Comparative Study of Vasodilator Effects of the Potassium Channel Openers NIP-121 and Levcromakalim in Dogs and Rats

The effects of potassium channel openers NIP-121 ((+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-piperidine-1-yl)-6H- pyrano[2,3-ss]benz-2,1,3-oxadiazole) and levcromakalim were examined in vitro and in vivo. In isolated canine vascular beds, NIP-121 (3 x 10(-9) to 10(-7) M) and levcromakalim (3 x 10(-8) to 10(-6) M) produced a concentration-dependent reduction in the vasoconstrictor responses to U46619. The effects were antagonized by glibenclamide, an ATP-sensitive potassium channel blocker. The maximal relaxation was more than 70% of the maximal vasodilation induced by papaverine (10(-4) M), except in the basilar artery. These compounds had very potent effects on the coronary and cranial mesenteric arteries and saphenous vein. In the coronary perfused rat heart, both compounds (10(-7) M) also increased coronary perfusion flow. The effects were also inhibited by glibenclamide (10(-6) M). In anesthetized dogs, NIP-121 (1 to 10 micrograms/kg (3.2 to 32 nmol/kg), i.v.) and levcromakalim (3 to 30 micrograms/kg (10.5 to 105 nmol/kg), i.v.) dose-dependently increased coronary and renal blood flow. NIP-121 and levcromakalim at higher doses produced the greatest increase in coronary blood flow among the blood vessels examined, in spite of the hypotensive effect. In conclusion, NIP-121 and levcromakalim were similarly selective vasodilators on the canine isolated coronary and cranial mesenteric arteries and saphenous vein, and they selectively increased coronary blood flow in vivo. With respect to increasing the coronary blood flow, NIP-121 had a fourfold greater potency than levcromakalim. This effect might be related to the glibenclamide-sensitive potassium channels.