title: Nifedipine facilitates neurotransmitter release independently of calcium channels.
abstract: Nifedipine, a drug used for treatment of hypertension and angina, exerts its effect by calcium channel blockade and nitric oxide production. We report here a previously uncharacterized action of nifedipine on central synaptic transmission that may partially explain its side effects. Nifedipine causes a long-lasting facilitation of tetrodotoxin-insensitive spontaneous glutamate release. This effect is independent of its L-type calcium channel blocking effect, and is not mimicked by other dihydropyridines such as nimodipine, nicardipine, or Bay K 8644. The effect was dose dependent, with EC(50) of 7.8 microM, with the lowest effective dose being 100 nM, a clinically relevant dose. At 10 microM, the increase is 14.7-fold. This effect is largely calcium-independent, because Cd(2+), thapsigargin, or BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester] did not inhibit the nifedipine effect. Thus, nifedipine seems to act on the release process downstream of calcium entry or release. Protein kinases A or C do not mediate its effect, because it is not blocked by inhibitors of these kinases. Our finding indicates that nifedipine may be a useful tool as a secretagogue to directly target the release process, but raises caution for its use as an L-type calcium channel blocker.
authors.affiliation: Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, AB, Canada T2N 4N1. hirasawa@ucalgary.ca
authors.forename: Michiru
authors.initials: M
authors.lastname: Hirasawa
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Pittman
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002104:Cadmium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018377:Neurotransmitter Agents; D011810:Quinoxalines; D002104:Cadmium; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C056723:FG 9041; D019284:Thapsigargin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine