Activation of a GPCR, ORL1 receptor: A novel therapy to prevent heart failure progression.

ABSTRACT

Purpose: The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in the rat heart. We also found that Gata4 overexpression significantly increased a Pnoc gene expression, an endogenous ligand for cell membrane receptor, ORL1. We hypothesized that an activation of ORL1 receptor would suppress HF in a rat ischemic heart model. Method: Adult Sprague Dawley rats (8 weeks old, 6 males and 6 females) underwent left anterior descending coronary artery ligation. Three weeks later, normal saline or MCOPPB (ORL1 activator, 2.5mg/kg/day) intraperitoneal injection was started, and continued 5 days a week, for 3 months. Echocardiography was performed six times, pre-operative, 3 days after coronary artery ligation, pre-MCOPPB or saline injection, and 1, 2, and 3 months after saline or MCOPPB injection started. Animals were euthanized after 3 months follow up and the heart was harvested for histological analysis. Results: ORL1 activator, MCOPPB, significantly improved cardiac function after myocardial infarction in rat (Ejection fraction, MCOPPB vs saline at euthanasia, 67 ± 3 vs 43 ± 2, p < 0.001). MCOPPB also decreased fibrosis and induced angiogenesis. Conclusion: ORL1 activator, MCOPPB, may be a novel treatment for preventing HF progression.