptor mRNA remained unaffected. In contrast, in the hippocampus, the antidepressant treatments augmented the density of α1A-adrenoceptor protein without changing the level of its mRNA expression there. The results suggest that the α1A-adrenoceptor subtype is specifically involved in the mechanism of action of classical antidepressant treatments.
Keywords: α1-Adrenoceptor subtype; Brain; [3H]Prazosin binding; Imipramine; Electroconvulsive shock; α1-Adrenoceptor mRNA;

Locomotor activity and sensorimotor gating (measured as prepulse inhibition of startle) are regulated by mesoaccumbal dopamine. Recent evidence indicated antagonistic interactions between adenosine A1 receptors and dopamine D1 receptors, as well as between adenosine A2 receptors and dopamine D2 receptors in the nucleus accumbens. Therefore, it is conceivable that accumbal dopamine and adenosine are both involved in the regulation of prepulse inhibition and locomotion. We tested whether accumbal adenosine A1 and dopamine D1 receptors control locomotor activity and prepulse inhibition using the following four treatments. (1) Injections of the selective adenosine A1 receptor agonist N 6-cyclopentanyladenosine (CPA 1.5 and 3 μg/μl per side) into the nucleus accumbens. (2) Stimulation of the ventral tegmental area by local infusion of the GABAA receptor antagonist picrotoxin (25–100 ng/0.5 μl bilaterally). (3) Picrotoxin injections into the ventral tegmental area (100 ng/0.5 μl) and simultaneous bilateral injections of CPA (3 μg/μl per side) into the nucleus accumbens. (4) Injections of the selective dopamine D1 receptor antagonist SCH 23390 (3 μg/0.5 μl per side) into the nucleus accumbens and ventral tegmental area stimulation by picrotoxin. Intra-accumbal CPA infusion reduced locomotor activity but had no effect on prepulse inhibition. Picrotoxin stimulation of the ventral tegmental area increased locomotor activity which was antagonized by co-administration of CPA or SCH 23390 into the nucleus accumbens. An enhancement of prepulse inhibition was observed after stimulation of the ventral tegmental area and co-administration of SCH 23390 into the nucleus accumbens. These findings demonstrate that adenosine A1 and dopamine D1 receptors are involved in the regulation of locomotor activity mediated by the mesoaccumbal dopamine system. The finding that locomotor effects induced by stimulation of the mesoaccumbal dopamine system were not accompanied by a prepulse inhibition-deficit suggests a dissociation of the neuronal substrates involved in the control of locomotion and the regulation of sensorimotor gating.
Keywords: Locomotion; Open field; Nucleus accumbens; Schizophrenia; Startle; Ventral tegmental area;

The effects of cannabinoids on sympathetic neurotransmission in the rat isolated perfused mesenteric arterial bed, were investigated. Electrically evoked sympathetic neurogenic vasocontraction was inhibited by the cannabinoid receptor agonists 11-hydroxy-dimethylheptyl-Δ8-tetrahydrocannabinol (HU210), (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]trans-4-(3-hydroxypropyl)-cyclohexanol (CP55,940) and methanandamide, and by (+)-11-hydroxy-Δ8-tetrahydrocannabinol (HU211), a (+)-stereoisomer of HU210. The inhibition was unaffected by cannabinoid CB1 and CB2 receptor antagonists. Electrically evoked release of endogenous noradrenaline from sympathetic nerves was inhibited by HU210, but not by HU211. Inhibition was blocked by a cannabinoid CB1, but not a CB2, receptor antagonist. HU210 attenuated contractions to noradrenaline, and all of the cannabinoids blocked contractions to KCl. Capsaicin pre-treatment had no significant effect on HU210- and CP55,940-mediated inhibition of sympathetic neurogenic contraction, but partly blocked inhibition mediated by methanandamide. These data show that cannabinoids can inhibit, by distinct pre- and postjunctional actions, sympathetic neurotransmission in the rat mesenteric arterial bed. The pre-junctional action is mediated by a cannabinoid CB1-like receptor, but the postjunctional action does not appear to involve either cannabinoid CB1 or CB2 receptors.
Keywords: Cannabinoid; Sympathetic neurotransmission; Sensory nerve; Mesenteric arterial bed; Capsaicin; Methanandamide;

