The p42/44mitogen-activated protein kinase inhibitor PD 98059, but not U 0126, increases a K+ current in cardiomyocytes.
1. The effects of the mitogen-activated protein kinase (MAPK) inhibitors PD 98059 and U 0126, useful tools to investigate MAPK involvement in intracellular signal transduction pathways, were assessed on cardiomyocytes. 2. In rat freshly isolated ventricular myocytes, under current-clamp conditions, PD 98059 (40 micro mol/L) shortened the action potential. Under whole-cell patch-clamp, this compound slowly induced a fast activating sustained outward K+ current that was sensitive to 1 mmol/L Ba2+, 100 micro mol/L Gd3+, 3 mmol/L 4-aminopyridine and 100 micro mol/L tetracain. The PD 98059-induced current was prevented by 40 micro mol/L AACOCF3, a cytosolic phospholipase A2 inhibitor. 3. U 0126 (1 micro mol/L), a recently developed highly potent p42/44 MAPK inhibitor, did not alter K+ currents. 4. PD 98059, but not U 0126, increased arachidonic acid content, probably as a consequence of its reported cyclo-oxygenase inhibitory effect. 5. These observations indicate that PD 98059 activates a TREK-1 like current. Thus, this MAPK inhibitor has to be used with caution because alterations in cell metabolism can be secondary to changes in electrophysiological behaviour.
Aimond
F
F
INSERM U-390, Physiopathologie Cardiovasculaire, IFR No. 3, Montpellier, France.
Fauconnier
J
J
Donadille
D
D
Vassort
G
G
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology*; D002478:Cells, Cultured; D005419:Flavonoids / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain; D051381:Rats; D017208:Rats, Wistar
D002070:Butadienes; D005419:Flavonoids; D009570:Nitriles; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C113580:U 0126; C103742:potassium channel protein TREK-1; D016718:Arachidonic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D011188:Potassium; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one