© 1997 American Heart Association, Inc.
Articles |
Bradykinin B2-Receptor Activation Augments Norepinephrine Exocytosis From Cardiac Sympathetic Nerve Endings
Mediation by Autocrine/Paracrine Mechanisms
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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