Bradykinin B 2 -Receptor Activation Augments Norepinephrine Exocytosis From Cardiac Sympathetic Nerve Endings

Abstract

Abstract 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 Ca 2+ , was inhibited by the N-type Ca 2+ -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 AT 1 -receptors and attenuated by adrenergic α 2 -receptors, adenosine A 1 -receptors, and histamine H 3 -receptors. Exogenous bradykinin enhanced norepinephrine exocytosis by 7% to 35% (EC 50 , 17 nmol/L), without inhibiting uptake 1. B 2 -receptor, but not B 1 -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% (EC 50 , 20 nmol/L) and ≈25% to 60%, respectively. This potentiation was prevented by serine protease inhibitors and was antagonized by B 2 -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 B 2 -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.