Modulation of the voltage-dependent K current by intracellular Mg in rat aortic smooth muscle cells

Abstract

Intracellular magnesium ions (Mg2+i) are important in the regulation of a wide range of cellular metabolic processes and modulation of a variety of ion channels. Mg2+ deficiency has been implicated in the aetiology of various cardiovascular diseases. However, potential targets and mechanisms of action of Mg2+i in the cardiovascular system remain poorly understood. We therefore investigated the effect of Mg2+i on the voltage-gated K+ (KV) channels in rat aortic myocytes (RAMs). KV currents (IKv) were investigated in single RAMs isolated from adult Wistar rat thoracic aorta using the whole-cell patch clamp technique. Changes in the vascular reactivity were also assessed in endothelium-denuded rat aortic rings loaded with Mg2+. An increase in Mg2+i caused several significant effects on IKv: (1) slowed down kinetics of activation at high (10 mM) Mg2+; (2) caused inward rectification at positive membrane potentials; (3) shifted the voltage-dependent inactivation, but not steady-state IKv activation; (4) the effect of Mg2+i on IKv inactivation was enhanced in the presence of intracellular ATP. Selective changes in the voltage-dependent characteristics predict a significant inhibition of the whole-cell steady-state IKv ("window current"), resulting in membrane depolarisation and enhanced tissue excitability. An increased sensitivity to KCl and the inhibitors of the IKv, tetraethylammonium and 4-aminopyridine (4-AP), was observed in Mg2+-loaded aortas, confirming this hypothesis. Our results demonstrate that intracellular magnesium can act as a potent modulator of the KV channel function in vascular smooth muscle cells in the physiological range of membrane potentials, representing a novel mechanism for the regulation of KV channel activity in the vasculature.