Differential positive inotropic effects of the I Kr-blocker dofetilide and the I TO/I Kur-blocker AVE0118 in canine atrial myocytes

Abstract

Background: Patients undergoing cardioversion of atrial tachyarrhythmias might benefit from positive inotropic stimulation of the atria. The shape of the atrial action potential (AP) is a major determinant of atrial contractility. Newly developed Ito/IKur-blockers prolong early repolarisation and increase the ’plateau potential’ of the atrial AP while IKr-blockers (e.g. dofetilide) prolong final repolarisation without affecting the plateau phase. We compared the inotropic effects of dofetilide and the Ito/IKur-blocker AVE0118 on isolated atrial myocytes. Methods: Shortening transients (edge detection) and transmembrane APs of isolated canine atrial myocytes were recorded under current clamp conditions using the perforated patch technique (37°C). The ’plateau potential’ was defined as the average potential between 10 and 50ms after the upstroke of the AP. The effect of changes of: 1) plateau duration, 2) plateau potential, and 3) the time required for final repolarisation (prolongation of APD90 without change in APD30) on cellular shortening of atrial myocytes was studied in voltage-clamp experiments. Results: Dofetilide (1 M) prolonged APD90 from 318 25ms to 435 35ms but did not significantly change the plateau potential or the shortening of atrial myocytes (7 cells, 4 dogs). In contrast, AVE0118 increased the plateau potential from -5 6mV to 21 8mV and enhanced myocyte shortening from 4.0 1.0% to 9.8 1.3% (9 cells, 5 dogs). APD90 was unchanged. In voltage clamp experiments, prolongation of the plateau increased myocyte shortening from 1.9 0.4% at 50ms to 16.6 1.2% at 600ms. Increasing the plateau potential enhanced shortening from 0.7 0.1% at -20mV to 17.8 1.2% at 60mV. In contrast, prolongation of APD90 by 200ms without changes of plateau potential or duration did not enhance shortening (9 cells, 5 dogs). Conclusion: AVE0118 enhances atrial contractility by increasing the plateau potential due to prolongation of the early repolarisation. Dofetilide does not affect the plateau phase of the AP and therefore does not enhance atrial contractility.