The effects of caffeine, a widely used pharmacological tool for releasing Ca2+ from the sarcoplasmic reticulum (SR), on the resting rate of oxygen consumption and left ventricular diastolic pressure development of isolated, KCl-arrested, guinea pig hearts was examined. Caffeine (10 mmol/l) had no effect on either the rate of oxygen consumption or left ventricular pressure development. However, when Ca2+ extrusion via the Na+/Ca2+ exchanger was retarded, whether by reducing the external Na+ concentration ([Na+]o) from 143 to 57 mmol/l or through further depolarizing the membrane by increasing external K+ concentration ([K+]o) from 20 to 40 mmol/l, the subsequent introduction of caffeine evoked a pronounced increase in the rate of oxygen consumption. This was accompanied by a small contracture in the low [Na+]o condition only. In the absence of external Ca2+ the stimulatory effects of caffeine on cardiac energetics in either the low [Na+]o or 40 mmol/l [K+]o condition was totally prevented. It is concluded that Na+/Ca2+ exchange plays a major role in dictating the energetic response of the cardiac cell to pharmacological activation of the SR Ca2+ release channel by caffeine.