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Background: Cardiac dysfunction is well-described in endotoxemia and diagnosed in up to 60% of patients with endotoxic shock. ATP-sensitive potassium (KATP) channels are critical to cardiac function. This study investigates the role of Kir6.2 subunits of KATP channels on cardiac dysfunction in lipopolysaccharide (LPS)-induced endotoxemia. Methods: Kir6.2 subunits knockout (Kir6.2-/-) and wild-type (WT) mice were injected with LPS to induce endotoxemia. Cardiac function was monitored by echocardiography. Left ventricles were taken for microscopy (both light and electron) and TUNEL examination. Serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities, and tumor necrosis factor-α (TNF-α) levels in both serum and left ventricular tissues were determined. Results: Compared to WT, Kir6.2-/- mice showed significantly declined cardiac function 360 min after LPS administration, aggravated myocardial damage and elevated serum LDH and CK activities. Apoptotic cells were obviously increased in heart tissues from Kir6.2-/- mice at 90, 180 and 360 min. TNF-α expression in both serum and heart tissues of Kir6.2-/- mice was significantly increased. Conclusions: We conclude that Kir6.2 subunits are critical in resistance to endotoxemia-induced cardiac dysfunction through reducing myocardial damage by inhibition of apoptosis and inflammation. KATP channels blockers are extensively used in the treatment of diabetes, their potential role should therefore be considered in the clinic when patients treated with antidiabetic sulfonylureas are complicated by endotoxemia. [ABSTRACT FROM AUTHOR]