U50,488H inhibits neutrophil accumulation and TNF-α induction induced by ischemia–reperfusion in rat heart

Abstract

The role of the κ-opioid receptor in inflammation is not well understood. The aim of this study was to investigate whether the κ-opioid receptor agonist U50,488H modulates neutrophil accumulation and TNF-α induction in an ischemia–reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia–reperfusion (MI/R) alone, MI/R+U50,488H, MI/R+U50,488H+Wortmannin, and MI/R+U50,488H+L-NAME. The results demonstrated that compared to MI/R, U50,488H reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) levels, and both serum and myocardial TNF-α production. Increases were seen in NOx levels in the myocardium subjected to MI/R injury. All demonstrated effects of U50,488H were abolished by Nor-BNI, a selective κ-opioid receptor antagonist; Wortmannin, a specific PI3K inhibitor; or L-NAME, a nitric oxide synthase (NOS) inhibitor. In summary, κ-opioid receptor stimulation with U50,488H produces both cardioprotective and anti-inflammatory effects. These effects may be associated with an increase in NO production and the inhibition of neutrophil accumulation and TNF-α induction via a PI3K sensitive pathway in myocardium subjected to MI/R.