Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes

AIMS: 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)). METHODS AND RESULTS: Rat atrial myocyte whole-cell currents were recorded at 36°C. Noradrenaline potently inhibited I(Kss) (IC(50) = 0.90 nM, 42.1 ± 4.3% at 1 µM, n = 7) and potentiated the L-type Ca(2+) current (I(CaL), EC(50) = 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 β(1)-/β(2)-adrenoceptor antagonism (1 µM propranolol or 10 µM β(1)-selective atenolol and 100 nM β(2)-selective ICI-118,551 in combination), but not by β(1)- or β(2)-antagonist alone. The action of noradrenaline could be mimicked by β(2)-agonists (zinterol and fenoterol) in the presence of β(1)-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 β(1)-adrenoceptors via a PTX-insensitive pathway. Noradrenaline prolonged APD(30) by 52 ± 19% (n = 5; P < 0.05), and this effect was abolished by combined β(1)-/β(2)-antagonism, but not by atenolol alone. CONCLUSION: Noradrenaline inhibits a rat atrial TREK-like K(+) channel current via a PTX-sensitive mechanism involving co-operativity of β(1)-/β(2)-adrenoceptors that contributes to atrial APD prolongation.