ABNORMALITIES IN THE REGULATION OF BLOOD-PLATELET FREE CYTOSOLIC CALCIUM IN MALIGNANT HYPERTHERMIA .1. HUMAN PLATELETS

The effect of halothane on the regulation of blood platelet free cytos olic calcium was investigated in Quin-2-loaded cells from patients sus ceptible to Malignant Hyperthermia (MH) and healthy controls, respecti vely. The resting level of free cytosolic calcium was slightly, but st atistically significantly, enhanced in platelets from patients (90 +/- 10 nM vs 110 +/- 35 nM). Halothane induced a dose-dependent, rapid Ca 2+ release from intracellular stores both in normal and in MH derived cells, but the resulting increase in cytosolic calcium was significant ly higher in the latter (2 mM halothane: [Ca2+]i = 117 +/- 12 nM vs 21 8 +/- 117 nM; 4 mM halothane: 225 +/- 35 nM vs. 417 +/- 201 nM). Where as in platelets from healthy donors a complete reversibility of the ha lothane effect could be observed within 30-45 min, the cytosolic Ca2transients in platelets from patients were different from those in nor mals either in a higher initial peak or in a diminished decline veloci ty or in both. The basal Ca2+ permeability of the platelet plasma memb rane was very low. Generally, halothane caused a dose-dependent increa se in Ca2+ permeability. However, the influx of external calcium was s ignificantly higher in platelets from patients than in controls (2 mM halothane: DELTA[Ca2+]i = 69 +/- 12 nM vs 135 +/- 63 nM; 4 mM halothan e: 127 +/- 33 nM vs. 258 +/- 111 nM). Combining the results, the sugge stion can be made that susceptibility to MH is characterized by a gene ralized membrane defect. A fast halothane-induced intracellular Ca2+ r elease and an increased Ca2+ permeability of the plasma membrane seem to be of particular importance for adverse cellular reactions on expos ure to the anaesthetic.