Using highly sensitive antimony-bismuth thermopiles, the heat that is liberated during isometric contraction (initial heat) was measured simultaneously with the force signal in right ventricular papillary muscles of guinea pigs (n = 10). Measurements were taken before and after application of enoximone in a concentration of 10(-5) M. Enoximone increased peak developed tension from 1.92 +/- 0.98 to 2.81 +/- 1.11 g/mm2 (p less than 0.01) and the tension-time integral from 1.52 +/- 0.87 to 1.86 +/- 0.86 g.s/mm2 (p less than 0.05). Initial heat was increased from 0.50 +/- 0.13 to 0.79 +/- 0.24 mcal/g (p less than 0.01). The ratio between initial heat and tension-time integral, which is an inverse measure of myocardial economy of force generation, was increased from 3.77 +/- 1.17 to 4.66 +/- 1.49 mucal/g.s.cm (p less than 0.05). To study the potential changes induced by enoximone on an intracellular level, the initial heat was separated into tension-dependent heat (cross-bridge cycling) and tension-independent heat (calcium cycling). The latter increased from 0.20 +/- 0.05 to 0.28 +/- 0.09 mcal/g (p less than 0.05). The tension-dependent heat as normalized for a unit of developed tension-time integral increased from 2.17 +/- 0.63 to 2.86 +/- 0.79 mucal/g.s.cm (p less than 0.01). From these data, we conclude that enoximone decreases the economy of myocardial force generation by (a) increasing the number of calcium ions cycling during one twitch and (b) by altering the fundamental mechanisms of the contractile proteins with respect to force generation, i.e., faster contraction velocity and decreased economy of force generation.