A1899, PK-THPP, ML365, and Doxapram inhibit endogenous TASK channels and excite calcium signaling in carotid body type-1 cells.

Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BK ) potassium channels which leads to membrane depolarization, voltage-gated Ca-entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca ] -signaling in isolated neonatal rat type-1 cells. PK-THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK-THPP, A1899 and Ml 365 all evoked a rapid increase in type-1 cell [Ca ] . These [Ca ] responses were abolished in Ca -free solution and greatly attenuated by Ni (2 mM) suggesting that depolarization and voltage-gated Ca -entry mediated the rise in [Ca ] Doxapram (50 μmol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased [Ca ] . We also tested the effects of combined inhibition of BK and TASK channels. TEA (5 mmol/L) slightly increased [Ca ] in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca ] in the presence of A1899 but not in the presence of PK-THPP. In general [Ca ] responses to TASK inhibitors, alone or in combination with BK inhibitors, were smaller than the [Ca ] responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca -entry but suggest that this, even with concomitant inhibition of BK channels, may be insufficient to account fully for the [Ca ] -response to hypoxia.