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

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 microM) 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 microM), 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 microM) 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 microM), 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 microM) decreased mitochondrial membrane potential (DeltaPsi) by approximately 14 mV (demonstrated by redistribution of DeltaPsi-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.

• Authors: Olga Jilkina, Bozena Kuzio, Gary J Grover, Clifford D L Folmes, Hee-Jeong Kong, Valery V Kupriyanov
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1618 Issue 1 Pg. 39-50 (Dec 03 2003) ISSN: 0006-3002 [Print] Netherlands
• PMID: 14643932 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Guanidines
• Pyridines
• Vasodilator Agents
• N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine
• Rubidium
• Potassium

Topics

• Animals
• Guanidines (pharmacology)
• Heart (drug effects)
• Heart Arrest, Induced
• Liver (metabolism)
• Male
• Membrane Potentials
• Mitochondria (drug effects)
• Potassium (metabolism)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rubidium (metabolism)
• Sarcolemma (drug effects)
• Vasodilator Agents (pharmacology)