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Dihydropyridine‐induced Ca 2+ release from ryanodine‐sensitive Ca 2+ pools in human skeletal muscle cells
Author(s) -
Weigl Lukas G.,
Hohenegger Martin,
Kress Hans G.
Publication year - 2000
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.2000.t01-1-00461.x
Subject(s) - ryanodine receptor , dihydropyridine , skeletal muscle , nifedipine , nitrendipine , dhps , chemistry , myocyte , extracellular , voltage dependent calcium channel , intracellular , medicine , biophysics , agonist , receptor , endocrinology , calcium , biochemistry , biology , organic chemistry , malaria , immunology , plasmodium falciparum
1 Dihydropyridines (DHPs) are widely used antihypertensive drugs and inhibit excitation‐contraction (E–C) coupling in vascular smooth muscle and in myocardial cells by antagonizing L‐type Ca 2+ channels (DHP receptors). However, contradictory reports exist about the interaction of the DHP with the skeletal muscle isoform of the DHP receptor and E–C coupling in skeletal muscle cells. 2 Using the intracellular fluorescent Ca 2+ indicator fura‐2, an increase in [Ca 2+ ] i was observed after extracellular application of nifedipine to cultured human skeletal muscle cells. The rise in [Ca 2+ ] i was dose dependent with a calculated EC 50 of 614 ± 96 n m nifedipine and a maximum increment in [Ca 2+ ] i of 80 ± 3.2 n m . Similar values were obtained with nitrendipine. 3 This effect of DHPs was restricted to differentiated skeletal muscle cells and was not seen in non‐differentiated cells or in PC12 cells. In spite of the observed increase in [Ca 2+ ] i , whole‐cell patch clamp experiments revealed that 10 μ m nifedipine abolished inward Ba 2+ currents through L‐type Ca 2+ channels completely. 4 Similar to nifedipine, (±)Bay K 8644, an agonist of the L‐type Ca 2+ channel, also increased [Ca 2+ ] i . This effect could not be enhanced by further addition of nifedipine, suggesting that both DHPs act via a common signalling pathway. 5 Based on the specific mechanism of the skeletal muscle E‐C coupling, we propose the stabilization of a conformational state of the DHP receptor by DHPs, which is sufficient to activate the ryanodine receptor.