KR-30450, a newly synthesized benzopyran derivative, activates the cardiac ATP-sensitive K+ channel

J Pharmacol Exp Ther. 1995 Nov;275(2):807-12.

Abstract

KR-30450 (2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrollidinyl) -6- nitro-2H-1-benzopyren) is a newly synthesized benzopyran derivative. We examined the effect of KR-30450 on the action potential duration of isolated rat papillary muscle and on the ATP-sensitive K+ channel (KATP) activity in single rat ventricular myocytes with 3 M KCl-filled conventional microelectrode and patch clamp techniques. KR-30450 (10(-7) approximately 10(-5) M) reduced the action potential duration in a concentration-dependent manner and this was inhibited by 3 microM glibenclamide, suggesting that KATP was involved. In cell-attached patches, KR-30450 (10(-5) M) in the pipette activated the KATP which was closed by 3 microM glibenclamide. In inside-out patches, the effects of KR-30450 on KATP activity were examined before and after run-down of the channel. Before run-down, KR-30450 increased the KATP activity only in the presence of ATP and shifted the [ATP]i-KATP activity relationship to the right. After run-down, KR-30450 did not affect the KATP activity either in the presence or absence of 3 mM UDP, but increased the UDP-induced KATP activity in the presence of 1 mM ATP-gamma-S. From these results, we conclude that KR-30450 antagonizes the inhibitory effect of ATP on the KATP in a competitive manner. These effects of KR-30450 are similar to those of ER-001533 and HOE-234, but different from those of pinacidil and lemakalim.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adenosine Triphosphate / metabolism
  • Animals
  • Benzopyrans / pharmacology*
  • Cells, Cultured
  • Cromakalim
  • Glyburide / pharmacology
  • Guanidines / pharmacology
  • Heart / physiology
  • Phenylbutyrates / pharmacology
  • Potassium Channels / drug effects*
  • Pyrroles / pharmacology
  • Pyrrolidinones / pharmacology*
  • Rats

Substances

  • Benzopyrans
  • Guanidines
  • Phenylbutyrates
  • Potassium Channels
  • Pyrroles
  • Pyrrolidinones
  • Cromakalim
  • ER 001533
  • KR 30450
  • Adenosine Triphosphate
  • Glyburide