European journal of pharmacology
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Prior studies indicate long-term reductions of striatal dopaminergic markers after sustained, high dose methamphetamine exposures in vivo, suggesting a neurotoxic effect. We have reported lack of regulation of vesicular monoamine transporter type-2 expression, as opposed to other markers of striatal dopaminergic terminals, under conditions that alter dopaminergic transmission without synaptic terminal losses. In the present study, we evaluated the vesicular monoamine transporter and the neuronal membrane dopamine transporter in rat striata after in vivo exposure to neurotoxic or to intermittent, low dose (behaviorally-sensitizing, non-neurotoxic) methamphetamine administrations. ⋯ Neurotoxic methamphetamine treatment reduced both striatal vesicular monoamine transporter (-26%) and dopamine transporter (-39%) bindings. There were no changes after the non-neurotoxic treatment regimen. The vesicular monoamine transporter may thus be a valuable marker in the further clinical study of psychostimulant drug neurotoxicity.
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Intraplantar co-administration of sub-anesthetic doses of bupivacaine (2.5 microg) or lidocaine (7.5 microg) increased the dose- and time-dependent analgesic effects of the 5-HT3 receptor antagonist, 3-a-tropanyl-1-H-indole-3-carboxylic ester (ICS-205 930) (1-100 microg; 50 microl) against inflammatory pain induced by hindpaw inoculation with complete Freund's adjuvant. The effects of bupivacaine were greater than lidocaine at all doses of ICS-205 930 tested. These findings may reflect facilitation of ICS-205 930 effects through negative allosteric modulation by bupivacaine and lidocaine of peripheral 5-HT3 receptors involved in nociceptive processing.
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Chronically instrumented awake healthy sheep (n = 6) received the synthetic catecholamine, dopexamine, during or without a background infusion of the nitric oxide synthase inhibitor. L-nitro-arginine-methylester (L-NAME). Three days later, hypotensive-hyperdynamic circulation was induced and maintained by continuous infusion of Salmonella typhosa endotoxin (10 ng/kg per min). ⋯ Dopexamine reduced some adverse effects of L-NAME treatment, like increased pulmonary vascular resistance and decreased oxygen delivery. In conclusion the haemodynamic effects of dopexamine are independent of the amount of nitric oxide production. Dopexamine may attenuate some of the adverse effects of nitric oxide synthase inhibition.
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The electrophysiological effect of levosimendan, a novel Ca(2+)-sensitizing positive inotropic agent and vasodilator, was examined on rat mesenteric arterial myocytes using the patch clamp technique. Resting potential was significantly hyperpolarized with levosimendan, with an EC50 of 2.9 microM and maximal effect (19.5 +/- 3.5 mV; n = 12) at 10 microM. Levosimendan (10 microM) significantly increased the whole-cell outward current. ⋯ Although significant hyperpolarization (4.7 +/- 1.5 mV, n = 8) was observed at 1 microM levosimendan, the same concentration did not affect Ca2+ channel currents (n = 10). In summary, levosimendan hyperpolarized the arterial myocytes, probably through activation of a glibenclamide-sensitive K+ channel. This mechanism may contribute to the vasodilating action of levosimendan.
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The enantiomers of the potent non-competitive NMDA receptor antagonist ketamine and its major metabolite, norketamine were evaluated as NMDA receptor antagonists using the rat cortical wedge preparation and the neonatal rat spinal cord preparation, respectively, for electrophysiological studies and [3H](RS)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine ([3H]MK801) in homogenate binding experiments. In agreement with earlier studies (S)-ketamine (Ki 0.3 microM) was found to possess a 5 times higher affinity for the NMDA receptor complex than (R)-ketamine (Ki 1.4 microM). (S)-Norketamine (Ki 1.7 microM) had approximately an 8 times higher affinity than (R)-norketamine (Ki 13 microM) in the inhibition of [3H]MK-801 binding. All compounds inhibited responses to NMDA in the rat cortical wedge preparation and the hemisected neonatal rat spinal cord, being approximately four times more potent in the cortex than in the spinal cord except for (R)-norketamine being only twice as potent. In light of the clinically obtained concentrations of norketamine after oral administration of ketamine, these data strongly suggest that (S)-norketamine may contribute significantly to the clinical activity of (S)-ketamine, especially when given orally.