EFFECT OF GLIBENCLAMIDE, FORSKOLIN, AND ISOPRENALINE ON THE PARALLEL ACTIVATION OF K-ATP AND REDUCTION OF I-K BY CROMAKALIM IN CARDIAC MYOCYTES

Objective: The aim was to investigate the effect of activation of ATP sensitive potassium channels by cromakalim on the delayed rectifier po tassium current (I-K) in guinea pig ventricular myocytes. Experiments were carried out in the absence and presence of forskolin or isoprenal ine to promote phosphorylation of I-K, and in the presence of glibencl amide to block the ATP sensitive potassium current (I-K(ATP)). Methods : Single cells were isolated from guinea pig ventricle. Potassium curr ents were studied under voltage clamp conditions. The delayed rectifie r was measured as an outward tail current upon repolarisation to a hol ding potential of -40 mV following depolarising steps to +40 mV. Induc tion of I-K(ATP) was indicated by changes in the holding current. Resu lts: Exposure to 20 mu M cromakalim caused a significant increase of 2 44(SEM 47)% in the holding current and simultaneous decreases of 22(5) % in the rapid component (I-Kr) and 45(5)% in the slow component (I-Kr ) of I-K. Exposure of the cells to 5 mu M forskolin or 100 nM isoprena line reduced bath these effects of cromakalim: with forskolin, the hol ding current increased by 59(17)%, I-Kr was reduced by 9(3)%, and I-Ks by 23(3)%; with isoprenaline, the holding current increase by 100(36) %, I-Kr was not significantly changed, and I-Ks was reduced by 27(5)%. With 10 mu M glibenclamide present, the only significant effect of cr omakalim was reduction of I-Ks [by 11(3)%]. Conclusions: Cromakalim ca used decreases in both components of I-K which developed in parallel w ith activation of I-K(ATP). The observations that forskolin, isoprenal ine, or glibenclamide all reduced the effects of cromakalim on both I- K and I-K(ATP) may result from separate effects on the two channel pat hways, but are also consistent with the single hypothesis that cromaka lim induces an interconversion of potassium channels which is reduced when potassium channels are modified by these three drugs.