Bradykinin B2-receptor activation augments norepinephrine exocytosis from cardiac sympathetic nerve endings. Mediation by autocrine/paracrine mechanisms.
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 Ca(2+)-channel blocker omega-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 alpha 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 approximately equal to 6% to 40% (EC50, 20 nmol/L) and approximately equal to 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.
Seyedi
N
N
Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
Win
T
T
Lander
H M
HM
Levi
R
R
D000818:Animals; D019898:Autocrine Communication; D005089:Exocytosis / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000294:innervation* / Q000502:physiology*; D008297:Male; D009411:Nerve Endings / Q000502:physiology; D009469:Neuromuscular Junction / Q000502:physiology; D009638:Norepinephrine / Q000502:physiology*; D019899:Paracrine Communication; D018002:Receptors, Bradykinin / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology*
D018002:Receptors, Bradykinin; D009638:Norepinephrine