The degree to which different volatile anesthetics depress carotid body hypoxic response relates to their ability to activate TASK potassium channels. Most commonly, volatile anesthetic pairs act additively at their molecular targets. We examined whether this applied to carotid body TASK channels.
We studied halothane and isoflurane effects on hypoxia-evoked rise in intracellular calcium (Ca2+i, using the indicator Indo-1) in isolated neonatal rat glomus cells, and TASK single-channel activity (patch clamping) in native glomus cells and HEK293 cell line cells transiently expressing TASK-1.
Halothane (5%) depressed glomus cell Ca2+i hypoxic response (mean ± SD, 94 ± 4% depression; P < 0.001 vs. control). Isoflurane (5%) had a less pronounced effect (53 ± 10% depression; P < 0.001 vs. halothane). A mix of 3% isoflurane/1.5% halothane depressed cell Ca2+i response (51 ± 17% depression) to a lesser degree than 1.5% halothane alone (79 ± 15%; P = 0.001), but similar to 3% isoflurane alone (44 ± 22%; P = 0.224), indicating subadditivity. Halothane and isoflurane increased glomus cell TASK-1/TASK-3 activity, but mixes had a lesser effect than that seen with halothane alone: 4% halothane/4% isoflurane yielded channel open probabilities 127 ± 55% above control, versus 226 ± 12% for 4% halothane alone (P = 0.009). Finally, in HEK293 cell line cells, progressively adding isoflurane (1.5 to 5%) to halothane (2.5%) reduced TASK-1 channel activity from 120 ± 38% above control, to 88 ± 48% (P = 0.034).
In all three experimental models, the effects of isoflurane and halothane combinations were quantitatively consistent with the modeling of weak and strong agonists competing at a common receptor on the TASK channel.
- Volatile anesthetic–induced activation of constitutively active TASK potassium channels in the carotid bodies blunts ventilatory response to hypoxia
- Whether volatile anesthetics differ in their efficacy of suppressing hypoxic ventilatory response is incompletely understood
- While additive effects after coadministration of pairs of volatile anesthetics have been reported, the possibility that the less efficacious of the two agents might antagonize the more efficacious one has not been previously demonstrated
- In vitro, both halothane and isoflurane depressed hypoxia-evoked rise in intracellular calcium in rat carotid body cells, and activated TASK potassium channels
- At equivalent concentrations, halothane exhibited stronger effects on hypoxic responses and TASK channel activation than isoflurane, but coapplications of these two drugs resulted in lesser effects than halothane alone
- These observations suggest that isoflurane and halothane act as competitive agonists on TASK channels where the weaker agonist (isoflurane) antagonizes the effects of the stronger agonist (halothane)