Geissoschizine methyl ether, an indole alkaloid extracted from Uncariae Ramulus et Uncus, is a potent vasorelaxant of isolated rat aorta by Mitsutoshi Yuzurihara; Yasushi Ikarashi; Kazuhiro Goto; Iwao Sakakibara; Terumasa Hayakawa; Hiroshi Sasaki (183-189).
Effects of geissoschizine methyl ether, an indole alkaloid isolated from the hook of Uncariae Ramulus et Uncus, on vascular responses were examined using isolated strips of rat aorta. Geissoschizine methyl ether (10−7–10−4 M) relaxed norepinephrine (5×10−8 M)-induced contraction in a dose-dependent manner. The potency (50% efficacy concentration, EC50=0.744 μM) was approximately 14 times greater than that (EC50=10.6 μM) of hirsutine, one of the indole alkaloids isolated from Uncariae Ramulus et Uncus that demonstrates a vasorelaxant effect by Ca2+-channel blocking. The vasorelaxant effect of geissoschizine methyl ether found at the lower concentrations (10−7–3×10−6 M) on the norepinephrine-induced contraction was abolished by pretreatment with N G-nitro-l-arginine (10−4 M), an inhibitor of nitric oxide synthesis, or by denuding aortas of endothelium, while the effects at the higher concentrations (10−5–10−4 M) were not completely prevented by either N G-nitro-l-arginine and deendothelialization. Furthermore, geissoschizine methyl ether did not relax high K+-, Ca2+- and a Ca2+-channel agonist Bay K8644-induced contractions at the lower concentrations that markedly relaxed the norepinephrine-induced contractions, while the higher concentrations of geissoschizine methyl ether relaxed the high K+-, Ca2+- and Bay K8644-induced contractions. These results suggest that the vasorelaxant effect of geissoschizine methyl ether is composed of two different mechanisms: endothelial dependency with nitric oxide and endothelial independency with voltage-dependent Ca2+-channel blocking.
Keywords: Ca2+ channel; Endothelium; Geissoschizine methyl ether; Nitric oxide (NO); Aorta; Vasorelaxation;

Effects of dronedarone and amiodarone on plasma thyroid hormones and on the basal and postischemic performance of the isolated rat heart by Constantinos Pantos; Iordanis Mourouzis; Martine Delbruyère; Vassiliki Malliopoulou; Stylianos Tzeis; Demosthenis D Cokkinos; Nikos Nikitas; Hariclia Carageorgiou; Dennis Varonos; Dennis Cokkinos; Dino Nisato (191-196).
The present study investigated the effects of dronedarone and amiodarone on plasma thyroid hormones and the possible consequences on the response of the heart to ischemia. Amiodarone (30 mg/kg/day per os) or dronedarone (30 mg/kg/day per os) were administered for 2 weeks in normal and thyroxine-treated animals (25 μg/100 g body weight od sc, for 2 weeks), while animals without amiodarone and dronedarone served as controls. Isolated rat hearts were perfused in a Langendorff mode and subjected to 20 and 30 min of zero-flow global ischemia followed by 45 min of reperfusion. Functional changes were assessed by measuring left ventricular developed pressure (LVDP) under resting conditions and in response to ischemia–reperfusion, LVDP%, as well as the severity of ischemic contracture. Amiodarone resulted in increased T4, T4/T3 and rT3, whereas dronedarone did not alter the thyroid hormone profile in normal animals. In thyroxine-treated animals, amiodarone increased T4/T3 ratio but T4, T3 and rT3 levels were not altered. Basal functional parameters and ischemic contracture did not change by amiodarone and/or dronedarone neither in normal nor in thyroxine-treated hearts. In normal hearts, postischemic functional recovery, LVDP%, was not altered by amiodarone or dronedarone administration. LVDP% was statistically higher in thyroxine-treated hearts than in normal and this beneficial effect was not abolished by amiodarone or dronedarone treatment.
Keywords: Amiodarone; Dronedarone; Thyroid hormone; Ischemia; Heart;

