The effect of volatile anesthetics (VA) on the pH dependence of calcium uptake by cardiac sarcoplasmic reticulum (SR) was studied. SR was incubated at 37 degrees C with 45CaCl2 in the control state (no anesthetic) and in the presence of each of the VA from pH 6.6-7.6. The VA used were: halothane, 1.3%; enflurane, 1.8%; and isoflurane, 1.2%. In the control state, the initial rate of calcium uptake, measured after a 2-min incubation, was maximal at pH 6.8 (mean +/- SEM: 665 +/- 37 nmoles/mg) and markedly inhibited at pH 7.6 (107 +/- 9 nmoles/mg). In the presence of the VA, the calcium uptake rate was mildly depressed (7-32%) at pH 6.6-6.8, unchanged at pH 7.0, and greatly enhanced (52-78%) at pH 7.2-7.6, when compared to control. The maximal uptake of calcium by the SR at a calcium concentration of 10(-6)M, measured by a 20-min incubation, had a similar pH dependence in the control state, with a decline first evident at pH 7.2 and a 50% drop in the maximal uptake of calcium from pH 7.0-7.6. The presence of the VA was associated with a uniform depression of the maximal uptake of calcium by the SR at all pH levels measured. In view of these findings, it appears that pH does affect SR function in the presence of VA. This alteration of the pH effect by VA may be a factor responsible for discrepancies in results previously reported by investigators studying the effects of VA on the uptake of calcium by the SR.