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ABSTRACT: The Ca(2+) sensitizer levosimendan (LEV) improves myocardial contractility by enhancing the sensitivity of the contractile apparatus to Ca(2+). In addition, LEV promotes Ca(2+) entry through L-type channels in human cardiac myocytes. In this study, which was performed using microdialysis, infusion of LEV at 0.25 microM for 160 min increased dopamine (DA) concentrations (up to fivefold baseline) in dialysates from the striatum of freely moving rats. Ca(2+) omission from the perfusion fluid abolished baseline DA release and greatly decreased LEV-induced DA release. Reintroduction of Ca(2+) in the perfusion fluid restored LEV-induced DA release. Chelation of intracellular Ca(2+) by co-infusing 1,2-bis (o-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester (BAPTA-AM, 0.2 mM) did not affect basal DA release and scarcely affected LEV-induced increases in dialysate DA. In addition, co-infusion of the L-type (Ca(v) 1.1-1.3) voltage-sensitive Ca(2+)-channel inhibitor nifedipine failed to inhibit LEV-induced increases in dialysate DA, which, in contrast, was inhibited by co-infusion of the N-type (Ca(v) 2.2) voltage-sensitive Ca(2+)-channel inhibitor omega-conotoxin GVIA. We conclude that LEV promotes striatal extracellular Ca(2+) entry through N-type Ca(2+) channels with a consequent increase in DA release.
Journal of Pharmacological Sciences 08/2004; 95(3):299-304. · 2.15 Impact Factor
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ABSTRACT: Levels of uric acid, xanthine, hypoxanthine, ascorbic acid (AA), dehydroascorbic acid (DHAA), glutathione (GSH), noradrenaline (NA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined in the striatum and/or in the brain stem of 3-month-old male Wistar rats given allopurinol (300 mg/kg day by gavage) for 3 days before a single MPTP 35 mg/kg dose IP. Allopurinol alone decreased uric acid and increased xanthine levels both in the striatum and in the brain stem; moreover, allopurinol decreased striatal DOPAC + HVA/DA ratio and increased 5-HIAA/5HT ratio in the brainstem. Allopurinol affected neither regional MPTP nor MPP+ disposition. Allopurinol potentiated the MPTP-induced decrease in the DOPAC+HVA/DA ratio and increase in striatal AA oxidation; in addition, allopurinol antagonised the MPTP-induced: (i) increase in uric acid levels; (ii) decrease in NA levels in both regions, in DA levels, and in the 5-HIAA/5-HT ratio in the brain stem: (iii) increase in AA oxidation in the brain stem. In conclusion, the MPP(+)-induced oxidative stress mediated by xanthine oxidase seems to be involved in DA depletion in the brainstem and in NA depletion in both regions; moreover, striatal uric acid may have an active role in the neuronal antioxidant pool.
Pharmacology Biochemistry and Behavior 07/1996; 54(2):377-83. · 2.61 Impact Factor
Pharmacological Research - PHARMACOL RES. 01/1995; 31:216-216.