Abstract
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.
Footnotes
This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL34415, HL73400, T32-HL007423].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.172262.
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ABBREVIATIONS:
- RAS
- renin-angiotensin system
- ANG I
- angiotensin I
- ANG II
- angiotensin II
- HBS
- HEPES-buffered saline solution
- HMC-1
- human mastocytoma cell line
- NE
- norepinephrine
- ROS
- reactive oxygen species
- VT/VF
- ventricular tachycardia/ventricular fibrillation
- ANOVA
- analysis of variance
- CGRP
- calcitonin gene-related peptide
- CP99994
- (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine)
- EXP3174
- 2-n-butyl-4-chloro-1-((2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5-carboxylic acid.
- Received June 29, 2010.
- Accepted July 23, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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