Reduction Of Cardiac Sodium Current Is Independent Of Cardiac Hypertrophy In Mice With Cardiac Specific Overexpression Of Type 1 Angiotensin Ii Receptor

Cardiac hypertrophy, arrhythmias and heart failure are serious outcomes of an overstimulation of renin angiotensin system. Indeed, when the type 1 angiotensin II (ANGII) receptor (AT1R) is overexpressed in a cardiac-specific manner in mice all of these pathologies are recapitulated. Nonetheless, the mechanism underlying these pathologies remain incompletely understood. Previously, we have shown that chronic stimulation of AT1R caused significant decreases in ventricular potassium and calcium currents. To further investigate the AT1R mediated regulation of ion channels, we examined the cardiac sodium current (INa) in AT1R mice. To distinguish the effect of a direct AT1R overexpression from AT1R induced hypertrophy, mice were used before (50-day, 50d) and after (6-month, 6m) the development of cardiac hypertrophy. Surface ECG recordings showed that QRS complex was prolonged independently of cardiac remodelling in AT1R mice compared to controls. (50d: CTL: 17.0±0.4 ms, n=11 and AT1R: 22.2±1.5 ms, n=7 and 6m: CTL: 17.0±0.6 ms, n=9 and AT1R: 21.7±0.6 ms, n=9). Current-clamp recordings revealed that the maximal velocity of the action potential (AP) upstroke (Vmax) was reduced to a similar extent in AT1R mice of both age groups compared to controls (50d: CTL: 107±4, n=20, AT1R: 76±4, n=22; 6m: CTL: 111±7, n=12, AT1R: 64±5, n=13). Lastly, voltage-clamp recordings showed a 65% reduction in INa density in AT1R mice of both ages (at −45mV, 50d: CTL: −41.8±2.6 pA/pF, n=26, AT1R: −14.1±1.1 pA/pF, n=23; 6m: CTL: −38.0±3.1 pA/pF, n=13 and AT1R: −13.5±2.1 pA/pF, n=7). In conclusion, overstimulation of the AT1R pathways leads to INa reduction and results in severe cardiac electrical disturbances which occurred before the development of cardiac hypertrophy suggesting they are not secondary to hypertrophy.