U50,488H inhibits ischemia/reperfusion-induced neutrophil accumulation and TNF-α production in rat hearts

AIM: To investigate alterations in neutrophil accumulation and TNF-α levels after activation of kappa (κ)-opioid receptor by U50,488H in ischemia/reperfusion-injured rat hearts and the possible mechanism involved. METHODS: 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. RESULTS: Compared with those in MI/R group, U50,488H reduced myocardial infarction area, myocardial myeloperoxidase (MPO) level, serum creatinine kinase (CK) level and serum and myocardial TNF-α production. U50,488H also increased the NOx level in myocardium subjected to I/R injury. All the effects of U50,488H were abolished by Nor-BNI, a selective κ-opioid antagonist, by Wortmannin, a specific PI3K inhibitor; and by L-NAME, a nitric oxide synthase (NOS) inhibitor. CONCLUSION: U50,488H is cardioprotective through the activation of κ-opioid receptor. This protective effect may be associated with the increase in NO production caused by activation of PI3K pathway and the inhibition of neutrophil accumulation and TNF-α introduction caused by U50,488H treatment in myocardium subjected to I/R.