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Published online on April 24, 2003, 10.1073/pnas.0936131100
PNAS | May 13, 2003 | vol. 100 | no. 10 | 6139-6144


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From the Cover
Neuroscience
 Nifedipine facilitates neurotransmitter release independently of calcium channels

Michiru Hirasawa* and Quentin J. Pittman

Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada T2N 4N1

Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA, and approved March 5, 2003 (received for review October 9, 2002)

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 EC50 of 7.8 µM, with the lowest effective dose being 100 nM, a clinically relevant dose. At 10 µM, the increase is 14.7-fold. This effect is largely calcium-independent, because Cd2+, 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.

* To whom correspondence should be addressed at: Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1. E-mail: hirasawa{at}ucalgary.ca.

www.pnas.org/cgi/doi/10.1073/pnas.0936131100
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