Background Our previous studies have demonstrated that Tongxinluo (TXL),a traditional Chinese medicine,can protect hearts against no-reflow and reperfusion injury in a protein kinase A (PKA)-dependent manner.The present study was to investigate whether the PKA-mediated cardioprotection of TXL against no-refiow and reperfusion injury relates to the inhibition of myocardial inflammation,edema,and apoptosis.Methods In a 90-minute ischemia and 3-hour reperfusion model,minipigs were randomly assigned to sham,control,TXL (0.05 g/kg,gavaged one hour prior to ischemia),and TXL + H-89 (a PKA inhibitor,intravenously and continuously infused at 1.0 μg/kg per minute) groups.Myocardial no-reflow,necrosis,edema,and apoptosis were determined by pathological and histological studies.Myocardial activity of PKA and myeloperoxidase was measured by colorimetric method.The expression of PKA,phosphorylated cAMP response element-binding protein (p-CREB) (Ser133),tumor necrosis factor a (TNF-α),P-selectin,apoptotic proteins,and aquaporins was detected by West blotting analysis.Results TXL decreased the no-reflow area by 37.4％ and reduced the infarct size by 27.0％ (P＜0.05).TXL pretreatment increased the PKA activity and the expression of Ser133 p-CREB in the reflow and no-reflow myocardium (P ＜0.05).TXL inhibited the ischemia-reperfusion-induced elevation of myeloperoxidase activities and the expression of TNF-α and P-selectin,reduced myocardial edema in the left ventricle and the reflow and no-reflow areas and the expression of aquaporin-4,-8,and-9,and decreased myocytes apoptosis by regulation of apoptotic protein expression in the reflow and no-reflow myocardium.However,addition of the PKA inhibitor H-89 counteracted these beneficial effects of TXL.Conclusion PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation,edema,and apoptosis in the reflow and no-reflow myocardium.