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Dihydropyridine-induced Ca²⁺ release from ryanodine-sensitive Ca²⁺ pools in human skeletal muscle cells

Lukas G. Weigl, Martin Hohenegger and Hans G. Kress

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 Ca²⁺ 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 Ca²⁺ indicator fura-2, an increase in [Ca²⁺]_i was observed after extracellular application of nifedipine to cultured human skeletal muscle cells. The rise in [Ca²⁺]_i was dose dependent with a calculated EC₅₀ of 614 ± 96 nM nifedipine and a maximum increment in [Ca²⁺]_i of 80 ± 3·2 nM. 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 [Ca²⁺]_i, whole-cell patch clamp experiments revealed that 10 µM nifedipine abolished inward Ba²⁺ currents through L-type Ca²⁺ channels completely.

4. Similar to nifedipine, (±)Bay K 8644, an agonist of the L-type Ca²⁺ channel, also increased [Ca²⁺]_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.

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