The effect of calcium channel antagonists and bay K 8644 on calcium fluxes of malignant hyperpyrexia-susceptible muscle

Abstract

1. 1. The calcium channel antagonists verapamil (100μM) and nifedipine (100μM) inhibited twitch response and KC1 induced hypercontractility in malignant hyperpyrexia (MH)-susceptible porcine skeletal muscle. These calcium channel antagonists did not effect hypercontractility induced by 3% halothane or 2 mM caffeine. 2. 2. The calcium channel agonist BAY K 8644 (50μM) induced contracture in MH-susceptible muscle but did not potentiate contracture response induced by 2 mM caffeine or 3% halothane. BAY K 8644 did not increase the resting tension of control muscle or increase the sensitivity of control muscle to 4 mM caffeine, 3% halothane or 80 mM KC1. 3. 3. The sarcoplasmic reticulum (SR) from MH-susceptible and control porcine skeletal muscle was separated into vesicular fractions enriched in the membrane elements of the terminal cisternae and longitudinal tubules. 4. 4. Verapamil and diltiazem [which has been previously shown to inhibit the hypercontractility of MH-susceptible porcine muscle to caffeine, halothane and KC1 (Foster and Denborough, 1989 Br. J. Anaesth. 62, 566–572)] did not effect Ca 2+ uptake or Ca 2+-dependent ATPase activities ofSR longitudinal tubule membranes, from MH-susceptible or control muscle. These calcium channel antagonists did not effect Ca 2+ release from terminal cisternae preparations. 5. 5. The skeletal muscle relaxant dantrolene inhibited Ca 2+ efflux and equilibrium-Ca 2+ exchange associated with the terminal cisternae membrane of MH-susceptible and control skeletal muscle. 6. 6. Calcium channel antagonists modify Ca 2+ fluxes in MH-susceptible and control muscle by acting at a site distal to the SR. Calcium channel antagonists may inhibit contractile response by modifying events of excitation-contraction coupling associated with the voltage sensor molecule (dihydropyridine-receptor) of the transverse-tubule membrane, whereas dantrolene directly acts on the terminal cisternae membrane to inhibit Ca 2+ efflux and equilibrium Ca 2+ exchange. Different calcium channel antagonists seem to modify the voltage-sensor mechanism in different ways in MH-susceptible muscle. 7. 7. An abnormality in the coupling mechanism of the voltage sensor-SR calcium release channel may exist in MH-susceptible muscle. This dysfunction may be an adaptation to the elevated levels of myoplasmic Ca 2+ and/or the molecular defect described in the Ca 2+ release channel of the SR of MH-susceptible porcine muscle. In view of these results it is unlikely that nifedipine or verapamil would be of therapeutic value for the treatment of MH.