Key result
Thiopental prolongs APD in rat myocytes by reducing Ito with an IC50 of 114 µM.
Thiopental prolongs action potential duration in rat ventricular myocytes primarily through the inhibition of the transient outward current (Ito), providing a mechanistic basis for its QT-prolonging effect.
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Thiopental may prolong QT via Ito inhibition in rat myocytes; leaves open human arrhythmia relevance.
Background: Patients with the long QT syndrome, either congenital or acquired, have an increased development of serious ventricular arrhythmia, Torsade de Pointes.Thiopental (5 mg/kg) has been reported to prolong the QTc interval in patients undergoing surgery with normal repolarization.Recent studies have indicated that the clinical concentration of thiopental prolonged the action potential duration (APD), which was attributed to inhibition of the delayed rectifier (Ik) and/or the inward rectifier (Ik1) at various animal myocardial preparations.The rat ventricular cells were used to study the contribution of transient outward current (Ito) and Ik1 because they possess a variety of K + channel subtypes including Ito and Ik1 with little or no Ik, similar to those of human ventricular myocytes.The effect on Ca 2+ current (ICa,L), which can alter the K + conductance, was also observed.Methods: With approval of the animal research committee in Yonsei University Medical College, isolated ventricular cells were obtained from enzymatically treated rat hearts.The ICa,L was elicited from a holding potential of -40 mV to + 60 mV under the modified Tyrode solution.Ik1 was obtained from a holding potential of -40 mV before their membrane potential was changed from -130 to + 50 mV.Ito was recorded during depolarizing steps from -80 mV followed by inactivation of Na + current by short pulses to -40 mV and then depolarized with 10 mV increments to test potentials up to + 60 mV.ICa,L was blocked by adding 0.5 mM CdCl2 during measurement of Ito.Normal action potential was measured using conventional microelectrode technique.Results: At membrane potential of +60 mV, 50μM thiopental caused modest depression of Ito to 82 ± 1% of control.From the dose-response curve from 1 to 1000μM, the IC50 of thiopental was 163μM.While 50μM thiopental caused modest depression of Ik1 of 87 ± 2% of control at a test potential of -130 mV, no depression was observed from -110 mV to + 50 mV.ICa,L was significantly reduced to 57 ± 5% of control.The APD90 was prolonged by 76% following application of 50μM thiopental.Conclusions: Prolongation of APD induced by thiopental was associated with reduction of Ito.Considering the high current density of Ito in rat ventricular myocytes, inhibition of Ito seems to play a major role in thiopental-induced APD prolongation.
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Kim et al. (2004) studied this question. Thiopental vs. Control (drug-free solution) was evaluated on Transient outward current (Ito) amplitude at +60 mV (IC50 114 µM). Thiopental prolonged action potential duration in rat ventricular myocytes, primarily associated with a concentration-dependent reduction of the transient outward current (Ito) with an IC50 of 114 µM.
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