K-ATP channel independent effects of pinacidil on ATP production in isolated cardiomyocyte or pancreatic beta-cell mitochondria

Biochem Pharmacol. 2003 Jun 1;65(11):1835-41. doi: 10.1016/s0006-2952(03)00179-5.

Abstract

Evidence has been presented that mitochondria contain ATP sensitive potassium channels (mK-ATP channels), which may confer tissue protection upon activation. It is, however, not known whether activation of mK-ATP channels has a direct effect on mitochondrial ATP production. This study was performed to define the effect of pinacidil (PIN) on ATP production by oxidative phosphorylation in isolated cardiomyocyte or pancreatic beta-cell mitochondria. Cardiomyocyte mitochondria produced seven times more ATP than beta-cell mitochondria in the presence of pyruvate/malate. PIN inhibited pyruvate/malate-induced mitochondrial ATP production with half maximal effect at 360 microM in both cell types. The inclusion of 5-hydroxydecanoate (5-HD) did not prevent this inhibition. Succinate induced a similar ATP production in cardiomyocyte or beta-cell mitochondria. In beta-cell mitochondria succinate-induced ATP production was inhibited by PIN with half maximal effects at 500 microM PIN. However, in cardiomyocyte mitochondria PIN stimulated succinate-induced ATP production 3-fold with half maximal effect at 100 microM and maximal effect at 200 microM. This PIN-dependent stimulation was mimicked by rotenone. The inclusion of 5-HD could not prevent these PIN effects. In conclusion, PIN may inhibit complex 1 of the respiratory chain without indications of opening mK-ATP channels. In cardiomyocytes with metabolically inhibited succinate dehydrogenase this results in a stimulation of ATP production conferring tissue protection. In beta-cells without a metabolically inhibited succinate dehydrogenase, there is no stimulation by PIN and tissue protection by PIN is not to be expected.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Adenylate Kinase / metabolism
  • Animals
  • Decanoic Acids / pharmacology
  • Drug Interactions
  • Female
  • Heart / drug effects
  • Hydroxy Acids / pharmacology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Membrane Proteins / drug effects
  • Membrane Proteins / metabolism*
  • Mice
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / enzymology
  • Mitochondria, Heart / metabolism
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Pinacidil / pharmacology*
  • Potassium Channels
  • Rotenone / pharmacology
  • Succinic Acid / pharmacology
  • Uncoupling Agents / pharmacology
  • Vasodilator Agents / pharmacology

Substances

  • Decanoic Acids
  • Hydroxy Acids
  • Membrane Proteins
  • Potassium Channels
  • Uncoupling Agents
  • Vasodilator Agents
  • mitochondrial K(ATP) channel
  • Rotenone
  • 5-hydroxydecanoic acid
  • Pinacidil
  • Adenosine Triphosphate
  • Succinic Acid
  • Adenylate Kinase