The p42/44mitogen-activated protein kinase inhibitor PD 98059, but not U 0126, increases a K+ current in...

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.