Inhibition of cardiac potassium currents by pentobarbital.
The inhibitory effects of the anesthetic barbiturate pentobarbital on the slow ( I(Ks)) and fast component ( I(Kr)) of cardiac delayed rectifier potassium currents ( I(K)) and on the inward rectifier potassium currents ( I(K1)) were examined in Xenopus oocytes expressing the human minK, human ether-á-go-go related gene (HERG) and guinea pig Kir2.2, respectively. Block of native I(K) ( I(Ks) and I(Kr)) and inward rectifier potassium current ( I(K1)) by pentobarbital was examined in guinea pig ventricular myocytes. In oocytes using the two electrode voltage clamp technique potassium currents of hminK-, HERG- and Kir2.2-expressing oocytes were inhibited by pentobarbital with IC50 values of 0.20, 1.58 and 0.54 mM, respectively. I(Ks) block was time- and voltage-independent and had no influence on activation at positive voltages although it shifted voltage-dependent activation to more positive voltages. Pentobarbital-induced HERG inhibition was not dependent on voltage but influenced the deactivation kinetics and shifted half-maximal activation to more negative voltages. In guinea pig cardiomyocytes, using the patch clamp technique, I(Ks) and I(Kr) were inhibited by pentobarbital with IC50 values of 0.18 mM and 2.75 mM, respectively. I(Kr) deactivation and I(Ks) activation kinetics were only slightly influenced by pentobarbital, if at all. Block of I(K1) was weakly voltage-dependent with IC(50) values of 0.26 mM (-40 mV) and 0.91 mM (-120 mV). The data show that pentobarbital suppresses both cloned ( I(K), I(Kir2.2)) and native ( I(K), I(K1)) cardiac potassium currents with the highest affinity for I(Ks).
Bachmann
Alexander
A
Aventis Pharma, DG Cardiovascular Diseases, H821, 65926 Frankfurt/Main, Germany. alexander.bachmann@aventis.com
Mueller
Stefan
S
Kopp
Karin
K
Brueggemann
Andrea
A
Suessbrich
Hartmut
H
Gerlach
Uwe
U
Busch
Andreas E
AE
D000759:Adjuvants, Anesthesia / Q000494:pharmacology*; D000818:Animals; D027682:Cation Transport Proteins; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016276:Ventricular Function; D014981:Xenopus
D000759:Adjuvants, Anesthesia; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D010424:Pentobarbital