Abstract P1054: Oral Administration Of New Agonist Of Adenosine Receptor Reduces Inflammatory Process And Cardiac Remodeling Induced By Myocardial Infarction In Rats

Abstract

Treatment of acute myocardial infarction (AMI) is based on strategies to relief pain and increase survival. Thus, this work investigates the effects of a new agonist of adenosine receptor called LASSBio-1860 in an experimental model of AMI, in order to improve cardiac function. The protocols were approved by the Ethics Committee for the Use of Animals at Federal University of Rio de Janeiro (# 103/17). The experimental AMI was induced by the ligation of the anterior descending coronary artery in male Wistar rats (180-200 g), which were randomly divided into groups treated orally with vehicle (DMSO) or 70 μmol/kg of LASSBio-1860 for 7 days. At the end of the experimental protocol, hemodynamic parameters were obtained using echocardiography and the expression of markers involved in the inflammatory pathway (TNF-alpha, p38) and cardiac remodeling (p-ERK-1/2 and t-ERK) was evaluated. AMI increased the left ventricular (LV) wall thickness from 0.11 ± 0.04 to 0.29 ± 0.02 cm (p <0.05) which was reduced to 0.21 ± 0.01 cm after treatment with LASSBio-1860. The impaired ejection fraction observed after AMI (reduction from 91.5 ± 0.5 to 45.2 ± 1.3%) was partially reversed to 60.1 ± 10.3% with the treatment. Additionally, the agonist of adenosine receptor normalized the increased filling pressure of 31.3 ± 4.4 to 15.9 ± 3.9. Increased LV final systolic pressure was detected after AMI, changing from 83.8 ± 12.5 (control group) to 104.7 ± 1.1, which was recovered to 95.3 ± 21.4 mmHg with LASSBio-1860. An increase in the TNF-alpha expression as well as nuclear p38 labeling was detected in the heart from infarcted animals which was reduced after administration of LASSBio-1860. Furthermore, AMI increased the ratio of phosphorylated and total ERK-1/2 from 0.78 ± 0.01 to 0.89 ± 0.01 while treatment with LASSBio-1860 reduced to 0.79 ± 0.01 (p < 0.05). Similarly, p38 increased from 0.72 ± 0.11 to 1.58 ± 0.36 induced by AMI but was reduced to 1.17 ± 0.43 by LASSBio-1860. An increase in collagen deposition from 3.6 ± 0.9 to 31.5 ± 4.29 was observed in hearts from infarcted animals, which was reduced to 26.8 ± 1.6 with treatment. Also, AMI promoted an increase in p38 nuclear labeling from 9.9 ± 3.9 to 40.8 ± 3.3 which was decreased to 29.9 ± 1.7 in treated animals. Similar increase and recovery was detected with iNOS because AMI caused an increase from 9.0 ± 4.1 to 25.3 ± 3.9 and improvement to 14.2 ± 0.6. In conclusion, the reduction of the inflammatory response may be related to the activation of adenosine receptors by LASSBio-1860, which leads to an improvement in AMI-induced cardiac remodeling and dysfunction.