Abstract 2517: Phlorizin Prevents Ischemia-induced Ventricular Tachyarrhythmia in Langendorff-perfused Guinea Pig Hearts
Introduction: Myocardial ischemia increases intracellular Na+ concentration leading to intra-cellular Ca2+ overload, which increases the left ventricular end diastolic pressure (LVEDP) and also plays an important role in ventricular tachyarrhythmia (VT). Phlorizin, one of the flavonoids, is a peroxynitrite scavenger and an inhibiter of sodium-glucose cotransporters (SGLT), which are expected to inhibit increases in intracelluar Na+ concentration during ischemia. However, whether phlorizin prevents ischemia-induced increases in LVEDP and VT is unknown.
Method and Results: Thirty-six Langendorff-perfused guinea pig hearts were prepared and subjected to no-flow ischemia. In the first series of experiments, optical action potentials were recorded for 10 sec from the anterior epicardial surface of the ventricle during programmed stimulation before and 5, 10, 15 and 20 min after ischemia was initiated. In the second series of experiments, left ventricular pressure was recorded for 30 min after ischemia was initiated. These experiments were performed in the control and in the presence of phlorizin (100 μM) or N-2-mercaptopropionylglycine (2-MPG, 1 mM), a peroxynitrite scavenger, respectively (n=6 of each). In the control, ischemia induced action potential duration (APD) shortening, slowing of impulse conduction. Phlorizin suppressed the slowing of ischemic conduction but not APD shortening. In contrast, 2-MPG did not suppress the slowing of ischemic conduction and increased the dispersion of APD. Programmed stimulation induced VT at 20 min of ischemia in the control and in the presence of 2-MPG. Isochrone maps on the initiation of VT demonstrated macroreentry with unidirectional conduction block, leading to figure-8 reentry on the epicardial surface. VT was not observed in the presence of phlorizin. Ischemia increased LVEDP in the control and in the presence of 2-MPG. Phlorizin inhibited increases in LVEDP.
Conclusions: These findings suggest that phlorizin prevents ischemia-induced VT through the inhibition of intracellular Ca2+ overload and SGLT is a novel therapeutic target for the VT.