We studied inward rectifier K+ (Kir) channels in smooth muscle cells isolated from coronary arteries from humanely killed rabbits. In the cells from small-diameter ( 200 mm, LCASMC). The presence of Kir2.1 protein was confirmed in SCASMC from a Western blot assay. Endothelin-1 (ET-1) inhibited Kir currents in a dose-dependent manner, which was blocked by BQ-123, an ETA receptor antagonist. The inhibition of Kir currents by ET-1 was abolished by pretreatment with the protein kinase C (PKC) inhibitor, staurosporine (100 nM) or GF 109203X (1 mM). The PKC activators, phorbol 12,13-dibutyrate (PDBu) and 1-oleoyl-2-acetyl-sn-glycerol (OAG), reduced Kir currents. ET-1 also inhibited the ATP-dependent K+ (KATP), Ca2+-activated K+ (BKCa), and voltage-dependent K+ (KV) currents, which were not different between SCASMC and LCASMC. In the Langendorff-perfused heart, an application of Ba2+ markedly reduced the coronary blood flow, which was augmented by raising the concentration of extracellular K+ to 15 mM. From the above results, we conclude that Kir channels are expressed at a higher density in SCASMC than larger arteries, and that the Kir channels activity is negatively regulated by the stimulation of ETA-receptors via PKC pathway. Thus, this response may represent a mechanism by which ET-1 could enhance coronary vasoconstriction in conditions such as coronary vasospasm and hypertension.