ACh-induced depolarization in inner ear artery is generated by activation of a TRP-like non-selective cation conductance and inactivation of a potassium conductance

Adequate cochlear blood supply by the spiral modiolar artery (SMA) is critical for normal hearing. ACh may play a role in neuroregulation of the SMA but several key issues including its membrane action mechanisms remain poorly understood. Besides its well-known endothelium-dependent hyperpolarizing action, ACh can induce a depolarization in vascular cells. Using intracellular and whole-cell recording techniques on cells in guinea pig in vitro SMA, we studied the ionic mechanism underlying the ACh-depolarization and found that: (1) ACh induced a DAMP-sensitive depolarization when intermediate conductance K_Ca channels were blocked by charybdotoxin or nitrendipine. The ACh-depolarization was associated with a decrease in input resistance (R_input) in high membrane potential (V_m) (∼-40 mV) cells but with no change or an increase in R_input in low V_m (∼-75 mV) cells. ACh-depolarization was attenuated by background membrane depolarization from ∼-70 mV in the majority of cells; (2) ACh-induced inward current in smooth muscle cells embedded in a SMA segment often showed a U-shaped I/V curve, the reversal potential of its two arms being near E_K and 0 mV, respectively; (3) ACh-depolarization was reduced by low Na⁺, zero K⁺ or 20 mM K⁺ bath solutions; (4) ACh-depolarization was inhibited by La³⁺ in all cells tested, by 4-AP and flufenamic acid in low V_m cells, but was not sensitive to Cd²⁺, Ni²⁺, nifedipine, niflumic acid, DIDS, IAA94, linopirdine or amiloride. We conclude that ACh-induced vascular depolarization was generated mainly by activation of a TRP-like non-selective cation channel and by inactivation of an inward rectifier K⁺ channel.