Effects of halothane on the transient outward K(+) current in rat ventricular myocytes.
1. Halothane has been shown to affect several membrane currents in cardiac tissue including the L-type calcium current (I(Ca)), sodium current and a variety of potassium currents. However, little is known about the effects of halothane on the transient outward K(+) current (I(to)). 2. Single ventricular myocytes from rat hearts were voltage clamped using the whole cell patch configuration and an EGTA-containing pipette solution to record the Ca(2+)-independent, 4-aminopyridine sensitive component of I(to). 300 microM Cd(2+) or 10 microM nifedipine was used to block I(Ca). 3. At +80 mV, I(to) (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 I(to) by halothane was concentration-dependent (K(0.5), 1.1+/-0.2 mM). 4. 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 I(to); the dominant time constant of inactivation was reduced from 14+/-1 to 9+/-1 ms (P:=0.017, mean+/-s.e.mean, n=6). 5. These data show that halothane reduced I(to); 0.3 mM, close to the MAC(50) value for halothane, inhibited the current by 15% and as such, the inhibition of I(to) will be relevant to the clinical situation. Halothane induced a shift in the steady-state inactivation curve and accelerated the inactivation process of I(to) which could be responsible for its inhibitory effect. 6. Due to the differential transmural expression of I(to) in ventricular tissue, inhibition of I(to) would reduce the transmural dispersion of refractoriness which could contribute to the arrhythmogenic properties of halothane.
Davies
L A
LA
School of Biomedical Sciences, University of Leeds, Leeds, LS2 9NQ.
Hopkins
P M
PM
Boyett
M R
MR
Harrison
S M
SM
D000200:Action Potentials / Q000187:drug effects; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D016276:Ventricular Function
D018685:Anesthetics, Inhalation; D015221:Potassium Channels; D002118:Calcium; D006221:Halothane