KR-30450, A NEWLY SYNTHESIZED BENZOPYRAN DERIVATIVE, ACTIVATES THE CARDIAC ATP-SENSITIVE K+ CHANNEL

KR-30450 (2-(2 ''(1 '',3 (2'-oxo-1'-pyrrollidinyl)-6-nitro-2H-1-benzop yren) is a newly synthesized benzopyran derivative. We examined the ef fect of KR-30450 on the action potential duration of isolated rat papi llary muscle and on the ATP-sensitive K+ channel (K-ATP activity in si ngle rat ventricular myocytes with 3 M KCl-filled conventional microel ectrode and patch clamp techniques. KR-30450 (10(-7) similar to 10(-5) M) reduced the action potential duration in a concentration-dependent manner and this was inhibited by 3 mu M glibenclamide, suggesting tha t K-ATP was involved. In cell-attached patches, KR-30450 (10(-5) M) in the pipette activated the K-ATP which was closed by 3 mu M glibenclam ide. In inside-out patches, the effects of KR-30450 on K-ATP activity were examined before and after run-down of the channel. Before run-dow n, KR-30450 increased the K-ATP activity only in the presence of ATP a nd shifted the [ATP](i) - K-ATP activity relationship to the right. Af ter run-down, KR-30450 did not affect the K-ATP activity either in the presence or absence of 3 mM UDP, but increased the UDP-induced K-ATP activity in the presence of 1 mM ATP-gamma-S. From these results, we c onclude that KR-30450 antagonizes the inhibitory effect of ATP on the K-ATP in a competitive manner. These effects of KR-30450 are similar t o those of ER-001533 and HOE-234, but different from those of pinacidi l and lemakalim.