LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1

Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g. dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use due to their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue WT or G601S Kv11.1 trafficking as shown by western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S Kv11.1 cells, dofetilide (10 μM) or dofetilide+LUF7244 (10+5 μM) restored Kv11.1 trafficking also, as demonstrated by western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased IKv11.1 despite the presence of dofetilide (1 μM) in WT Kv11.1 cells. In G601S expressing cells, long-term treatment (24-48 h) with LUF7244 (10 μM) and dofetilide (1 μM) increased IKv11.1 compared to non-treated, or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of LUF7244 and an IKV11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects.Toxicolog

Molecular dynamics study of isobaric and isochoric glass transitions in a model amorphous polymer

We perform molecular dynamics simulations of the glass transition through isobaric and isochoric cooling of a model polymeric material. In general, excellent agreement between the simulation results and the existing experimental trends is observed. The glass transition temperature (Tg)(Tg) is found to be a function of pressure under isobaric conditions and specific volume under isochoric conditions. Under both isobaric and isochoric conditions, the trans-state fraction and the torsional contributions to the energy undergo abrupt changes at the glass transition temperature. We analyze these data to show that the glass transition is primarily associated with the freezing of the torsional degrees of the polymer chains which is strongly coupled to the degree of freedom associated with the nonbonded Lennard-Jones potential. We attribute the greater strength of the glass transition under constant pressure conditions to the fact that the nonbonded Lennard-Jones potential is sensitive to the specific volume, which does not change during cooling under isochoric conditions. Comparison of the isochoric and isobaric data demonstrate that the thermodynamic state is independent of cooling path above Tg,Tg, while path-dependent below Tg.Tg. The simulation data show that the free volume at the isobaric glass transition temperature is pressure dependent. We also find that a glass transition occurs under isochoric conditions, even though the free volume actually increases with decreasing temperature. © 1999 American Institute of Physics