On the mechanism of levosimendan-induced dopamine release in the striatum of freely moving rats.
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.
Rocchitta
Gaia
G
Department of Pharmacology, Faculty of Medicine, University of Sassari, viale S. Pietro 43B, 07100 Sassari, Italy.
Delogu
Rosaria M
RM
Migheli
Rossana
R
Solinas
Luigi
L
Susini
Giuseppe
G
Desole
Maria S
MS
Miele
Egidio
E
Miele
Maddalena
M
Serra
Pier Andrea
PA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis* / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077464:Simendan; D013997:Time Factors
D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D018491:Dopamine Agonists; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D002118:Calcium; D004298:Dopamine