Inhibition of a TREK-like K⁺ channel current by noradrenaline requires both β₁- and β₂-adrenoceptors in rat atrial myocytes

Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the identity of the modulated channels, their mechanisms of modulation, and their role in the action potential remain unclear. This study aimed to investigate the noradrenergic modulation of an atrial steady-state outward current (I_Kss).

Rat atrial myocyte whole-cell currents were recorded at 36°C. Noradrenaline potently inhibited I_Kss (IC₅₀ = 0.90 nM, 42.1 ± 4.3% at 1 µM, n = 7) and potentiated the L-type Ca²⁺ current (I_CaL, EC₅₀ = 136 nM, 205 ± 40% at 1 µM, n = 6). Noradrenaline-sensitive I_Kss was weakly voltage-dependent, time-independent, and potentiated by the arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (EYTA; 10 µM), or by osmotically induced membrane stretch. Noise analysis revealed a unitary conductance of 8.4 ± 0.42 pS (n = 8). The biophysical/pharmacological properties of I_Kss indicate a TREK-like K⁺ channel. The effect of noradrenaline on I_Kss was abolished by combined β₁-/β₂-adrenoceptor antagonism (1 µM propranolol or 10 µM β₁-selective atenolol and 100 nM β₂-selective ICI-118,551 in combination), but not by β₁- or β₂-antagonist alone. The action of noradrenaline could be mimicked by β₂-agonists (zinterol and fenoterol) in the presence of β₁-antagonist. The action of noradrenaline on I_Kss, but not on I_CaL, was abolished by pertussis toxin (PTX) treatment. The action of noradrenaline on I_CaL was mediated by β₁-adrenoceptors via a PTX-insensitive pathway. Noradrenaline prolonged APD₃₀ by 52 ± 19% (n = 5; P < 0.05), and this effect was abolished by combined β₁-/β₂-antagonism, but not by atenolol alone.

Noradrenaline inhibits a rat atrial TREK-like K⁺ channel current via a PTX-sensitive mechanism involving co-operativity of β₁-/β₂-adrenoceptors that contributes to atrial APD prolongation.