Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1

Abstract

Volatile anesthetics have been shown to activate various two-pore (2P) domain K(+) (K(2P)) channels such as TASK-1 and TREK-1 (TWIK-related acid-sensitive K(+) channel), and mice deficient in these channels are resistant to halothane-induced anesthesia. Here, we investigated whether K(2P) channels were also potentially important targets of intravenous anesthetics. Whole cell patch-clamp techniques were used to determine the effects of the commonly used intravenous anesthetics etomidate and propofol on the acid-sensitive K(+) current in rat ventricular myocytes (which strongly express TASK-1) and selected human K(2P) channels expressed in Xenopus laevis oocytes. In myocytes, etomidate decreased both inward rectifier K(+) (K(ir)) current (I(K1)) and acid-sensitive outward K(+) current at positive potentials, suggesting that this drug may inhibit TASK channels. Indeed, in addition to inhibiting guinea pig Kir2.1 expressed in oocytes, etomidate inhibited human TASK-1 (and TASK-3) in a concentration-dependent fashion. Propofol had no effect on human TASK-1 (or TASK-3) expressed in oocytes. Moreover, we showed that, similar to the known effect of halothane, sevoflurane and the purified R-(-)- and S-(+)-enantiomers of isoflurane, without stereoselectivity, activated human TASK-1. We conclude that intravenous and volatile anesthetics have dissimilar effects on K(2P) channels. Human TASK-1 (and TASK-3) are insensitive to propofol but are inhibited by supraclinical concentrations of etomidate. In contrast, stimulatory effects of sevoflurane and enantiomeric isoflurane on human TASK-1 can be observed at clinically relevant concentrations.

Knock-Out of the Potassium Channel TASK-1 Leads to a Prolonged QT Interval and a Disturbed QRS Complex

“…These changes in the electrocardiogram were not observed when the mice were treated with an intraperitoneal infusion of isoprenaline. In addition, we found that isoflurane, which activates TASK-1 channels [9,10], slows heart rate and atrioventricular conduction in wildtype mice, whereas these effects are not present in TASK-1 -/-mice. Taken together, our results suggest that TASK-1 may be important for the conduction of cardiac excitation and for the ventricular repolarization under resting conditions of the heart.…”

“…Isoflurane exerts cardiac side effects via activation of TASK-1 channels, at concentrations which are in a clinically relevant range [9]. In previous work, general anesthesia with 1% isoflurane was found to reduce the heart rate of wildtype C57BL6 mice from 615 to 468 beats per minute (bpm) [22], whereas an anesthesia with Avertin ® did not bring about a reduction of heart rate [23].…”

“…Activation of TASK-1 channels by volatile anesthetics like isoflurane [9,10] provides a putative mechanism of action for general anesthesia [10]. Isoflurane exerts cardiac side effects via activation of TASK-1 channels, at concentrations which are in a clinically relevant range [9].…”

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

“…Originally, anandamide was reported to be highly specific for TASK-1 within the K 2P family (220). Based on this original report, anandamide and methanandamide were routinely used for the identification of TASK-1 in native tissues, glomus cells (95), smooth muscle cells of the pulmonary artery (123), cardiomyocytes (280), and cerebellar granule neurons (220). However, reexamination disproved the specificity; anandamide and methanandamide were found to inhibit TASK-1 and TASK-3 with comparable potency in different species (2, 21, 323).…”

Monitoring (un)consciousness: the implications of a new definition of ‘anaesthesia’

“…interference of sleep or of Table 1 Crude overview of anaesthetic actions on the main putative candidate receptors/channels (red, strongly activating; orange, weakly activating; dark blue, strongly inhibiting; pale blue, weakly inhibiting; 0, no effect; n/a, data unavailable). Adapted from Rudolph and Antkowiak [19] using their broad definitions of strong/weak activation/ inhibition (with TASK results added from data of Putzke et al [20] and Pandit et al [21,22]. Results taken for sevoflurane and AMPA from [23], NMDA from [24] and HCN1 from [25].…”