We investigated the effects of nicorandil, which is a hybrid between a nitrate and an ATP-sensitive potassium channel (K<sub>ATP</sub>) opener, on cultured rat mesangial cell proliferation. Nicorandil (1 µ M to 1 m M inhibited [<sup>3</sup>H]thymidine incorporation into rat mesangial cells in a concentration-dependent manner. Nicorandil (1 µ M to 1 m M) also inhibited the number of cells. Nicorandil increased cyclic guanosine 3′,5′-cyclic monophosphate accumulation in mesangial cells. A protein kinase G inhibitor, KT5823, partially eliminated the inhibition of mesangial cell proliferation by nicorandil. Methylene blue, a guanylate cyclase inhibitor, blocked the inhibitory effect of nicorandil on mesangial cell proliferation. We also examined the effects of K<sub>ATP</sub> mediators. Cromakalim, a K<sub>ATP</sub> activator, and glibenclamide, a K<sub>ATP</sub> inhibitor, had little effect on the proliferation of mesangial cells. These results suggest that the inhibitory effects of nicorandil on mesangial cell proliferation are mediated via the protein kinase G pathway.