Bimakalim

A novel coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), or 2019 novel coronavirus] has been identified as the pathogen of coronavirus disease 2019. The main protease (Mpro, also called 3‐chymotrypsin‐like protease) of SARS‐CoV‐2 is a potential target for treatment of COVID‐19. A Mpro homodimer structure suitable for docking simulations was prepared using a crystal structure (PDB ID: 6Y2G; resolution 2.20 Å). Structural refinement was performed in the presence of peptidomimetic α‐ketoamide inhibitors, which were previously disconnected from each Cys145 of the Mpro homodimer, and energy calculations were performed. Structure‐based virtual screenings were performed using the ChEMBL database. Through a total of 1 485 144 screenings, 64 potential drugs (11 approved, 14 clinical, and 39 preclinical drugs) were predicted to show high binding affinity with Mpro. Additional docking simulations for predicted compounds with high binding affinity with Mpro suggested that 28 bioactive compounds may have potential as effective anti‐SARS‐CoV‐2 drug candidates. The procedure used in this study is a possible strategy for discovering anti‐SARS‐CoV‐2 drugs from drug libraries that may significantly shorten the clinical development period with regard to drug repositioning.

To assess the electrophysiological impact of aldosterone during myocardial ischemia-reperfusion.

We used an in vitro model of "border zone" using rabbit right ventricle and standard microelectrodes.

Aldosterone (10 and 100 nmol/L) shortened ischemic action potential [action potential duration at 90% of repolarization (APD90), from 55 ± 3 to 39 ± 1 ms and 36 ± 3 ms, respectively, P < 0.05] and induced resting membrane potential (RMP) hyperpolarization in the nonischemic zone (from -83 ± 1 to -93 ± 7 mV and -94 ± 3 mV, respectively, P < 0.05) and in the ischemic zone during reperfusion (from -81 ± 2 to -88 ± 2 mV and -91 ± 2 mV, respectively, P < 0.05). Bimakalim, an ATP-sensitive potassium (K(ATP)) channel opener, also induced RMP hyperpolarization and APD90 shortening. Aldosterone (10 and 100 nmol/L) increased APD90 dispersion between ischemic and nonischemic zones (from 96 ± 3 to 117 ± 5 ms and 131 ± 6 ms, respectively, P < 0.05) and reperfusion-induced severe premature ventricular contraction occurrence (from 18% to 67% and 75%, respectively, P < 0.05). Adding glibenclamide, a nonspecific K(ATP) antagonist, to aldosterone superfusion abolished these effects different to sodium 5-hydroxydecanoate, a mitochondrial-K(ATP) antagonist.

In this in vitro rabbit model of border zone, aldosterone induced RMP hyperpolarization and decreased ischemic APD90 evoking the modulation of K currents. Glibenclamide prevented these effects different to 5-hydroxydecanoate, suggesting that sarcolemmal-K(ATP) channels may be involved in this context.