Intravenous Anesthetic Propofol Inhibits Multiple Human Cardiac Potassium Channels

Abstract Background: Propofol is widely used clinically for the induction and maintenance of anesthesia. Clinical case reports have shown that propofol has an antiatrial tachycardia/fibrillation effect; however, the related ionic mechanisms are not fully understood. The current study investigates the effects of propofol on human cardiac potassium channels. Methods: The whole cell patch voltage clamp technique was used to record transient outward potassium current (Ito) and ultrarapidly activating delayed rectifier potassium current (IKur) in human atrial myocytes and hKv1.5, human ether-à-go-go-related gene (hERG), and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells. Current clamp mode was used to record action potentials in human atrial myocytes. Results: In human atrial myocytes, propofol inhibited Ito in a concentration-dependent manner (IC50 = 33.5 ± 2.0 μM for peak current, n = 6) by blocking open channels without affecting the voltage-dependent kinetics or the recovery time constant; propofol decreased IKur (IC50 = 35.3 ± 1.9 μM, n = 6) in human atrial myocytes and inhibited hKv1.5 current expressed in HEK 293 cells by preferentially binding to the open channels. Action potential duration at 90% repolarization was slightly prolonged by 30 μM propofol in human atrial myocytes. In addition, propofol also suppressed hERG and hKCNQ1/hKCNE1 channels expressed in HEK 293 cells. Conclusion: Propofol inhibits multiple human cardiac potassium channels, including human atrial Ito and IKur, as well as hKv1.5, hERG, and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, and slightly prolongs human atrial action potential duration, which may contribute to the antiatrial tachycardia/fibrillation effects observed in patients who receive propofol.

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Inhibitory effects of hesperetin on Kv1.5 potassium channels stably expressed in HEK 293 cells and ultra-rapid delayed rectifier K + current in human atrial myocytes

European Journal of Pharmacology ◽

10.1016/j.ejphar.2016.07.015 ◽

2016 ◽

Vol 789 ◽

pp. 98-108 ◽

Cited By ~ 3

Author(s):

Huan Wang ◽

Hong-fei Wang ◽

Chen Wang ◽

Yu-fang Chen ◽

Rong Ma ◽

...

Keyword(s):

Potassium Channels ◽

Delayed Rectifier ◽

Atrial Myocytes ◽

Inhibitory Effects ◽

Hek 293 ◽

Human Atrial Myocytes ◽

Hek 293 Cells ◽

293 Cells ◽

K Current

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Inhibitory effects of hesperetin on Nav1.5 channels stably expressed in HEK 293 cells and on the voltage-gated cardiac sodium current in human atrial myocytes

Acta Pharmacologica Sinica ◽

10.1038/aps.2016.97 ◽

2016 ◽

Vol 37 (12) ◽

pp. 1563-1573

Author(s):

Huan Wang ◽

Hong-fei Wang ◽

Hao Zhang ◽

Chen Wang ◽

Yu-fang Chen ◽

...

Keyword(s):

Sodium Current ◽

Atrial Myocytes ◽

Inhibitory Effects ◽

Hek 293 ◽

Human Atrial Myocytes ◽

Voltage Gated ◽

Hek 293 Cells ◽

293 Cells

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Abstract 5316: hERG 1b as a Potential Target for Inherited and Acquired Long QT Syndrome

Circulation ◽

10.1161/circ.118.suppl_18.s_525-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Gail A Robertson ◽

Harinath Sale ◽

David Tester ◽

Thomas J O’Hara ◽

Pallavi Phartiyal ◽

...

Keyword(s):

Action Potential ◽

Long Qt Syndrome ◽

Time Course ◽

Drug Sensitivity ◽

Long Qt ◽

Hek 293 ◽

Hek 293 Cells ◽

Acquired Long Qt Syndrome ◽

293 Cells ◽

Qt Syndrome

Cardiac I Kr is a critical repolarizing current in the heart and a target for inherited and acquired long QT syndrome. Biochemical studies show that native I Kr channels are heteromers composed of both hERG 1a and 1b subunits, yet our current understanding of I Kr functional properties derives primarily from studies of homo-oligomers of the original hERG 1a isolate. The hERG 1a and 1b subunits are identical except at the amino (NH2) terminus, which in hERG 1b is much shorter and has a unique primary sequence. We compared the biophysical properties of currents produced by hERG 1a and 1a/1b channels expressed in HEK-293 cells at near-physiological temperatures. We found that heteromeric hERG 1a/1b currents are much larger than hERG 1a currents and conduct 80% more charge during an action potential. This surprising difference corresponds to a two-fold increase in the apparent rates of activation and recovery from inactivation, which reduces rectification and facilitates current rebound during repolarization. Kinetic modeling shows these gating differences account quantitatively for the differences in current amplitude between the two channel types. Depending on the action potential model used, loss of 1b predicts an increase in action potential duration of 27 ms (7%) or 41 ms (17%), respectively. Drug sensitivity was also different. Compared to homomeric 1a channels, heteromeric 1a/1b channels were inhibited by E-4031 with a slower time course and a corresponding four-fold positive shift in the IC 50 . Differences in current kinetics and drug sensitivity were modeled by “NH2 mode” gating with conformational states bound by the amino terminus in hERG 1a homomers but not 1a/1b heteromers. The importance of hERG 1b in vivo is supported by the identification of a 1b-specific A8V missense mutation in 1/269 unrelated genotype-negative LQTS patients and absent in 400 control alleles. Mutant 1bA8V expressed alone or with hERG 1a in HEK-293 cells nearly eliminated 1b protein. Thus, mutations specifically disrupting hERG 1b function are expected to reduce cardiac I Kr , prolong QT interval and enhance drug sensitivity, thus representing a potential mechanism underlying inherited or acquired LQTS.

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