MODULATORY EFFECTS OF ARACHIDONIC-ACID ON THE DELAYED RECTIFIER K- STRUCTURAL ASPECTS AND INVOLVEMENT OF PROTEIN-KINASE-C( CURRENT IN RAT PULMONARY ARTERIAL MYOCYTES )

The effect of arachidonic acid (AA) on the delayed rectifier K+ curren t (I-K) was evaluated in rat pulmonary myocytes by using the whole-cel l patch-clamp technique. Externally applied AA (50 mu mol/L) caused a membrane depolarization, averaging 16 mV in six cells. AA (1 to 50 mu mol/L) caused a dual effect on I-K. First, AA accelerated the rate of I-K activation, increasing current amplitude at the beginning of volta ge step. Second, AA caused a marked acceleration of current decay, the reby reducing I-K amplitude measured toward the end of the depolarizin g steps. These effects were not prevented by indomethacin or nordihydr oguaiaretic acid, blockers of cyclooxygenase and lipoxygenase, respect ively. AA did not affect the voltage dependence of current activation or inactivation. The magnitude of the inhibitory effect on I-K was cor related with the number of double bonds but was independent of tail le ngth in fatty acids containing between 14 and 22 carbons. Linoleic aci d (18:2, cis-9,12) inhibited I-K much more than did its tras-stereoiso mer, linolelaidic acid. Arachidonyl alcohol, which is uncharged, and a rachidonyl coenzyme A, which does not 'flip' across the cell membrane, were less effective than AA in inhibiting I-K; this effect of fatty a cids may therefore require passage across the cell membrane. The enhan cement of early I-K was mimicked by the protein kinase C (PKC) stimula tor 1-oleoyl-2-acetyl-sn-glycerol (10 mu mol/L), was suppressed by ATP removal from the pipette solution, and was blocked by PKC inhibitors chelerythrine (10 mu mol/L) and staurosporine (100 nmol/L). This effec t may therefore require PKC-dependent phosphorylation.