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

Abstract

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.

Hemodynamic Effects of Levcromakalim in Neonatal Porcine Pulmonary Hypertension

“…LKM is also a vasodilator in isolated coronary, cranial, and mesenteric arteries [14]. Herity et al [15] noted that both LKM and sodium nitroprusside reduced systemic and pulmonary vascular resistance, and mean systemic and pulmonary arterial pressures in adult pigs, the effects being greater in animals pre-treated with saline rather than (L-NAME).…”

Cardiovascular Pharmacology of NIP‐121, A Potassium Channel Opener

“…NIP-121 and cromakalim were about lo00 times less potent in the heart than on the vasculature. At pharmacologically effective doses, the cardioprotective effect of NIP-121 may be due, at least in part, to the increase of oxygen supply due to coronary vasodilation (59).…”

“…In contrast to these agents, K + channel openers activate the channels and increase K + permeability through the cell membrane (8,18). Glibenclamide antagonizes the action of the K + channel openers: cromakalim (5,15,26,44,(55)(56)(57)(58)(59)(60)(61), pinacidil (15,44), minoxidil sulfate ( 5 9 , RP 49356 (15), nicorandil (44), and NIP-I21 (26,5658). Apparent competitive antagonism is demonstrated by the slopes of Schild plots.…”

“…NIP-12 1 relaxed some canine blood vessels (coronary, renal, mesenteric, femoral arteries, and saphenous vein) precontracted with the thromboxane A, analog U46619 (59). NIP-121 exhibited potent vasodilating actions in the coronary artery; similar effects were produced by other K + channel openers, such as cromakalim (20) and pinacidil (24,40).…”

Levcromakalim decreases vascular tone, cytoplasmic Ca2+ and Ca2+ sensitivity in canine basilar artery

“…Among various kinds of K+ channels, both large conductance Ca2+-activated K+ (BK) channels and ATP-sensitive K+ (KATp) channels are reported to contribute to vasorelaxation [15,301. Yamashita et al [27], however, showed that the relaxation induced by K+ channel openers in canine basilar arteries was relatively less efficient compared with that in coronary arteries or superior mesenteric arteries.…”