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Abstract: In a previous paper we showed that bradykinin (BK), interacting with its B2 receptor, inhibits proximal tubule Na+-ATPase activity but does not change (Na+ +K+)ATPase activity. The aim of this paper was to investigate the molecular mechanisms involved in B2-mediated modulation of proximal tubule Na+-ATPase by BK. To abolish B1 receptor-mediated effects, all experiments were carried out in the presence of (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Leu), des-Arg9-[Leu8]-BK (DALBK), a specific antagonist of B1 receptor. A dual effect on the Na+-ATPase activity through the B2 receptor was found: short incubation times (1–10 min) stimulate the enzyme activity; long incubation times (10–60 min) inhibit it. The stimulatory effect of BK is mediated by activation of phosphoinositide-specific phospholipase C β (PI-PLCβ)/protein kinase C (PKC); its inhibitory action is mediated by Ca2+-independent phospholipase A2 (iPLA2). Prior activation of the PI-PLCβ/PKC pathway is required to activate the iPLA2-mediated inhibitory phase. These results reveal a new mechanism by which BK can modulate renal sodium excretion: coupling between B2 receptor and activation of membrane-associated iPLA2. [Copyright &y& Elsevier]