Abstract
We have studied the effects of the class Ic antiarrhythmic propafenone on K+ currents in freshly isolated smooth muscle cells from rat portal veins and on the spontaneous contractions in whole tissues. Under Ca2+-free conditions, when cells were clamped at −80 mV (whole-cell configuration) depolarizing steps from −80 to +50 mV induced a family of K+ currents (IKtotal) that mainly comprised the delayed rectifier current [IK(V)], whereas when held at −10 mV only small-amplitude, noninactivating, currents (INI) were recorded. Propafenone (10 μM) markedly inhibited IKtotal, but at potentials positive to +30 mV it also induced a noisy outwardly rectifying current [IBK(Ca)] that was abolished by iberiotoxin (0.1 μM). Inhibition of IKtotal by propafenone was concentration-dependent (EC50 = 0.059 ± 0.009 μM). Propafenone also inhibited the transient outward current [IK(A)] and ATP-sensitive potassium current [IK(ATP)] induced by levcromakalim (10 μM). Inhibition of IK(V), IK(A), and IK(ATP) by propafenone was voltage-independent. In Ca2+-containing conditions propafenone inhibited IK(V) and IBK(Ca) and immediately abolished spontaneous outward transient K+ currents. In whole veins, propafenone behaved as the KV inhibitor 4-aminopyridine, increasing the amplitude and duration of spontaneous contractions. Propafenone also inhibited the inhibitory effects of the KATP channel opener levcromakalim on spontaneous contractions. These results indicate that in vascular smooth muscle cells, propafenone inhibits KV, KA, BKCa, and KATP channels. These actions correlated with its effects on mechanical activity in whole portal veins.
Footnotes
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This work was supported by a Comision Interministerial de Ciencia y Technologia Grant (SAF 99/0069). A.C. and F.P.-V. are supported by grants from Comunidad Autónoma de Madrid.
- Abbreviations:
- KATP
- ATP-sensitive K+channel
- KA
- voltage-dependent transient K+channel
- KV
- delayed rectifier K+ channel
- BKCa
- large conductance Ca2+-activated K+ channel
- KIR
- inward rectifier K+ channel
- Ca2+-free PSS
- calcium-free physiological salt solution
- KB
- Kraftbrühe
- I-V
- current-voltage
- INI
- noninactivating current
- Ca2+-PSS
- calcium-containing physiological salt solution
- STOC
- spontaneous transient outward K+ current
- Received May 14, 2001.
- Accepted August 1, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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