Metabolic acidosis induces a decrease in the developed force of cardiac muscle by affecting every step of the excitation--contraction coupling pathway. Due to transient worsening in intracellular acidosis, the value of administering sodium bicarbonate therapeutically during acute acidosis has been questioned. An alternative therapeutic drug, Tris-hydroxymethyl aminomethane (THAM) has the advantage of diffusing into the intracellular space. This study was designed to evaluate the effects of metabolic acidosis on myocardial performance and to determine the effects of alkalinization with sodium bicarbonate, THAM, and their combination. Using a blood-perfused isolated heart preparation, left ventricular contractility and relaxation were measured at normal pH and during metabolic acidosis (pH = 7.0). Acidosis dramatically impaired myocardial contractility and relaxation. After buffering with sodium bicarbonate, although plasma bicarbonate concentration was normalized, pH remained below normal owing to an increased PaCO2. Contractility and relation were initially worsened, then slightly improved to return to control values. THAM uncompletely buffered acidosis but significantly improved contractility and relaxation. The combination of THAM with sodium bicarbonate perfectly buffered acidosis without modifying PaCO2 and significantly improved contractility. The combination of THAM with sodium bicarbonate is based on the ability of THAM to capture the CO2 produced by the sodium bicarbonate buffer. This combination achieves a perfect correction of metabolic acidosis and improves myocardial performance.