Cardiomyocytic apoptosis limited by bradykinin via restoration of nitric oxide after cardioplegic arrest
ABSTRACT 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.
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.
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.
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.
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ABSTRACT: One of the most common health problems are diseases of the cardiovascular system with a great bulk of disease burden; while a considerable number of cardiac patients undergo cardiac surgery; cardiac surgical procedures with cardiopulmonary bypass (CPB) are nowadays among the top list of surgical procedures. More than half of a century has passed since the introduction of total cardiopulmonary bypass (CPB). One of the main untoward effects of CPB is systemic inflammation; causing an “acute phase reaction” responsible for the production of other unwanted postoperative complications. The humoral and cellular components of the immune system are among the main parts of these compensatory mechanisms. There are a number of therapeutic agents used to suppress this inflammatory process. Since CPB is composed of a multitude of items, there are many studies assessing the possible methods and therapeutics for prevention or treatment of inflammation in patients undergoing CPB. According to a conventional classification, the anti-inflammatory methods are classified as either pharmacologic strategies or technical strategies. The pharmacologic strategies are those with the usage of one or more therapeutic agents; while the technical strategies are those that try to modify the CPB techniques. However, in this manuscript, the main pharmacological strategies are discussed.Iranian journal of pharmaceutical research (IJPR) 03/2012; 11(3):705-14. · 0.51 Impact Factor
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ABSTRACT: Radiation-induced heart disease (RIHD) is a serious side effect of radiotherapy for intrathoracic and chest wall tumors. The threshold dose for development of clinically significant RIHD is believed to be lower than previously assumed. Therefore, research into mechanisms of RIHD has gained substantial momentum. RIHD becomes clinically apparent ten to fifteen years after radiation exposure. Chronic manifestations of RIHD include accelerated atherosclerosis, cardiomyopathy, and valve abnormalities. Reducing exposure of the heart during radiotherapy is the only known method of preventing RIHD, and there are no approaches to reverse RIHD once it occurs. We use a combination of pharmacological and genetic animal models to determine biological mechanisms of RIHD. Major technological advances in small animal research have made this type of study more valuable. The long-term goal of this work is to identify targets for intervention in RIHD, thereby enhancing the efficacy and safety of thoracic radiotherapy.Radiation Research 06/2012; 178(1):1-6. DOI:10.2307/23261971 · 2.45 Impact Factor