Selective Inhibition of Cardiac Late Na+ Current Is Based on Fast Offset Kinetics of the Inhibitor

The present study was designed to test the hypothesis that the selectivity of blocking the late Na+ current (INaL) over the peak Na+ current (INaP) is related to the fast offset kinetics of the Na+ channel inhibitor. Therefore, the effects of 1 µM GS967 (INaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on INaL and INaP were compared in canine ventricular myocardium. INaP was estimated as the maximum velocity of action potential upstroke (V+max). Equal amounts of INaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of INaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V+max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of INaL over INaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of INaL over INaP is related to the fast offset kinetics of the Na+ channel inhibitor

Photoisomerization Ability of Molecular Switches Adsorbed on Au(111): Comparison between Azobenzene and Stilbene Derivatives

High resolution electron energy loss spectroscopy and two-photon photoemission was employed to derive the adsorption geometry, electronic structure, and the photoisomerization ability of the molecular switch tetra-tert-butyl-stilbene (TBS) on Au(111). The results are compared with the azobenzene analogue, tetra-tert-butyl-azobenzene (TBA), adsorbed on Au(111). TBS was found to adsorb on Au(111) in a planar (trans) configuration similar to TBA. The energetic positions of several TBS-induced electronic states were determined, and in comparison to TBA, the higher occupied molecular states (e.g., the highest occupied molecular orbital, HOMO) are located at similar energetic positions. While surface-bound TBA can be switched with light between its trans and cis configurations, in TBS this switching ability is lost. In TBA on Au(111), the trans → cis isomerization is driven by a substrate-mediated charge transfer process, whereby photogenerated hot holes in the Au d band lead to transient positive ion formation (transfer of the holes to the TBA HOMO level). Even though the energetic positions of the HOMOs in TBA and TBS are almost identical and thus a charge transfer should be feasible, this reaction pathway is obviously not efficient to induce the trans → cis isomerization in TBS on Au(111). Quantum chemical calculations of the potential energy surfaces for the free molecules support this conclusion. They show that cation formation facilitates the isomerization for TBA much more pronounced than for TBS due to the larger gradients at the Franck−Condon point and the much smaller barriers on the potential energy surface in the case of the TBA

Selective Inhibition of Cardiac Late Na⁺ Current Is Based on Fast Offset Kinetics of the Inhibitor

The present study was designed to test the hypothesis that the selectivity of blocking the late Na+ current (INaL) over the peak Na+ current (INaP) is related to the fast offset kinetics of the Na+ channel inhibitor. Therefore, the effects of 1 µM GS967 (INaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on INaL and INaP were compared in canine ventricular myocardium. INaP was estimated as the maximum velocity of action potential upstroke (V+max). Equal amounts of INaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of INaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V+max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of INaL over INaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of INaL over INaP is related to the fast offset kinetics of the Na+ channel inhibitor