Chronic in vivo angiotensin II administration differentially modulates the slow delayed rectifier channels in atrial...

In the heart, slow delayed rectifier channels provide outward currents (I_Ks) for action potential (AP) repolarization in a region- and context-dependent manner. In diseased hearts, chronic elevation of angiotensin II (Ang II) may remodel I_Ks in a region-dependent manner, contributing to atrial and ventricular arrhythmias of different mechanisms.

The purpose of this study was to study whether/how chronic in vivo Ang II administration remodels I_Ks in atrial and ventricular myocytes.

We used the guinea pig (GP) model whose myocytes express robust I_Ks. GPs were implanted with minipumps containing Ang II or vehicle. Treatment continued for 4-6 weeks. We used patch clamp, immunofluorescence/confocal microscopy, and immunoblots to evaluate changes in I_Ks function and to explore the underlying mechanisms.

We confirmed the pathologic state of the heart after chronic Ang II treatment. I_Ks density was increased in atrial myocytes but decreased in ventricular myocytes in Ang II- vs vehicle-treated animals. The former was correlated with an increase in KCNQ1/KCNE1 colocalization in myocyte periphery, whereas the latter was correlated with a decrease in KCNQ1 protein level. Interestingly, these changes in I_Ks were not translated into expected alterations in AP duration or plateau voltage, indicating that other currents were involved. In atrial myocytes from Ang II-treated animals, the L-type Ca channel current was increased, contributing to AP plateau elevation and AP duration prolongation.

I_Ks is differentially modulated by chronic in vivo Ang II administration between atrial and ventricular myocytes. Other currents remodeled by Ang II treatment also contribute to changes in action potentials.