In vivo effects of fenoldopam on autonomic nervous system after inhibition or activation of ganglionic transmission by Fabienne Vernejoul; Christine Damase-Michel; Jean-Louis Montastruc; Marie-Antoinette Tran (197-202).
The study investigated the effects of dopamine D1-like receptor stimulation on the autonomic nervous system. Fenoldopam (20 μg/kg) was injected i.v. in conscious sinoaortic denervated dogs, that is, surgically deprived of baroreflex pathways. In barodenervated dogs, fenoldopam (20 μg/kg) induced arterial hypotension as well as bradycardia and reduced noradrenaline plasma levels. Pentolinium (0.1 mg/kg i.v.), used to induce partial blockade of nicotinic ganglionic receptors, suppressed the fenoldopam-induced decrease in sympathetic tone, suggesting a ganglionic location for the dopamine D1-like receptor. Moreover, the inability of fenoldopam to reduce the nicotine-induced increase in sympathetic tone suggests that a postsynaptic ganglionic location can be excluded for the dopamine D1-like receptor. The results of these “in vivo” experiments strongly suggest a presynaptic location for the ganglionic dopamine D1-like receptor, stimulation of which results in a reduction of sympathetic tone.
Keywords: Dopamine D1-like receptor; Ganglion; Fenoldopam; Sympathetic tone;

The effect of 2-arachidonoylglycerol, a cannabimimetic eicosanoid, was studied on mucosa-free longitudinal muscle strips isolated from the guinea-pig distal colon. In the presence of indomethacin (3 μM) and N G-nitro-l-arginine (100 μM), 2-arachidonoylglycerol (10 nM–10 μM) produced concentration-dependent and tetrodotoxin (1 μM)-sensitive contractions of the longitudinal muscle strips. The contractions were markedly attenuated in the presence of atropine (0.2 μM), and partially by hexamethonium (100 μM) pretreatment. The response to 2-arachidonoylglycerol was mimicked with N-arachidonoylethanolamine (anandamide, 0.1–30 μM), another cannabimimetic eicosanoid, but the cannabinoid CB1/CB2 receptor agonist, R-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2) (0.1–10 μM), and the vanilloid receptor agonist, (all Z)-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide (AM 404) (10–30 μM), were without effect. The cannabinoid CB1 receptor antagonist, N-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-caroxamide (SR141716A) (1 μM), the cannabinoid CB2 receptor antagonist, [N-[1S]-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-l-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) (1 μM), and the vanilloid receptor antagonist, capsazepine (10 μM), did not shift the concentration–response curve for 2-arachidonoylglycerol to the right. The contractile action of 2-arachidonoylglycerol was also partially attenuated in the presence of nordihydroguaiaretic acid (10 μM), a lipoxygenase inhibitor. These results indicate that 2-arachidonoylglycerol produces contraction of longitudinal muscle of the guinea-pig distal colon via mainly stimulation of myenteric cholinergic neurones, and that neither cannabinoid CB1/CB2 receptors nor vanilloid receptors contributed to the response. The present results suggest the possibility that lipoxygenase metabolites may also contribute, at least in part, to the contractile action of 2-arachidonoylglycerol.
Keywords: 2-Arachidonoylglycerol; Anandamide; Cannabinoid; Colon;

In this study, we compared the effects of cimetidine and omeprazole on the healing of acetic acid-induced gastric ulcers in 8-, 48-, and 96-week-old rats. The repeated oral administration of cimetidine or omeprazole for 14 consecutive days markedly accelerated the ulcer healing in 8- and 48-week-old rats. However, both drugs were ineffective in 96-week-old rats. The basal gastric acid secretion of 8-, 48-, and 96-week-old rats decreased with aging. A single oral administration of cimetidine or omeprazole strongly decreased basal gastric acid secretion in the three different ages of rats. Cimetidine and omeprazole produced a potent and sustained serum gastrin-elevating action in 8- and 48-week-old rats. However, the gastrin-elevating actions of both drugs in 96-week-old rats were much weaker than in the 8- and 48-week-old rats. These results indicate that cimetidine and omeprazole have potent gastric ulcer healing actions in 8- and 48-week-old rats, as well as potent serum gastrin-elevating actions, but both drugs are ineffective in 96-week-old rats, which have lost their gastrin-elevating actions.
Keywords: Gastric ulcer; Aging; Cimetidine; Omeprazole; (Rat);

Author ndex (217-218).

Keyword index (219-223).