To assess the physiological role of intracellular Ca2+ in the changes of microrheological red blood cell (RBC) properties (RBC deformability and aggregation), we employed several types of chemicals that can increase and decrease of the intracellular Ca2+ concentration. The rise of Ca2+ influx, stimulated by mechanical loading, A23187, thrombin, prostaglandin F2 alpha was accompanied by a moderate red cell deformability lowering and an increase of their aggregation. In contrast, Ca2+ entry blocking into the red cells by verapamil led to a significant RBC aggregation decrease and deformability rise. Similar microrheological changes were observed in the red blood cells treated with phosphodiesterase inhibitors IBMX, vinpocetine, rolipram, pentoxifylline. When forskolin (10 mu M), an AC stimulator was added to RBC suspension, the RBC deformability was increased (p < 0.05). Somewhat more significant deformability rise appeared after RBC incubation with dB-AMP. Red cell aggregation was significantly decreased under these conditions (p < 0.01). On the whole the total data clearly show that the red cell aggregation and deformation changes were connected with an activation of both intracellular signaling pathways: Ca2+ regulatory mechanism and Gs-protein/adenylyl-cyclase-cAMP system. And the final red cell microrheological regulatory effect is connected with the crosstalk between these systems.