Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers

Malignant hyperthermia (MH) is associated with abnormal regulation of intra cellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ri bose (cADPR) is an endogenous metabolite of beta-NAD(+) that induces Ca2+ r elease from intracellular stores in many tissues. Microinjection of cADPR ( 0.5 or 1 CIM) increased the intracellular resting Ca2+ concentration ([Ca2],) in intact swine skeletal muscle in a dose-dependent manner. However, th e increase in [Ca2+](i) was greater in malignant-hyperthermia-susceptible ( MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibe rs 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 mu M), a k nown inhibitor of intracellular Ca2+ release, decreased resting [Ca2+](i) a nd prevented the cADPR-induced increase in [Ca2+](i). These results provide evidence: (1) for the existence of Ca2+ release mechanisms occurring via n on-ryanodine or inositol 1,4,5-trisphosphate (InsP(3)) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribo se-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 e ffect on resting [Ca2+](i).