The excessive contraction of small arteries under high blood pressure is the main contributor to the pathological change of hypertension. Current anti-hypertensive drugs, which lack a selective effect on small arteries in a hypertensive state, may cause many adverse effects. We have developed a novel opener of ATP-sensitive potassium channels, iptakalim, the vasorelaxing action of which is determined by the hypertensive status of small arteries. In conscious strokeprone, spontaneously hypertensive rats and “two-kidneys, one-clip” renal hypertensive dogs, this compound produced long-lasting hypotensive effects, with no tolerance. Furthermore, it exerted a protective effect against hypertensive damage to target organs. Given its potency and fewer side effects, iptakalim hydrochloride is a promising drug for the treatment of hypertension.