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 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...

Mind-altering miniature neurotransmitter release?

“…The activation of protein kinase A or C pathways has been shown to facilitate transmitter release, and both are possible candidates (18,19). However, the results of Hirasawa and Pittman (12) show that the nifedipine effect was independent of these pathways. Furthermore, because the effect of nifedipine was still observed after nicardipine treatment, it was thought to facilitate mEPSC frequency at a site different than the Ltype VDCC.…”

“…DHPs also block L-type VDCCs in CNS neurons and have been used to implicate the channel in stimulus transcription coupling (14). Regarding the mechanism by which nifedipine increases miniature synaptic activity, Hirasawa and Pittman (12) clearly show that it is completely independent of calcium-induced changes in basal release probability. The nifedipine-induced stimulatory effect on mEPSC frequency was not blocked by several strategies that interfere with calcium elevation including thapsigargin, a Ca 2ϩ -ATPase inhibitor that depletes Ca 2ϩ stores, chelation of [Ca 2ϩ ] i with 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetateacetoxymethyl ester (BAPTA-AM), or nonselective blockade of VDCCs with Cd 2ϩ .…”

“…Drugs with core 1,4-DHP structures potently block the L-type VDCC, which is required for muscle contraction. In the article by Hirasawa and Pittman (12) in this issue of PNAS, a paradoxical effect of the DHP nifedipine was found on miniature excitatory postsynaptic currents (mEPSCs) recorded from magnocellular neurons of the supraoptic nucleus of the hypothalamus. Specifically, nifedipine but not close chemical cousins such as nimodipine or nitrendipine potentially induces up to a 15-fold increase in the rate of miniature synaptic activity.…”

“…In this study (23) nifedipine was compared with lacidipine and found to be considerably better at promoting membrane rigidity. Unfortunately, Hirasawa and Pittman (12) did not examine the effects of DHPs with differential effects on membrane rigidity (nifedipine versus lacidipine) on miniature release. ␣-Latrotoxin, a black widow spider neurotoxin, is well studied and known to bind to the nerve terminal leading to stimulation of amino acid transmitter release machinery independently of intra-and extracellular Ca 2ϩ (24).…”

“…Again the concentrations of nifedipine used ( M versus 100s mM) are inconsistent with promotion of miniature release through osmotic stress. In support of the mechanism being through an action of nifedipine on membrane lipids, Hirasawa and Pittman (12) reference an article that shows that different classes of DHP VDCC antagonists can have differential effects on membrane rigidity. In this study (23) nifedipine was compared with lacidipine and found to be considerably better at promoting membrane rigidity.…”