The effects on whole body or cardiac metabolism of carbon dioxide, calcium, potassium, or digoxin were studied in 16 normal swine and 31 swine susceptible to malignant hyperthermia (MHS). Malignant hyperthermia (MH) was defined as an increase in metabolism that occurred in MHS but not in normal pigs. Whole body response: despite a sustained PaCO2greater than 130 mmHg, MH did not develop in four intact MHS swine during thiopental-N2O anesthesia and controlled ventilation. Drugs given during total cardiopulmonary bypass: MH did not develop in five MHS pigs with blood ionized calcium to 15 mEq/1, in four MHS pigs with digoxin levels to 60 ng/ml, or in four normal pigs with potassium to 10 mEq/1. In six MHS pigs, oxygen consumption increased from 6.5 to 11.6 ml O2· Min-1·kg-1when potassium exceeded 6 mEq/l; lactate did not increase. Cardiac response (during extracorporeal right heart bypass): eight pigs (four normal, four MHS) with blood ionized calcium to 5 mEq/l and eight pigs (four normal, four MHS) with digoxin levels above 7.5 ng/ml had increased myocardial oxygen consumption. Cardiac potassium efflux or lactate production did not occur in normal or MHS pigs. Increased arterial potassium (7.4–8.5 mEq/l) did not alter myocardial oxygen consumption or lactate production in four MHS or four normal pigs. MH responses were initiated only by potassium and only in regard to whole body metabolism. Cardiac metabolism increased as a result of specific drugs (calcium, digoxin), unrelated to MH phenomena. Porcine inbreeding resulting in MH susceptibility of skeletal muscle does not imply abnormality in other tissues.