Cardiomyocytic apoptosis limited by bradykinin via restoration of nitric oxide after cardioplegic arrest.
BACKGROUND
Our previous studies revealed that cardioplegia-induced cardiac arrest under cardiopulmonary bypass (CPB) decreased cardiomyocytic nitric oxide and increased apoptosis. We hypothesized that pretreatment with bradykinin (BK) would improve the profile of anti-apoptotic proteins and inhibit cardiomyocytic apoptosis.


METHODS
New Zealand white rabbits received total CPB. Rabbits were weaned from CPB and reperfused for 4 h. Blood was sampled at various time points. Bradykinin and/or nitric oxide synthase (NOS) inhibitors or BK-receptor antagonists were infused systemically 30 min before beginning of CPB, and continued throughout the procedure. The ascending aorta was cross-clamped for 60 min while cold crystalloid cardioplegic solution was intermittently infused into the aortic root. The hearts were harvested and studied for evidence of apoptosis and ischemia/reperfusion induced inflammation-related cytokine production by cardiomyocytes.


RESULTS
Our results revealed that bradykinin supplementation during cardioplegia could prevent I/R-induced inflammatory and apoptotic effects, which could be reversed with a NOS inhibitor. BK antagonists and NOS inhibitors worsened the inflammatory and apoptotic responses of cardiomyocytes, which could be reversed with an exogenous NO donor.


CONCLUSIONS
Restoring the NO concentration after cardioplegia-induced cardiac arrest (CCA) under CPB with bradykinin could modulate (1) the nuclear translocation of NF-kappaB, (2) the plasma levels of inflammation-related cytokines, (3) the Bcl-2/Bax ratio, and (4) the occurrence of apoptosis. Exogenous bradykinin administration was associated with the myocardial apoptotic response by inhibition of NF-kappaB translocation, inflammatory cytokine production, Akt activation, and elevation of the Bcl-2/Bax ratio via a NO-mediated pathway.
Yeh
Chi-Hsiao
CH
Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan. yehccl@cgmh.org.tw
Chen
Tzu-Ping
TP
Wang
Yao-Chang
YC
Lin
Yu-Min
YM
Fang
Shu-Wen
SW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology / Q000627:therapeutic use*; D002315:Cardiopulmonary Bypass; D053148:Caspase 3 / Q000378:metabolism; D006324:Heart Arrest, Induced / Q000009:adverse effects; D020287:In Situ Nick-End Labeling; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D019210:Troponin I / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016277:Ventricular Function, Left; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016328:NF-kappa B; D019210:Troponin I; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D001920:Bradykinin