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(Circulation Research. 1997;81:774-784.)
© 1997 American Heart Association, Inc.

Articles

Bradykinin B₂-Receptor Activation Augments Norepinephrine Exocytosis From Cardiac Sympathetic Nerve Endings

Mediation by Autocrine/Paracrine Mechanisms

Nahid Seyedi, Terrance Win, Harry M. Lander, , Roberto Levi

From the Department of Pharmacology, Cornell University Medical College, New York, NY.

Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021. E-mail rlevi{at}mail.med.cornell.edu

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 Ca²⁺, was inhibited by the N-type Ca²⁺-channel blocker -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 ₂-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.

Key Words: bradykinin • cardiac synaptosome • norepinephrine exocytosis • adrenergic nerve ending • autocrine/paracrine

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