MDIMP, a novel cardiac Ca(2+) channel blocker with atrial selectivity

Area of Science:

• Cardiovascular Physiology
• Molecular Pharmacology
• Biophysics

Background:

• Cardiac muscle cells express T-type Ca(2+) channels (TTCCs) and L-type Ca(2+) channels (LTCCs).
• LTCCs are crucial for excitation-contraction coupling (ECC) in the heart.
• Isoindolines are suggested to bind to the LTCC CaV1.2 based on docking studies.

Purpose of the Study:

• To investigate the modulatory effects of methyl (S)-2-(1,3-dihydroisoindol-2-yl)-4-methylpentanoate (MDIMP) on cardiac Ca(2+) channels and ECC.
• To determine the potency and mechanism of MDIMP's action on TTCCs and LTCCs in cardiac myocytes and heterologous expression systems.

Main Methods:

• Patch-clamp electrophysiology to measure Ca(2+) currents and channel activity.
• Measurement of Ca(2+) transients and cell mechanics in isolated cardiac myocytes.
• Transient expression of CaV1.2 in HEK 293T/17 cells to study direct effects.

Main Results:

• MDIMP demonstrated an inhibitory effect on CaV1.2 with an IC50 of 450µM, showing reversible kinetics.
• Atrial TTCCs, atrial LTCCs, and ventricular LTCCs were inhibited by MDIMP in decreasing order of potency.
• MDIMP preferentially reduced Ca(2+) transients, contractions, and LTCC window currents in atrial cells compared to ventricular cells.
• LTCC modulation by MDIMP was state-independent in atrial cells but state-dependent and dual in ventricular cells, potentially due to a higher proportion of closed channels at rest.

Conclusions:

• MDIMP acts as an inhibitor of cardiac Ca(2+) channels, modulating ECC.
• The study elucidates structure-function relationships of isoindolines binding to Ca(2+) channels.
• MDIMP's preferential down-regulation of atrial activity suggests potential therapeutic relevance for conditions requiring reduced atrial function.