The effects of temperature, pH, voltage and K+ were tested on Na+-Ca2+ and Ca2+-Ca2+ exchanges with a goal to elucidate the rate-limiting mechanisms. The initial rates (t = 1 s) of Nai- and Cai-dependent 45Ca uptakes were measured in the sarcolemma vesicles. At pH 7.4 the Ca2+-Ca2+ exchange shows a bell-shaped temperature curve with a maximum at 27-29 °C. This effect is not caused by irreversible inactivation of the exchanger. The increase of pH from pH 6.0 to 7.4 in the K+-free medium decelerates the Ca2+-Ca2+ exchange 1.5-2.0-fold, while the addition of K+ accelerates the Ca2+-Ca2+ exchange 2.0-3.0-fold. Therefore, the accelerating effect of K+ opposes the decelerating effect of deprotonation. Temperatures increase (6-45 °C) in the K+-free medium (pH 7.4) elevates the Na+- Ca2+/Ca2+-Ca2+ exchange ratio from 0.8 to 5.0. With varying temperatures (6-37 °C) and pH 5.0-9.7, K+ has no considerable effect on Na+-Ca2+ exchange but accelerates the Ca2+-Ca2+ exchange 2-3-fold. At 6-45 °C and fixed pH 7.4, the inside-positive potential (∆Ψ ≥ +200 mV) accelerates the Na+-Ca2+ exchange 1.7-2.0-fold, suggesting that the same rate-limiting reaction controls the Na+- Ca2+ exchange at various temperatures. It is concluded that (a) At pH > 6.5 (6-45 °C and 0-100 mM K+) the voltage-sensitive Na+ efflux limits the Na+-Ca2+ exchange, while the Ca2+ efflux limits the Ca2+-Ca2+ exchange, (b) At pH < 6.1 (6-45 °C and 0-100 mM K+) the voltage-insensitive Ca2+ influx limits both Na+-Ca2+ and Ca2+-Ca2+ exchanges (this may represent a reduced voltage sensitivity of Na+-Ca2+ exchange and the similar rates of Na+-Ca2+ and Ca2+-Ca2+ exchanges), (c) The bellshaped temperature curve of Ca2+-Ca2+ exchange cannot be described by a simple reversible reaction involving two species (the exchange has to involve at least three species), (d) K+ interacts with a deprotonated species (pH >6.1) accelerating the rate-limiting Ca2+ efflux of Ca2+-Ca2+ exchange.