Abstract
Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ribose (cADPR) is an endogenous metabolite of β-NAD+ that induces Ca2+ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 μM) increased the intracellular resting Ca2+ concentration ([Ca2+](i)) in intact swine skeletal muscle in a dose- dependent manner. However, the increase in [Ca2+](i) was greater in malignant-hyperthermia-susceptible (MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibers in low external Ca2+ solution or in the presence of L-type Ca2+ channel entry blockers, or intracellular microinjection of heparin or ruthenium red did not modify the effect of cADPR on [Ca2+](i). Dantrolene (50 μM), a known inhibitor of intracellular Ca2+ release, decreased resting [Ca2+](i) and prevented the cADPR-induced increase in [Ca2+](i). These results provide evidence: (1) for the existence of Ca2+ release mechanisms occurring via non-ryanodine or inositol 1,4,5-trisphosphate (InsP3) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribose-induced release of Ca2+ and (3) that the ability of dantrolene to block cADP- ribose-induced release of Ca2+ could be related to its pharmacologic effect on resting [Ca2+](i).
Original language | English (US) |
---|---|
Pages (from-to) | 236-242 |
Number of pages | 7 |
Journal | Pflugers Archiv European Journal of Physiology |
Volume | 440 |
Issue number | 2 |
DOIs | |
State | Published - 2000 |
Externally published | Yes |
Keywords
- Ca microelectrodes
- cADP-ribose
- Calcium
- Dantrolene
- Heparin
- Malignant hyperthermia
- Ruthenium red
- Ryanodine
- Skeletal muscle
ASJC Scopus subject areas
- Physiology