We studied the effect of temperature, lithium and indomethacin on Na+, K+, 2Cl-- and K+, Cl--cotransport stimulated in rat erythrocytes by osmotic shrinkage and swelling, respectively. The heat treatment at 49-degrees-C disturbing organization of the membrane carcass protein has no effect on the basal Na+, K+, 2Cl--cotransport but suppresses a shrinkage-induced activation of this system. Unlike Na+, K+, 2Cl--cotransport, the rate of K+, Cl--cotransport in isoosmotic medium increases more than 10-fold after the preincubation at 49-degrees-C which makes it difficult to study the influence of hypotonic swelling. The loading with lithium used to inhibit phosphoinositol phosphatases leads to a 2-fold decrease of the increment in the rate of Na+, K+, 2Cl--cotransport induced by shrinkage but is without effect on K+, Cl--cotransport activated by swelling. Based on this, it is suggested that the molecular mechanisms of volumedependent activation of the ion-transporting systems are significantly different.