Comparison of the respiratory effects of GAL‐021 in BK α subunit knockout (Slo1−/ −) and wild‐type mice

Abstract

GAL‐021 is a novel respiratory stimulant that increases minute ventilation (Vmin) in rats and Cynomolgus monkeys. Transecting the carotid sinus nerve decreases this effect in rats, suggesting that part of the evoked stimulation is mediated by effects at the level of the carotid body. BK (or Maxi K) channels, which consist of a pore‐forming α‐subunit (slo1) and various â regulatory subunits, are present in the carotid body and have been implicated in oxygen sensing. Hypoxia reportedly decreases BK potassium current and increases carotid sinus nerve activity. In preliminary studies using GH3 cells we demonstrated that GAL‐021 exerts modest inhibition of BK channels (56%I at 10 μM). To test the hypothesis that GAL‐021 may stimulate breathing via inhibition of BK channels, we administered GAL‐021 (0.03 ‐ 3 mg/kg, IV) as bolus injections to isoflurane anesthetized, wild‐type and BK á‐subunit knockout (Slo1−/−) mice. In wild‐type mice, GAL‐021 dose‐dependently increased Vmin (maximum response 143 ± 34 % above baseline; ED50 0.5 mg/kg) consistent with prior studies in rats and monkeys. In Slo1−/− mice the effects of GAL‐021 on Vmin (maximum response 64 ± 24 % above baseline; ED50 2.1 mg/kg) were significantly attenuated (but not abolished) in comparison to the wild‐type. These data suggest that BK channels contribute to the effects of GAL‐021 on ventilation but that non‐BK‐dependent mechanisms are also involved.