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

摘要

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?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.