Effects of intracellular MgADP and acidification on the inhibition of cardiac sarcolemmal ATP-sensitive potassium channels by propofol.
OBJECTIVE
Propofol inhibits adenosine triphosphate-sensitive potassium (K(ATP)) channels, which may result in the blocking of ischemic preconditioning in the heart. During cardiac ischemia, sarcolemmal K(ATP) channel activity is regulated by the increased levels of cytosolic metabolites, such as adenosine diphosphate (ADP) and protons. However, it remains unclear whether these cytosolic metabolites modulate the inhibitory action of propofol. The aim of this study was to investigate the effects of intracellular MgADP and acidification on K(ATP) channel inhibition by propofol.


METHODS
We used inside-out patch-clamp configurations to investigate the effects of propofol on the activities of recombinant cardiac sarcolemmal K(ATP) channels, which are reassociated by expressed subunits, sulfonylurea receptor (SUR) 2A, and inwardly rectifying potassium channels (Kir6.2).


RESULTS
In the absence of MgADP, propofol inhibited the SUR2A/Kir6.2 channel currents in a concentration-dependent manner, and an IC(50) of 78 microM. Increasing the intracellular MgADP concentrations to 0.1 and 0.3 mM markedly attenuated the inhibitory potency of propofol, and shifted the IC(50) to 183 and 265 microM, respectively. Moreover, decreasing the intracellular pH from 7.4 to 6.5 attenuated the inhibitory potency of propofol, and shifted the IC(50) to 277 microM. In addition, propofol-induced inhibition of truncated Kir6.2DeltaC36 currents, which form a functional channel without SUR2A, was not affected by an increase in intracellular MgADP. However, intracellular acidification (pH 6.5) significantly reduced the propofol sensitivity of Kir6.2DeltaC36 channels.


CONCLUSIONS
Our results demonstrated that the existence of intracellular MgADP and protons attenuated the direct inhibitory potency of propofol on recombinant cardiac sarcolemmal K(ATP) channels, via SUR2A and Kir6.2 subunits, respectively.
Yamada
Hirohide
H
Department of Anesthesiology, Tokushima University School of Medicine, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
Kawano
Takashi
T
Tanaka
Katsuya
K
Yasui
Sonoko
S
Mawatari
Kazuaki
K
Takahashi
Akira
A
Nakaya
Yutaka
Y
Oshita
Shuzo
S
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000244:Adenosine Diphosphate / Q000502:physiology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors; D015742:Propofol / Q000494:pharmacology*; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000187:drug effects; D012508:Sarcolemma / Q000378:metabolism; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate; D018686:Anesthetics, Intravenous; D054086:KATP Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D015742:Propofol; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel