Effects of halothane on the transient outward K⁺ current in rat ventricular myocytes

Abstract

Halothane has been shown to affect several membrane currents in cardiac tissue including the L‐type calcium current (ICa), sodium current and a variety of potassium currents. However, little is known about the effects of halothane on the transient outward K+ current (Ito). Single ventricular myocytes from rat hearts were voltage clamped using the whole cell patch configuration and an EGTA‐containing pipette solution to record the Ca2+‐independent, 4‐aminopyridine sensitive component of Ito. 300 μM Cd2+ or 10 μM nifedipine was used to block ICa. At +80 mV, Ito (peak current minus current at the end of the pulse) was 1.8±0.2 nA under control conditions which was reduced to 1.3±0.2 nA by 1 mM halothane (P<0.001, mean±s.e.mean, n=9). The inhibition of Ito by halothane was concentration‐dependent (K0.5, 1.1±0.2 mM). One mM halothane led to a 16 mV shift in the steady‐state inactivation curve towards negative membrane potentials (P=0.005, n=8) but had no significant effect on the activation‐voltage relationship (P=0.724). One mM halothane also increased the rate of inactivation of Ito; the dominant time constant of inactivation was reduced from 14±1 to 9±1 ms (P=0.017, mean±s.e.mean, n=6). These data show that halothane reduced Ito; 0.3 mM, close to the MAC50 value for halothane, inhibited the current by 15% and as such, the inhibition of Ito will be relevant to the clinical situation. Halothane induced a shift in the steady‐state inactivation curve and accelerated the inactivation process of Ito which could be responsible for its inhibitory effect. Due to the differential transmural expression of Ito in ventricular tissue, inhibition of Ito would reduce the transmural dispersion of refractoriness which could contribute to the arrhythmogenic properties of halothane. British Journal of Pharmacology (2000) 131, 223–230; doi:

Sevoflurane Inhibition of the Slowly Activating Delayed Rectifier K+ Current in Guinea Pig Ventricular Cells

“…Halothane inhibits the fast Na + current (36), the I CaL , and T-type Ca 2+ current (I CaT ) (11) in guinea pig ventricles and the transient outward K + current in rat ventricles (37). Conversely, only a slight change or no effects were reported on the inward rectifier K + current (10,11,38).…”

A TREK-1–Like Potassium Channel in Atrial Cells Inhibited by β-Adrenergic Stimulation and Activated by Volatile Anesthetics

“…This initial inhibition at ϩ40 mV is probably due to an effect on voltage-dependent potassium channels, as already reported for halothane in other preparations. 28,29,39 When chloroform application was maintained, a noninactivating outward current finally developed at ϩ40 mV. This current, not sensitive to 10 mol/L glibenclamide, was mainly carried by potassium ions as indicated by the reversal potential (Ϫ80 mV in this example) of the current-voltage curve obtained under chloroform ( Figure 1B).…”

“…26 This channel, also sensitive to intracellular acidosis and activated by stretch, produces an outwardly rectifying current, named I KAA , on application of AA. Despite the lack of specific effectors for TREK-1, this K 2P channel presents an interesting property; it is activated by volatile anesthetics, 27 whereas all cardiac potassium channels studied until now are either inhibited or not sensitive to these agents (I to , 28 I K , 29 -31 I K1 , 32 and I KATP , 33,34 with the exception of I KACh , which is activated by halothane. 35 The purpose of this work is to establish the presence of the TREK-1 protein in the heart using specific antibodies to demonstrate that TREK-1 is the channel responsible for I KAA and that I KAA , like TREK-1, 24,27 is activated by clinical concentrations of volatile anesthetics and is inhibited by increases of cAMP that activate protein kinase A (PKA) and that can be triggered by ␤-adrenergic stimulation.…”

“…26 This channel, also sensitive to intracellular acidosis and activated by stretch, produces an outwardly rectifying current, named I KAA , on application of AA. Despite the lack of specific effectors for TREK-1, this K 2P channel presents an interesting property; it is activated by volatile anesthetics, 27 whereas all cardiac potassium channels studied until now are either inhibited or not sensitive to these agents (I to , 28 …”

Qt-Rr Relationships and Suitable Qt Correction Formulas for Halothane-Anesthetized Dogs

“…Halothane is known to inhibit several cardiac channels including the hERG channel (Davies et al, 2000;Stadnicka et al, 2000;Li and Correa, 2002;Shibata et al, 2004) and might potently reduce the repolarization reserve (Biliczki et al, 2002), suggesting that the QT-RR relationship under anesthesia with halothane might be different from other anesthetics. Although we do not suggest that the formulas proposed in this study be used to correct the QT interval data in dogs under other anesthetics, we do strongly consider the formulas to be suitable for QT studies using halothane-anesthetized dogs.…”