EFFECTS OF CAFFEINE AND 3-ISOBUTYL-1-METHYLXANTHINE ON VOLTAGE-ACTIVATED POTASSIUM CURRENTS IN VERTEBRATE NEURONS AND SECRETORY-CELLS

1 The effects of caffeine and 3-isobutyl-1-methylxanthine (IBMX) on vo ltage-activated K+ currents were examined by use of patch clamp record ing techniques in dissociated chick autonomic ganglion neurones, chick pineal cells and rat anterior pituitary cells. 2 In chick ciliary gan glion neurones, caffeine (0.1-10 mM) produced a robust blockade of del ayed rectifier K+ currents (I-DR). Blockade was rapid in onset and con centration- and voltage-dependent. Caffeine produced greater inhibitio n with larger depolarizing voltage pulses. Similar inhibition of I-DR was observed in excised outside-out 'maxi-patches' indicating a direct effect on the K+ channels. Caffeine also inhibited I-DR in chick symp athetic neurones, chick pineal cells and rat anterior pituitary cells. 3 Application of 10 mM caffeine caused inhibition of transient A-curr ents (I-A) in chick ciliary ganglion neurones. Inhibition of I-A was v oltage-dependent with greater inhibition observed at more positive com mand potentials. Application of 1 mM caffeine did not cause inhibition of I-A. 4 Application of 1 mM IBMX, a structural analogue of caffeine , caused inhibition of I-DR and I-A in chick ciliary ganglion neurones . The voltage-dependence of the inhibition of both currents was qualit atively different from that observed with caffeine. The inhibitory eff ects of 1 mM IBMX and 10 mM caffeine on I-DR and I-A were additive. 5 Direct inhibition of voltage-activated K+ currents can potentially pro duce significant secondary effects on intracellular free Ca2+. These r esults indicate that caution must be used in the design and interpreta tion of experiments in which millimolar concentrations of caffeine or IBMX are used in pharmacological studies of intracellular Ca2+ dynamic s or other second messenger mechanisms.