The effects of verapamil and diltiazem on N-, P- and Q-type calcium channels mediating dopamine release in rat striatum.
1. The putative inhibitory effects of verapamil and diltiazem on neuronal non-L-type Ca2+ channels were studied by investigating their effects on either K+- or veratridine-evoked [3H]-dopamine ([3H]-DA) release in rat striatal slices. Involvement of N-, P- and Q-type channels was identified by sensitivity of [3H]-DA release to omega-conotoxin GVIA (omega-CTx-GVIA), omega-agatoxin IVA (omega-Aga-IVA) and omega-conotoxin MVIIC (omega-CTx-MVIIC), respectively. 2. KCl (50 mM)-evoked [3H]-DA release was abolished in the absence of Ca2+, and was insensitive to dihydropyridines (up to 30 microM). It was significantly blocked by omega-CTx-GVIA (1 microM), omega-Aga-IVA (30 nM) and was confirmed to be abolished by omega-CTx-MVIIC (3 microM), indicating involvement of N-, P- and Q-type channel subtypes. 3. Verapamil and diltiazem inhibited K+-evoked [3H]-DA release in a concentration-dependent manner. The inhibitory effects of verapamil or diltiazem (each 30 microM) were fully additive to the effect of omega-CTx-GVIA (1 microM), whereas co-application with omega-Aga-IVA (30 nM) produced similar effects to those of omega-Aga-IVA alone. 4. As shown previously, veratridine-evoked [3H]-DA release in Ca2+ containing medium exclusively involves Q-type Ca2+ channels. Here, diltiazem (30 microM) did not inhibit veratridine-evoked [3H]-DA release, whereas verapamil (30 microM) partially inhibited it, indicating possible involvement of Q-type channels in verapamil-induced inhibition. However, verapamil (30 microM) inhibited this release even in the absence of extracellular Ca2+, suggesting that Na+ rather than Q-type Ca2+ channels are involved. 5. Taken together, our results suggest that verapamil can block P- and at higher concentrations possibly N- and Q-type Ca2+ channels linked to [3H]-DA release, whereas diltiazem appears to block P-type Ca2+ channels only.
Dobrev
D
D
Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Technology, Dresden, Germany. dobrev@Rcs1.urz.tu-dresden.de
Milde
A S
AS
Andreas
K
K
Ravens
U
U
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D004110:Diltiazem / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D066298:In Vitro Techniques; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D013779:Tetrodotoxin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D004110:Diltiazem; D004298:Dopamine; D011188:Potassium; D013779:Tetrodotoxin; D014700:Verapamil; D014701:Veratridine