Why Does Halothane Relax Cardiac Muscle but Contract Malignant Hyperthermic Skeletal Muscle?
We have studied the question of the possible role of sarcoplasmic reticulum (SR) in the interaction of volatile anesthetics (such as halothane, enflurane and isoflurane) with muscle. We used two cardiac muscle models, i.e., isolated rat myocytes and Langendorff perfused rat hearts. We compared the results with those for skeletal muscle SR from rabbits, rats and pigs susceptible to malignant hyperthermia (MH). In both skeletal and cardiac muscle SR, volatile anesthetics enhanced the calcium release from the SR. In cardiac muscle, these agents are known to decrease contracility (negative inotropism). We found that caffeine, a well-known agent which releases calcium from the SR, also had a negative inotropic effect in cardiac muscle, raising the possibility of an unexpected link between the potentiation of calcium release and mechanism underlying the observed negative inotropism. Current understanding of anesthetic mechanisms does not include this possibility. We further found that both volatile anesthetics and caffeine decrease the content of calcium in the SR, suggesting that the increase of calcium permeability results in the decrease of calcium ions in the SR which are available for excitation-contraction (E-C) coupling. In MH-susceptible skeletal muscle, a similar increase in calcium permeability does not cause a decrease of contractility, but rather may contribute to a fatal syndrome of temperature increase provoked by abnormal contracture. This difference may be because in skeletal myoplasm calcium ions recycle internally, while in the cardiac muscle cell they are in dynamic equilibrium with extracellular calcium ions.
KeywordsSarcoplasmic Reticulum Calcium Release Volatile Anesthetic Malignant Hyperthermia Malignant Hyperthermia
Unable to display preview. Download preview PDF.
- 2.S. T. Ohnishi, Calcium-Induced calcium release as a gated calcium transport, in: “Mechanism of Gated Calcium Transport Across Biological Membranes,” S. T. Ohnishi, M. Endo, eds., Academic Press, New York (1981).Google Scholar
- 3.S. T. Ohnishi, A. J. Waring, S. G. Fang, K. Horiuchi, J. L. Flick, K. K. Sadanaga, T. Ohnishi, Abnormal membrane properties of the sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia: Modes of action of halothane, caffeine, dantrolene and two other drugs, Arch Biochem Biophys 247:294–301, (1986).PubMedCrossRefGoogle Scholar
- 8.A. Fabiato, F. Fabiato, Contractions induced by a calcium triggered release of calcium from the sarcoplasmic reliculum of single skinned cardiac cells, J Physiol (Lond) 249:469–495 (1975).Google Scholar
- 9.W. R. Brewster, J. P. Isaacs, T. Waing-Anderson, Depressant effect of ether on myocardium of the dog and its modification by reflex release of epinephrine and norepinephrine, J Pharmacol Exp Ther 175:399–414 (1953).Google Scholar
- 30.J. S. Herland, D. G. Stephenson, F. J. Julian, Halothane affects the contractile apparatus and sarcoplasmic reticulum of mechanically skinned rat ventricular fibers (abstract), Biophys J 53:335a (1988).Google Scholar
- 31.H. L. Price, S. T. Ohnishi, Effects of anesthetics on the heart, Fed Proc 39:575–1579 (1980).Google Scholar
- 35.G. Grynkiewiez, M. Poenie, R. Y. Tsien, A new generation of Ca2+ indicators with greatly improved fluorescence properties, J Biol Chem 260:3440–3450 (1985).Google Scholar
- 37.M. Endo, Mechanism of action of caffeine on the sarcoplasmic reticulum of skeletal muscle, Proc Japan Acad 51:479–484 (1975).Google Scholar
- 38.R. S. V. Heide, R. A. Altschuld, K. G. Lamka, C. E. Ganote, Modification of caffeine-induced injury in calcium-free perfused rat hearts, Am J Pathol 123:351–364 (1986).Google Scholar
- 47.E. Caraboeuf, P. Gautier, P. Guiraudou, Potential and tension changes induced by sodium removal in dog Purkinje fibers: Role of an electrogenic sodium-calcium exchange, J Physiol (Land) 311:605–622 (1981).Google Scholar