Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion.
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.
Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Christina J
CJ
Mackins
Seiichiro
S
Kano
Nahid
N
Seyedi
Ulrich
U
Schäfer
Alicia C
AC
Reid
Takuji
T
Machida
Randi B
RB
Silver
Roberto
R
Levi
D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D006168:Guinea Pigs; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009638:Norepinephrine / Q000378:metabolism*; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D013564:Sympathetic Nervous System / Q000378:metabolism
D000809:Angiotensins; D012083:Renin; D009638:Norepinephrine