The effect of phospholipid and MgATPase modulation was evaluated on the cardiovascular actions of vasopressin in normal and lithium carbonate- (Li2CO3) induced polyuric rats. We examined the effects of the phospholipase inhibitor neomycin, the diacylglycerol kinase II inhibitor R59949 and the MgATPase activator sphingosine on heart rate (HR) and blood pressure (BP) responses to vasopressin analogues lysine vasopressin (LVP) and arginine vasopressin (AVP). R59949 (20 microg/kg) produced an increase while sphingosine (30 microg/kg) caused a decrease in HR responses in both control and polyuric rats. Pretreatment with sphingosine caused significant enhancement of LVP- (10 microg/kg) induced bradycardia in polyuria rats compared with control animals (p < 0.01). R59949 induced a potentiation of vasopressin-induced bradycardia in control animals compared with polyuria rats. Pretreatment with sphingosine and R59949 produced a significant increase in BP per se and potentiated the actions of LVP in control animals, while the response in the lithium-treated animals was attenuated. Neomycin caused a reduction in HR and BP in control and lithium-treated animals. To evaluate the central role of the MgATPase enzyme we used sphingosine, which significantly increased the locomotor activity of lithium-treated animals, suggesting a possible central interaction of lithium and MgATPase (p < 0.05). These results strongly suggest that phospholipid mediators and MgATPase modulation contribute to the alteration of the cardiovascular effects of vasopressin in lithium carbonate-induced polyuric rats.