Modulation of the voltage-dependent K+ current by intracellular Mg2+ in rat aortic smooth muscle cells.
OBJECTIVE
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).


METHODS
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+.


RESULTS
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.


CONCLUSIONS
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.
Tammaro
Paolo
P
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
Smith
Amy L
AL
Crowley
Barry L
BL
Smirnov
Sergey V
SV
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002412:Cations; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium / Q000494:pharmacology
D002412:Cations; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D019789:Tetraethylammonium; D015761:4-Aminopyridine; D008274:Magnesium