Effect of glibenclamide, forskolin, and isoprenaline on the parallel activation of KATP and reduction of IK 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 potassium current (IK) in guinea pig ventricular myocytes. Experiments were carried out in the absence and presence of forskolin or isoprenaline to promote phosphorylation of IK, and in the presence of glibenclamide to block the ATP sensitive potassium current (IK(ATP)).


METHODS
Single cells were isolated from guinea pig ventricle. Potassium currents were studied under voltage clamp conditions. The delayed rectifier was measured as an outward tail current upon repolarisation to a holding potential of -40 mV following depolarising steps to +40 mV. Induction of IK(ATP) was indicated by changes in the holding current.


RESULTS
Exposure to 20 microM cromakalim caused a significant increase of 244(SEM 47)% in the holding current and simultaneous decreases of 22(5)% in the rapid component (IKr) and 45(5)% in the slow component (IKs) of IK. Exposure of the cells to 5 microM forskolin or 100 nM isoprenaline reduced both these effects of cromakalim: with forskolin, the holding current increased by 59(17)%, IKr was reduced by 9(3)%, and IKs by 23(3)%; with isoprenaline, the holding current increased by 100(36)%, IKr was not significantly changed, and IKs was reduced by 27(5)%. With 10 microM glibenclamide present, the only significant effect of cromakalim was reduction of IKs [by 11(3)%].


CONCLUSIONS
Cromakalim caused decreases in both components of IK which developed in parallel with activation of IK(ATP). The observations that forskolin, isoprenaline, or glibenclamide all reduced the effects of cromakalim on both IK and IK(ATP) may result from separate effects on the two channel pathways, but are also consistent with the single hypothesis that cromakalim induces an interconversion of potassium channels which is reduced when potassium channels are modified by these three drugs.
Heath
B M
BM
University Department of Pharmacology, Oxford, United Kingdom.
Terrar
D A
DA
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology*; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D005576:Colforsin; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol; D005905:Glyburide