Abstract
The modulation of spontaneous release of acetylcholine by specific Ca2+ channel blockers was studied at neonatal rat neuromuscular junction. During early postnatal periods (0–4 days), blockers of N- and P/Q-type Ca2+ channels did not affect miniature endplate potential (MEPP) frequency. Unexpectedly, treatment with the L-type Ca2+ channel antagonist nifedipine, although not when treated with isradipine, nitrendipine, or calciseptine, resulted in strong increase in MEPP frequency. The potentiation effect of nifedipine was dose-dependent with a 56-fold maximum effect with 15 μM. The effect decreased during the first two postnatal weeks and disappeared by the third. The effect of nifedipine was not dependent on extracellular Ca2+ and was not altered by the presence of other Ca2+ channel blockers. In contrast, it was abolished by depleting intracellular Ca2+ stores with 2 μM thapsigargin and was partially inhibited by 10 μM ryanodine. In conclusion, we report a new ryanodine receptor-mediated effect of nifedipine on neonatal neuromuscular junction that may indicate the developmental expression of a specific receptor channel that interacts with intracellular Ca2+ stores. This effect of nifedipine should also be considered when using this drug as either a therapeutic or a research tool.
Footnotes
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This work was supported by the Muscular Dystrophy Association Inc. (Tucson, AZ); Ministerio de Salud, Beca Carrillo Oñativia; Agencia Nacional de Ciencia y Técnica 6220; and National Institutes of Health Grant R03TW01312–02 and UBACYT (Argentina)
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DOI: 10.1124/jpet.103.051524.
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ABBREVIATIONS: VDCC, voltage-dependent calcium channel; MEPP, miniature endplate potential; DHP, dihydropyridine; NMJ, neuromuscular junction; ω-CgTx GVIA, ω-conotoxin GVIA; ω-Aga IVA, ω-agatoxin IVA; BAY-K, BAY-K8644, S-(–)-1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)-3-pyridine carboxylic acid methyl ester.
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↵1 Current address: Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, 28002 Madrid, Spain.
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↵2 Current address: Biophysics Sector and Istituto Nazionale di Fisica della Materia Unit, International School for Advanced Studies, Via Beirut 2-4 (34014), Trieste, Italy.
- Received March 11, 2003.
- Accepted April 16, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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