We determined whether local bradykinin production modulates cardiac adrenergic activity. Depolarization of guinea pig heart sympathetic nerve endings (synaptosomes) with 1 to 100 mmol/L K⁺ caused the release of endogenous norepinephrine (10% to 50% above basal level). This release was exocytotic, because it depended on extracellular Ca²⁺, was inhibited by the N-type Ca²⁺-channel blocker ω-conotoxin and the protein kinase C inhibitor Ro31-8220, and was potentiated by the neuronal uptake-1 inhibitor desipramine. Typical of adrenergic terminals, norepinephrine exocytosis was enhanced by activation of prejunctional angiotensin AT₁-receptors and attenuated by adrenergic α₂-receptors, adenosine A₁-receptors, and histamine H₃-receptors. Exogenous bradykinin enhanced norepinephrine exocytosis by 7% to 35% (EC₅₀, 17 nmol/L), without inhibiting uptake 1. B₂-receptor, but not B₁-receptor, blockade antagonized this effect. The kininase II/angiotensin-converting enzyme inhibitor enalaprilat and the addition of kininogen or kallikrein enhanced norepinephrine exocytosis by ≈6% to 40% (EC₅₀, 20 nmol/L) and ≈25% to 60%, respectively. This potentiation was prevented by serine protease inhibitors and was antagonized by B₂-receptor blockade. Therefore, norepinephrine exocytosis is augmented when bradykinin synthesis is increased or when its breakdown is inhibited. This is the first report of a local kallikrein-kinin system in adrenergic nerve endings capable of generating enough bradykinin to activate B₂-receptors in an autocrine/paracrine fashion and thus enhance norepinephrine exocytosis. This amplification process may operate in disease states, such as myocardial ischemia, associated with severalfold increases in local kinin concentrations.