Interaction between sensory C-fibers and cardiac mast cells in ischemia/reperfusion: activation of a local renin-angiotensin system culminating in severe arrhythmic dysfunction.
Renin, the rate-limiting enzyme in the activation of the renin-angiotensin system (RAS), is synthesized and stored in cardiac mast cells. In ischemia/reperfusion, cardiac sensory nerves release neuropeptides such as substance P that, by degranulating mast cells, might promote renin release, thus activating a local RAS and ultimately inducing cardiac dysfunction. We tested this hypothesis in whole hearts ex vivo, in cardiac nerve terminals in vitro, and in cultured mast cells. We found that substance P-containing nerves are juxtaposed to renin-containing cardiac mast cells. Chemical stimulation of these nerves elicited substance P release that was accompanied by renin release, with the latter being preventable by mast cell stabilization or blockade of substance P receptors. Substance P caused degranulation of mast cells in culture and elicited renin release, and both of these were prevented by substance P receptor blockade. Ischemia/reperfusion in ex vivo hearts caused the release of substance P, which was associated with an increase in renin and norepinephrine overflow and with sustained reperfusion arrhythmias; substance P receptor blockade prevented these changes. Substance P, norepinephrine, and renin were also released by acetaldehyde, a known product of ischemia/reperfusion, from cardiac synaptosomes and cultured mast cells, respectively. Collectively, our findings indicate that an important link exists in the heart between sensory nerves and renin-containing mast cells; substance P released from sensory nerves plays a significant role in the release of mast cell renin in ischemia/reperfusion and in the activation of a local cardiac RAS. This culminates in angiotensin production, norepinephrine release, and arrhythmic cardiac dysfunction.
Morrey
Christopher
C
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065-4896, USA.
Brazin
Jacqueline
J
Seyedi
Nahid
N
Corti
Federico
F
Silver
Randi B
RB
Levi
Roberto
R
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D009411:Nerve Endings / Q000473:pathology / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000473:pathology*; D009638:Norepinephrine / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000473:pathology*; D013373:Substance P / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D000447:Aldehydes; D013373:Substance P; D001619:beta-N-Acetylhexosaminidases; D012083:Renin; D015740:Calcitonin Gene-Related Peptide; D009638:Norepinephrine