Activation of α₁-adrenoceptors modulates the inwardly rectifying potassium currents of mammalian atrial myocytes

Abstract

The selective α₁-adrenergic agonist methoxamine (10⁻⁴–10⁻³M), in the presence of propranolol (10⁻⁶M), can reduce both the inwardly rectifying K⁺ background current (I _K1) and the muscarinic cholinergic receptor-activated K⁺ current (I _{K, ACh}) in rabbit atrial myocytes resulting in action potential prolongation during the final phase of repolarization and a depolarization of the resting membrane potential. The reduction of these K⁺ current(s) by α₁-adrenoceptor stimulation was insensitive to pre-treatment of artial myocytes with pertussis toxin (0.15–0.5 μg/ml) and was irreversible following intracellular dialysis with the non-hydrolysable guanosine triphosphate (GTP) analogue, Gpp(NH)p (1−5×10⁻³M). Neither the protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulphonyl)-2-methylpiperoxine (H-7) (5×10⁻⁵M) and staurosporine (1×10⁻⁷M), nor “downregulation” of PKC by prolonged phorbol ester exposure (5×10⁻⁷M, for 7–8 h) had an effect on the α₁-adrenergic modulation of this K⁺ current. Under cellattached patch-clamp conditions, bath application of methoxamine reversibly decreased acetylcholine-induced single-channel activity, thus confirming the observed reduction of the ACh-induced current under whole-cell voltage clamp. These results demonstrate that the α₁adrenoceptor, once activated, can reduce current through two different inwardly rectifying K⁺ channels in rabbit atrial myocytes. These current changes are mediated via a pertussis toxin-insensitive GTP-binding protein, and do not appear to involve the activation of PKC.