Yonsei Med J.  2012 Jan;53(1):204-212. 10.3349/ymj.2012.53.1.204.

Ionic Mechanisms of Desflurane on Prolongation of Action Potential Duration in Rat Ventricular Myocytes

• Chae JE
• Kim HS
• Ahn DS
• Park WK

• KMID: 1779708
• DOI: http://doi.org/10.3349/ymj.2012.53.1.204

Abstract

PURPOSE
Despite the fact that desflurane prolongs the QTC interval in humans, little is known about the mechanisms that underlie these actions. We investigated the effects of desflurane on action potential (AP) duration and underlying electrophysiological mechanisms in rat ventricular myocytes.
MATERIALS AND METHODS
Rat ventricular myocytes were enzymatically isolated and studied at room temperature. AP was measured using a current clamp technique. The effects of 6% (0.78 mM) and 12% (1.23 mM) desflurane on transient outward K+ current (I(to)), sustained outward current (I(sus)), inward rectifier K+ current (I(KI)), and L-type Ca2+ current were determined using a whole cell voltage clamp.
RESULTS
Desflurane prolonged AP duration, while the amplitude and resting membrane potential remained unchanged. Desflurane at 0.78 mM and 1.23 mM significantly reduced the peak I(to) by 20+/-8% and 32+/-7%, respectively, at +60 mV. Desflurane (1.23 mM) shifted the steady-state inactivation curve in a hyperpolarizing direction and accelerated inactivation of the current. While desflurane (1.23 mM) had no effects on I(sus) and I(KI), it reduced the L-type Ca2+ current by 40+/-6% (p<0.05).
CONCLUSION
Clinically relevant concentrations of desflurane appear to prolong AP duration by suppressing Ito in rat ventricular myocytes.

Keyword

Desflurane; cardiac myocytes; action potential; transient outward K+ current; rat

MeSH Terms

Action Potentials/*drug effects
Anesthetics, Inhalation/*pharmacology
Animals
Calcium Channels, L-Type/physiology
Heart Conduction System/drug effects/physiology
Heart Ventricles/drug effects
Isoflurane/*analogs & derivatives/pharmacology
Myocardial Contraction/*drug effects/physiology
Myocytes, Cardiac/*drug effects/physiology
Patch-Clamp Techniques
Potassium Channels/physiology
Rats
Rats, Sprague-Dawley

Figure

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  Fig. 1 Effect of desflurane (DES) on action potential duration in a rat ventricular myocyte. C, control.

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  Fig. 2 Effects of desflurane (DES) on transient outward K+ current (Ito) in rat ventricular myocytes. (A) Recordings of control, 1.23 mM DES, and recovery in rat ventricular myocytes. Closed and open circles indicate the peak current of Ito at every potential in the control and 1.23 mM DES. Triangles represent the plateau currents at the end of the test pulses before (closed) and after (open) applying of 1.23 mM DES. Squares represent the peak (closed) and plateau (open) currents after wash. The currents shown are for depolarization from -40 to +60 mV in 10 mV steps. (B) Current-voltage relations of Ito in 10 cells. Closed and open circles indicate the peak current of Ito at every potential in the control and 1.23 mM DES. Triangles represent the plateau currents at the end of the test pulses before (closed) and after (open) application of 1.23 mM DES. (C) Effects of 0.78 mM and 1.23 mM DES on the amplitude of the peak Ito at +60 mV in 10 cells. *p<0.05 versus control. †p<0.05 versus 0.78 mM DES. Error bars indicate mean±SD.

• 

  Fig. 3 Steady state inactivation curves of transient outward K+ currents under control conditions and 1.23 mM desflurane (DES). Closed and open circles indicate control and 1.23 mM DES, respectively. Data are presented as mean±SD for 10 cells and were fitted with the Boltzman function. The half inactivations (V1/2) of the control and 1.23 mM DES were -29.3±0.6 mV and -34.3±0.9 mV, respectively.

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  Fig. 4 Effect of desflurane (DES) on current inactivation. The inactivation phase of transient outward K+ current (Ito) were best fitted by single and double exponential functions under control conditions (A) and 1.23 mM DES (B), respectively, in a rat ventricular myocyte. Mean values of T1 in 7 cells under control conditions, 1.23 mM DES, and after washout (C). *p<0.05 versus control and recovery. Error bars indicate mean±SD.

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  Fig. 5 Time-dependent inhibition of transient outward K+ currents (Ito) by desflurane. Time course of the development of inhibition by 0.78 mM and 1.23 mM desflurane in each of the 8 cells during a depolarizing pulse to +60 mV from a holding potential of -40 mV. The reduction of Ito in the presence of desflurane is expressed as a proportion of the control current at any given time after the start of the depolarizing pulse.

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  Fig. 6 The effects of desflurane (DES) on sustained outward currents (Isus) in a rat ventricular myocyte. (A) A control recording of transient outward K+ currents (Ito). (B) Isus obtained after application of 5 mM 4-aminopyridine (4-AP), which preferentially blocks Ito. (C) 1.23 mM DES exposure after application of 5 mM 4-aminopyridine.

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  Fig. 7 Effect of desflurane (DES) on the inward rectifier K+ current (IKI) in rat ventricular myocytes. (A) Closed and open circles indicate control and 1.23 mM DES in a rat ventricular myocyte, respectively, at a membrane potential of -140 mV. The dotted line indicates recovery after wash. (B) Current-voltage relations for IKI before and after applying 1.23 mM DES in 9 cells. Closed and open circles indicate control and 1.23 mM DES, respectively. Error bars indicate mean±SD.

• 

  Fig. 8 Effect of desflurane (DES) on L-type Ca2+ current (ICa,L). (A) A representative example of the effect of DES on ICa,L in a rat ventricular myocyte. The open circles represent the peak of an individual current record. The horizontal bar indicates the period of DES application. (B) An example of individual currents recorded in the presence of 1.23 mM DES. Closed and open circles indicate control and 1.23 mM DES, respectively. The dotted line indicates recovery after wash.

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