BRADYKININ B-2-RECEPTOR ACTIVATION AUGMENTS NOREPINEPHRINE EXOCYTOSISFROM CARDIAC SYMPATHETIC-NERVE ENDINGS - MEDIATION BY AUTOCRINE PARACRINE MECHANISMS/

We determined whether local bradykinin production modulates cardiac ad renergic activity. Depolarization of guinea pig heart sympathetic nerv e endings (synaptosomes) with 1 to 100 mmol/L K+ caused the release of endogenous norepinephrine (10% to 50% above basal level). This releas e was exocytotic, because it depended on extracellular Ca2+, was inhib ited by the N-type Ca2+-channel blocker omega-conotoxin and the protei n kinase C inhibitor Ro31-8220, and was potentiated by the neuronal up take-1 inhibitor desipramine. Typical of adrenergic terminals, norepin ephrine exocytosis was enhanced by activation of prejunctional angiote nsin AT(1)-receptors and attenuated by adrenergic alpha(2)-receptors, adenosine A(1)-receptors, and histamine H-3-receptors. Exogenous brady kinin enhanced norepinephrine exocytosis by 7% to 35% (EC50, 17 nmol/L ), without inhibiting uptake 1. B-2-receptor, but not B-1-receptor, bl ockade antagonized this effect. The kininase II/angiotensin-converting enzyme inhibitor enalaprilat and the addition of kininogen or kallikr ein enhanced norepinephrine exocytosis by approximate to 6% to 40% (EC 50, 20 nmol/L) and approximate to 25% to 60%, respectively. This poten tiation was prevented by serine protease inhibitors and was antagonize d by B-2-receptor blockade. Therefore, norepinephrine exocytosis is au gmented when bradykinin synthesis is increased or when its breakdown i s inhibited. This is the first report of a local kallikrein-kinin syst em 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 oper ate in disease states, such as myocardial ischemia, associated with se veralfold increases in local kinin concentrations.