title: K-ATP channel independent effects of pinacidil on ATP production in isolated cardiomyocyte or pancreatic beta-cell mitochondria.
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.
authors.affiliation: Department of Pharmacology, University of Tübingen, Tübingen, Germany. nicolas.lembert@uni-tuebingen.de
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lembert
authors.forename: Lars Ake
authors.initials: LA
authors.lastname: Idahl
authors.forename: Hermann P T
authors.initials: HP
authors.lastname: Ammon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D003652:Decanoic Acids / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006321:Heart / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D020110:Pinacidil / Q000494:pharmacology*; D015221:Potassium Channels; D012402:Rotenone / Q000494:pharmacology; D019802:Succinic Acid / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D003652:Decanoic Acids; D006880:Hydroxy Acids; D008565:Membrane Proteins; D015221:Potassium Channels; D014475:Uncoupling Agents; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D012402:Rotenone; C052853:5-hydroxydecanoic acid; D020110:Pinacidil; D000255:Adenosine Triphosphate; D019802:Succinic Acid; D000263:Adenylate Kinase