Abstract
Excessive inflammatory and oxidative stress lead to circulatory failure, multiple organ dysfunction, and high mortality in patients with sepsis. Microbial infection-induced DNA hypermethylation is associated with the augmentation of inflammation and oxidative stress. In our previous study, the antiarrhythmic drug procainamide inhibits the expression of DNA methyltransferase 1 (DNMT1) and diminishes IL-6 levels in rats with rhabdomyolysis. Thus, we further evaluated the effects of procainamide on the development of circulatory failure and multiple organ dysfunction in rats with endotoxic shock. Male Wistar rats were intravenously infused with saline or lipopolysaccharide (LPS) followed by procainamide administration. The changes of hemodynamics, blood glucose, biochemical variables, and plasma nitric oxide (NO) levels were analyzed during the experimental period. At the end of experiments, animal organs were also obtained for examining superoxide production, neutrophil infiltration, and DNA methylation status. Our results showed that LPS induced circulatory failure, multiple organ dysfunction, and high mortality rate in endotoxemic rats. Overt neutrophil infiltration and superoxide production, accompanied by the elevations of DNMT1 and 5-methylcytosine levels in the lung of endotoxemic rats were also observed. Treatment of endotoxemic animals with procainamide not only inhibited the increased levels of DNMT1 and 5-methylcytosine but also ameliorated neutrophil infiltration and superoxide production in the lung. In addition, the anti-inflammatory gene, IL27RA, was down-regulated in the LPS group and up-regulated in the LPS + Procainamide group. Procainamide also diminished IL27RA methylation in the lung of endotoxemic rat. Moreover, both DNMT inhibitors procainamide and hydralazine improved hypotension, hypoglycemia, and multiple organ dysfunction of LPS-treated rats. Thus, we suggest that the beneficial effects of procainamide could be attributed to the suppression of DNA methylation, neutrophil infiltration, superoxide production, and NO formation. It seems that this old drug may have new potential uses in infectious diseases, in particular, associated with endotoxemia.
Highlights
Sepsis is a life-threatening disease triggered by the invasion of microbes and dysregulation of innate immune system [1]
The animals in the LPS group showed a significant decrease in mean arterial blood pressure (MAP) and pressor responses to NE, and a significant increase in heart rate (HR) during the experimental period
The administration of LPS rats with hydralazine significantly improved hypotension and hypoglycemia at 6 h after LPS (Fig 10A and 10B), but hydralazine had no effects on tachycardia and vascular hyporesponsiveness to NE induced by LPS
Summary
Sepsis is a life-threatening disease triggered by the invasion of microbes and dysregulation of innate immune system [1]. Certain microbial toxins, such as lipopolysaccharide (LPS), are capable of engaging Toll-like receptors to activate the immune cells and other cell types. Reactive oxygen species (ROS), and nitric oxide (NO) causes systemic inflammatory response, redox imbalance, and arterial hypotension. These phenomena lead to progressive and irreversible multiple organ dysfunction and high mortality during sepsis [2]. New therapeutic options for further improvement in outcome of sepsis are needed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
