Attenuation Of Inward Rectifier Potassium Current Contributes To The Alpha 1-Adrenergic Receptor-Induced Proarrhythmicity In The Caval Vein Myocardium

Aim This study is aimed at investigation of electrophysiological effects of alpha 1-adrenoreceptor (alpha 1-AR) stimulation in the rat superior vena cava (SVC) myocardium, which is one of the sources of proarrhythmic activity.Methods alpha 1-ARs agonists (phenylephrine-PHE or norepinephrine in presence of atenolol-NE + ATL) were applied to SVC and atrial tissue preparations or isolated cardiomyocytes, which were examined using optical mapping, glass microelectrodes or whole-cell patch clamp. alpha 1-ARs distribution was evaluated using immunofluorescence. Kir2.X mRNA and protein level were estimated using RT-PCR and Western blotting.Results PHE or NE + ATL application caused a significant suppression of the conduction velocity (CV) of excitation and inexcitability in SVC, an increase in the duration of electrically evoked action potentials (APs), a decrease in the maximum upstroke velocity (dV/dt(max)) and depolarization of the resting membrane potential (RMP) in SVC to a greater extent than in atria. The effects induced by alpha 1-ARs activation in SVC were attenuated by protein kinase C inhibition (PKC). The whole-cell patch clamp revealed PHE-induced suppression of outward component of I-K1 inward rectifier current in isolated SVC, but not atrial myocytes. These effects can be mediated by alpha 1A subtype of alpha-ARs found in abundance in rat SVC. The basal I-K1 level in SVC was much lower than in atria as a result of the weaker expression of Kir2.2 channels.Conclusion Therefore, the reduced density of I-K1 in rat SVC cardiomyocytes and sensitivity of this current to alpha 1A-AR stimulation via PKC-dependent pathways might lead to proarrhythmic conduction in SVC myocardium by inducing RMP depolarization, AP prolongation, CV and dV/dt(max) decrease.