The effects of a new benzopyran derivative, NIP-142, on atrial fibrillation (AF) and flutter (AFL) and on electrophysiological variables were studied in the dog. NIP-142 (3mg/kg) was administered intravenously to pentobarbital-anesthetized beagles during vagally-induced AF and during AFL induced after placement of an intercaval crush. Isolated canine atrial tissues were studied using standard microelectrode technique. NIP-142 terminated AF in 5 of 6 dogs after an increase in fibrillation cycle length (CL) and prevented reinitiation of AF in all 6 dogs. NIP-142 terminated AFL in all 6 dogs without any appreciable change in flutter CL, and prevented reinitiation of AFL in all 6 dogs. NIP-142 prolonged atrial effective refractory periods (11+/-5%, 3+/-3%, 12+/-3%, and 10+/-5% from the baseline value at basic CLs of 150, 200, 300, and 350ms, respectively) without changes in intraatrial conduction time. The prolongation of the atrial effective refractory period was greater in the presence of vagal stimulation. NIP-142 decreased action potential phase-1 notch and increased phase-2 plateau height without making any changes in the action potential duration, although it did reverse carbachol-induced shortening of the action potential duration. In conclusion, NIP-142 is effective in treating AFL and vagally-induced AF by prolonging atrial refractoriness.

ABSTRACT-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 f]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' 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-'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-' M) also increased coronary perfusion flow. The effects were also inhibited by glibenclamide (10-6 M). In anesthetized dogs, NIP-121 (1 to 10 t€g/kg (3.2 to 32 nmol/kg), i.v.) and levcromakalim (3 to 30 tag/kg (10.5 to 105 nmol/kg), i.v.) dosedependently 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.

NIP-141 terminated AF in aconitine-induced AF and prevented the atrial remodelling by short-term rapid pacing in dogs, possibly via the blocking of Na(+) and Ca(2+) channels.

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