Aminophylline affects the cardiac rat inward rectifier potassium current in a dual way

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education, Youth and Sports of the Czech Republic Introduction Aminophylline, a bronchodilator used in clinical practice to treat namely severe astma attacks, often induces atrial fibrillation in patients. Modifications of the inward rectifier potassium current IK1 are known to play a role in the genesis of fibrillation. Purpose We aimed to investigate the effect of aminophylline at clinically-relevant concentrations between 3 and 100 µM on IK1 in isolated rat ventricular myocytes. Methods Experiments were performed by the whole cell patch clamp technique on enzymatically isolated rat right ventricular myocytes at room temperature. IK1 was measured as the current sensitive to 100 µM Ba2+. Results We observed a dual steady-state effect of aminophylline at most of the applied concentrations. Either inhibition or activation was apparent in individual cells during application of aminophylline at a given concentration. The smaller was magnitude of the control IK1, the more likely was activation of the current in the presence of aminophylline and vice versa (tested at 10 and 30 µM). The effect was voltage-independent and fully reversible during the subsequent wash-out. The mean aminophylline effect was inhibitory at all concentrations (10, 15, 4, and 23%-inhibition at -50 mV at 3, 10, 30, and 100 µM, respectively). Using a modified version of the population model of IK1 channels that we published before, the dual effect can be explained by interaction of aminophylline with two channel populations in a different way, the first one being inhibited and the second one being activated by the drug. Considering various fractions of these two channel populations in individual cells, varying effects observed in the measured cells can be simulated. Conclusions Aminophylline at clinically-relevant concentrations affects IK1 in rat ventricular myocytes in a dual way, showing both the steady-state activation and inhibition in various cells, even at the same concentration. It may be related to a different effect of the drug on various Kir2.x subunits forming the heterotetrameric IK1 channels present at the cell membrane of a single cell.