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Cardiac mast cell–derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion
Christina J. Mackins, … , Randi B. Silver, Roberto Levi
Christina J. Mackins, … , Randi B. Silver, Roberto Levi
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):1063-1070. https://doi.org/10.1172/JCI25713.
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Research Article Cardiology Article has an altmetric score of 4

Cardiac mast cell–derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion

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Abstract

Having identified renin in cardiac mast cells, we assessed whether its release leads to cardiac dysfunction. In Langendorff-perfused guinea pig hearts, mast cell degranulation with compound 48/80 released Ang I–forming activity. This activity was blocked by the selective renin inhibitor BILA2157, indicating that renin was responsible for Ang I formation. Local generation of cardiac Ang II from mast cell–derived renin also elicited norepinephrine release from isolated sympathetic nerve terminals. This action was mediated by Ang II-type 1 (AT1) receptors. In 2 models of ischemia/reperfusion using Langendorff-perfused guinea pig and mouse hearts, a significant coronary spillover of renin and norepinephrine was observed. In both models, this was accompanied by ventricular fibrillation. Mast cell stabilization with cromolyn or lodoxamide markedly reduced active renin overflow and attenuated both norepinephrine release and arrhythmias. Similar cardioprotection was observed in guinea pig hearts treated with BILA2157 or the AT1 receptor antagonist EXP3174. Renin overflow and arrhythmias in ischemia/reperfusion were much less prominent in hearts of mast cell–deficient mice than in control hearts. Thus, mast cell–derived renin is pivotal for activating a cardiac renin-angiotensin system leading to excessive norepinephrine release in ischemia/reperfusion. Mast cell–derived renin may be a useful therapeutic target for hyperadrenergic dysfunctions, such as arrhythmias, sudden cardiac death, myocardial ischemia, and congestive heart failure.

Authors

Christina J. Mackins, Seiichiro Kano, Nahid Seyedi, Ulrich Schäfer, Alicia C. Reid, Takuji Machida, Randi B. Silver, Roberto Levi

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Figure 6

The release of mast cell renin in isolated mouse hearts subjected to ischemia/reperfusion is associated with NE release and reperfusion arrhythmias.

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            Mast cell stabilization, renin inhibition, and AT1
        ...
Nineteen mouse hearts were subjected to 20-minute ischemia (i.e., perfusion with glucose- and pyruvic acid–free KH buffer bubbled with 95% N2 + 5% CO2) followed by a 30-minute reperfusion with oxygenated KH buffer, either in the absence (n = 7) or presence of cromolyn (300 μM; n = 6) or BILA2157 (100 nM; n = 6). Bars indicate means α SEM. (A) Duration of reperfusion arrhythmias (VT/VF). Note that reperfusion arrhythmias were prevented in hearts pretreated with BILA2157. (B and C) Overflow of NE and Ang I–forming activity collected over 30 minutes either before ischemia or at the start of reperfusion. *Significantly different from own control; P < 0.05 by 1-way ANOVA with Dunnett’s produre.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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