An endocannabinoid is an important regulatory system for the many physiological functions in all vertebrate organisms. There are a lot of clinical data describing the role of endocannabinoids in the function of salivary gland. However their role in salivation remains almost unclear. Experiments were performed on male Wistar rats (6-7 weeks old, 100-150 g). Gland was removed after intraperitoneal injection of pentobarbital. Submandibular salivary gland acinar cells were isolated by collagenase treatment. Calcium concentration was estimated by arsenazo III. Protein content was determined using Lowry method. We showed that in vitro application of synthetic agonist of CB1 and CB2 cannabinoid receptors – WIN 55,212-2 (5 μM) to Ca²⁺-free extracellular solution (1 mM EGTA, 5 min) decreased total calcium content on 39±6 % (p<0,001, n=6). At the same time the agonist of the CB2 cannabinoid receptors – virodhamine (30 μM) caused the decrease of calcium content in isolated acini on 28±4 % (p<0,001, n=8). After that we found that addition of 2 mM CaCl₂ (for 5 min) in the presence of virodhamine evoked significant increase of total Ca²⁺ content in the acinar cells on 130±22 % (p<0,001, n=6) whereas in control – on 57±15 % (p<0,01, n=6). In addition, when WIN 55,212-2 (5 μM) and virodhamine (30 μM) was applied to isolated acini separately in the presence of thapsigargin (0,1 μM) in Ca²⁺-free medium (1 mM EGTA, 10 min) we observed a decrease in the total calcium content on 30±6 % (p<0,01, n=8) and 19±3 % (p<0,001, n=8) accordingly to the effect of thapsigargin only. The latter suggest the potentiation of the Ca²⁺ release from the endoplasmic reticulum upon activation of CB1 and CB2 receptors. We have also found that addition of 2 mM CaCl₂ (for 5 min) in the presence of the mixture of WIN 55,212-2 and thapsigargin occurs dramatic increase of the total Ca²⁺-content on 310±34 % (p<0,01, n=6) whereas in the presence of thapsigargin only – on 126±41 % (p<0,05, n=9). Likewise, the addition of 2 mM CaCl₂ (for 5 min) in the presence of the mixture of virodhamine and thapsigargin induces increase of the total Ca²⁺-content on 213±46 % (p<0,001, n=7) whereas the thapsigargin only – on 108±38 % (p<0,001, n=7). In conclusion, our data suggest that endogenous CB1 and CB2 cannabinoid receptors contribute to the regulation of submandibular salivary gland and this regulation occurs via Ca²⁺-dependent mechanisms (Ca²⁺ release from the endoplasmic reticulum and consequent store-operated Ca²⁺-entry).