KRN4884 is a K+ channel opener. In the presence of intracellular ATP (1 mM), KRN4884 (0.1-3 μM) activates KATP channels in a concentration-dependent manner (EC50=0.55 μM). KRN4884 (0.3 μM) shifts the concentration-response relationship for ATP-induced KATP channel inhibition to the right and slightly upward direction without altering the slope. After either the spontaneous or Ca2+-induced channel rundown, KRN4884 (1 and 3 μM) partially restores the KATP channel activity. Furthermore, the effect of KRN4884 is augmented by the presence of uridine 5′-diphosphate (3 mM). KRN4884 activates cardiac KATP channels through not only decreasing the sensitivity of the channel to ATP but also directly stimulating the opening of the channel. KRN4884 (0.3 and 3 μM) increases the outward current in a concentration-dependent manner, and the unitary current amplitudes are similar to that of KATP channels in the ATP-free solution. The effects of KRN4884, a novel pyridinecarboxamidine type KATP channel opener, on serum triglyceride levels are investigated in Sprague-Dawley rats. Oral administration of KRN4884 (3 mg/kg) for 10 days causes a significant reduction in serum triglyceride levels, which is comparable to that of Clofibrate (160 mg/kg). Reduction in serum triglyceride levels by KRN4884 and Clofibrate are accompanied by a reduction in triglyceride levels both in chylomicron and in very low density lipoprotein. KRN4884 treatment does not affect serum concentrations of total cholesterol and phospholipid, but increases free fatty acid levels. Rats receiving KRN4884 exhibite an increase in lipoprotein lipase (LPL) activity both in adipose tissue and in skeletal muscle.