Sarcolemmal and mitochondrial effects of a KATP opener, P-1075, in "polarized" and "depolarized" Langendorff-perfused rat hearts

Olga Jilkina, Bozena Kuzio, Gary J. Grover, Clifford D.L. Folmes, Hee Jeong Kong, Valery V. Kupriyanov

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

We investigated consequences of cardiac arrest on sarcolemmal and mitochondrial effects of ATP-sensitive potassium channel (KATP) opener, P-1075, in Langendorff-perfused rat hearts. Depolarised cardiac arrest (24.7 mM KCl) did not affect glibenclamide-sensitive twofold activation of rubidium efflux by P-1075 (5 μM) from rubidium-loaded hearts, but eliminated uncoupling produced by P-1075 in beating hearts: 40% depletion of phosphocreatine and ATP, 50% increase in oxygen consumption, and reduction of cytochrome c oxidase. Depolarized cardiac arrest by calcium channel blocker, verapamil (5 μM), also prevented uncoupling. Lack of P-1075 mitochondrial effects in depolarized hearts was not due to changes in phosphorylation potential, because 2,4-dintrophenol (10 μM) reversed the [PCr]/[Cr] increase and Pi decrease, characteristic of KCl-arrest, but did not restore uncoupling. In agreement with this conclusion, pyruvate (5 mM) increased [PCr]/[Cr] and decreased Pi, but did not prevent uncoupling in beating hearts. A decrease in mean [Ca2+] in KCl-arrested hearts could not account for lack of P-1075 mitochondrial effects, because calcium channel opener, S-(-)-Bay K8644 (50 nM), and beta-agonist, isoproterenol (0.5 μM), did not facilitate uncoupling. In contrast, in adenosine (1 mM) -arrested hearts (polarized arrest), P-1075 caused 40% phosphocreatine and ATP depletion. In isolated rat liver mitochondria, P-1075 (20 μM) decreased mitochondrial membrane potential (ΔΨ) by approximately 14 mV (demonstrated by redistribution of ΔΨ-sensitive dye, rhodamine 800) in a glibenclamide-sensitive manner. We concluded that cell membrane depolarization does not prevent activation of sarcolemmal KATP by P-1075, but it plays a role in mitochondrial uncoupling effects of P-1075.

Original languageEnglish (US)
Pages (from-to)39-50
Number of pages12
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1618
Issue number1
DOIs
StatePublished - Dec 3 2003

Keywords

  • ATP-sensitive potassium channel
  • Cytochrome c oxidase
  • K opener
  • Oxidative phosphorylation
  • Oxygen consumption
  • P-1075
  • Rb/K efflux
  • Sarcolemmal polarization

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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