We evaluated whether cromakalim (BRL 34915), a vasorelaxant agent which acts by opening potassium channels, could affect the systemic effects of endothelin, a newly discovered vasoconstrictive peptide. Intravenous administration of endothelin alone (400 pmol/kg) to anesthetized dogs produced blood pressure elevation, which was associated with an increase in cardiac output in the early phase, and was associated with an increase in total peripheral resistance in the late phase. Electrocardiogram showed significant ST-elevation in II, III, and aVF, and ST-depression in aVR and aVL. The same dose of endothelin given to dogs pretreated with cromakalim did not induce these hemodynamic and electrocardiographic changes. Thus, cromakalim, a potassium activator, inhibited the hemodynamic and electrocardiographic actions of endothelin, suggesting that hyperpolarization due to potassium channel activation inhibited the voltage-dependent calcium channel, which is thought to be a major mechanism for the pressor action of endothelin.