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 M, with the lowest effective dose being 100 nM, a clinically relevant dose. At 10 M, 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. N ifedipine has been a commonly prescribed compound for treatment of angina and hypertension. Its clinical effect is attributed to its blocking action on L-type calcium channels or release of nitric oxide (NO) from the vascular endothelium, which will result in relaxation or prevention of cardiac or vascular smooth muscle contraction. Compared with other dihydropyridines (DHPs), nifedipine has been reported to have relatively high incidence of neurologic adverse reactions, such as dizziness (4.1-27%) and nervousness (Ͼ7.0%) (information obtained from www.drugdigest.org͞DD͞SE͞DisplayDrug͞1,3997,488,00. html?DVHNameϭNifedipine). Nifedipine can easily cross the brain-blood barrier (1); thus, it may have a direct effect in the brain. The present report introduces a previously uncharacterized action of nifedipine on synaptic transmission in the central nervous system. Nifedipine induces a profound increase in spontaneous glutamate release in a calcium-independent manner. This effect was unique to nifedipine and could not be mimicked by other DHPs; thus, its action is not through blockade of L-type calcium channels. Such synaptic activation in the central nervous system may underlie some of its adverse neurologic reactions.Spontaneous, action potential-independent transmitter release occurs when a synaptic vesicle fuses spontaneously to the presynaptic plasma membrane and releases its content. It is not yet clear what may be the role of spontaneous release for the function of the nervous system. Recent studies indicate that spontaneously released glutamate acts to maintain the postsynaptic dendritic structure (2) and to induce clustering of AMPA (␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors on the postsynaptic membran...