PMID- 26040988 OWN - NLM STAT- MEDLINE DCOM- 20160119 LR - 20181113 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 13 DP - 2015 Jun 4 TI - The effects of phosphodiesterase-5 inhibitor sildenafil against post-resuscitation myocardial and intestinal microcirculatory dysfunction by attenuating apoptosis and regulating microRNAs expression: essential role of nitric oxide syntheses signaling. PG - 177 LID - 10.1186/s12967-015-0550-9 [doi] LID - 177 AB - BACKGROUND: Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion (I/R) injury. Sildenafil has been shown to attenuate postresuscitation myocardial dysfunction in piget models of ventricular fibrillation. This study was designed to investigate if administration of sildenafil will attenuate post-resuscitation myocardial dysfunction by attenuating apoptosis and regulating miRNA expressions, furthermore, ameliorating the severity of post-microcirculatory dysfunction. METHODS: Twenty-four male pigs (weighing 30 +/- 2 kg) were randomly divided into groups, sildenafil pretreatment (n = 8), saline (n = 8) and sham operation (sham, n = 8). Sildenafil pretreatment consisted of 0.5 mg/kg sildenafil, administered once intraperitoneally 30 min prior to ventricular fibrillation (VF). Eight minutes of untreated VF was followed by defibrillation in anesthetized, closed-chest pigs. Hemodynamic status and blood samples were obtained at 0 min, 0.5, 1, 2, 4 and 6 h after return of spontaneous circulation (ROSC). Surviving pigs were euthanatized at 24 h after ROSC, and hearts were removed for analysis by electron microscopy, western blotting, quantitative real-time polymerase chain reaction (PCR), and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Intestinal microcirculatory blood flow was visualized by a sidestream dark-field imaging device at baseline and 0.5, 1, 2, 4, and 6 h after ROSC. RESULTS: Compared with the saline group, the sildenafil group had a higher 24-hour survival (7/8 versus 3/8 survivors, p < 0.05) and a better outcome in hemodynamic parameters. The protective effect of sildenafil also correlated with reduced cardiomyocyte apoptosis, as evidenced by reduced TUNEL-positive cells, increased anti-apoptotic Bcl-2/Bax ratio and inhibited caspase-3 activity in myocardium. Additionally, sildenafil treatment inhibited the increases in the microRNA-1 levels and alleviated the decreases in the microRNA-133a levels which negatively regulates pro-apoptotic genes. At 6 h after ROSC, post-resuscitation perfused vessel density and microcirculatory flow index were significantly lower in the saline group than in the sildenafil group. CONCLUSIONS: The major findings of this study are as follows: (1) sildenafil improved post-resuscitation perfusion of the heart, and thus reduced cardiac myocyte apoptosis and improved cardiac function; (2) sildenafil treatment inhibited the increases in the microRNA-1 levels, but alleviated the decreases in the microRNA-133a levels. FAU - Zhang, Qian AU - Zhang Q AD - Department of Emergency Medicine, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China. zqian604@163.com. FAU - Wang, Guoxing AU - Wang G AD - Department of Emergency Medicine, Beijing You-yi Hospital, Capital Medical University, Beijing, 100050, China. 13520240749@163.com. FAU - Yuan, Wei AU - Yuan W AD - Department of Emergency Medicine, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China. 2000ywei@sina.com. FAU - Wu, Junyuan AU - Wu J AD - Department of Emergency Medicine, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China. wu007838@sina.com. FAU - Wang, Miaomiao AU - Wang M AD - Department of Emergency Medicine, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China. wmm0327@126.com. FAU - Li, ChunSheng AU - Li C AD - Department of Emergency Medicine, Beijing Chao-yang Hospital, Capital Medical University, Beijing, 100020, China. lcscyyy@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150604 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (MicroRNAs) RN - 0 (Phosphodiesterase 5 Inhibitors) RN - 0 (bcl-2-Associated X Protein) RN - 31C4KY9ESH (Nitric Oxide) RN - BW9B0ZE037 (Sildenafil Citrate) RN - EC 1.14.13.39 (Nitric Oxide Synthase) RN - EC 3.4.22.- (Caspase 3) RN - H2D2X058MU (Cyclic GMP) SB - IM MH - Animals MH - Apoptosis/*drug effects/genetics MH - Blood Gas Analysis MH - *Cardiopulmonary Resuscitation MH - Caspase 3/metabolism MH - Cyclic GMP/metabolism MH - Hemodynamics/drug effects MH - Intestines/*blood supply MH - Male MH - MicroRNAs/*genetics/metabolism MH - Microcirculation/*drug effects MH - Myocardium/*pathology MH - Myocytes, Cardiac/drug effects/metabolism/pathology/ultrastructure MH - Nitric Oxide/*metabolism MH - Nitric Oxide Synthase/metabolism MH - Phosphodiesterase 5 Inhibitors/pharmacology MH - Signal Transduction/drug effects/genetics MH - Sildenafil Citrate/*pharmacology MH - Survival Analysis MH - Sus scrofa MH - Ventricular Function/drug effects MH - bcl-2-Associated X Protein/metabolism PMC - PMC4467614 EDAT- 2015/06/05 06:00 MHDA- 2016/01/20 06:00 PMCR- 2015/06/04 CRDT- 2015/06/05 06:00 PHST- 2015/01/06 00:00 [received] PHST- 2015/05/26 00:00 [accepted] PHST- 2015/06/05 06:00 [entrez] PHST- 2015/06/05 06:00 [pubmed] PHST- 2016/01/20 06:00 [medline] PHST- 2015/06/04 00:00 [pmc-release] AID - 10.1186/s12967-015-0550-9 [pii] AID - 550 [pii] AID - 10.1186/s12967-015-0550-9 [doi] PST - epublish SO - J Transl Med. 2015 Jun 4;13:177. doi: 10.1186/s12967-015-0550-9.