The use of aequorin as an intracellular calcium indicator in ventricular muscle is described. If the increase of intracellular calcium concentration associated with each contraction (the calcium transient) is measured during inotropic interventions, it is possible to distinguish two classes of inotropic intervention. One class leads to changes in the calcium transient which parallel the changes in tension. The second class leads to changes in the calcium transient and tension which are different in magnitude or direction. In this latter class, changes in the sensitivity of the contractile proteins to calcium are occurring and represent an important part of the inotropic mechanism. When oxidative phosphorylation is inhibited in an isolated mammalian papillary muscle, tension declines but the amplitude of the calcium transients is unaffected. Intracellular acidosis caused by lactate production associated with the increased rate of glycolysis is the probable mechanism of this decline in tension. When both oxidative phosphorylation and glycolysis are inhibited, both the calcium transient and the developed tension decline rapidly to zero. This profound contractile failure may be a consequence of a decline in the free energy of hydrolysis of ATP so that the sarcoplasmic reticulum can no longer accumulate calcium. Hypoxic contractures occur in the absence of significant increases in resting [Ca2+]i and are probably due to rigor produced by the low [ATP].