Cannabidiol protects against lipopolysaccharides-induced inflammation in cardiac sodium channels

Inflammatory infections by gram-negative bacteria, known as sepsis, can lead to arrhythmias. However, the mechanisms underlying sepsis-induced inflammation, and how inflammation provokes cardiac arrhythmias, are not well understood. We hypothesized there is a common pathway involved in the immunological and cardiac responses, via cardiac sodium channels (Nav1.5), to lipopolysaccharides. Lipopolysaccharides (LPS), the major component of the outer membrane of gram-negative bacteria, is known to be a key trigger for the inflammatory effects. We incubated human immune cells (THP-1 macrophages) with LPS for 24 hours to stimulate the release of inflammatory cytokines, then extracted the THP-1 incubation media. ELISA showed that LPS, in a concentration-dependent manner, stimulated the THP-1 cells to release inflammatory cytokines. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were subsequently incubated for 24 hours in the media extracted from LPS-stimulated THP-1 cells. Voltage clamp experiments showed that the voltage dependence of Nav1.5 steady state fast inactivation (SSFI) was right-shifted and persistent current increased in hiSPC-CM incubated in the LPS-THP-1 media. Current clamp was used to measure the duration of action potential in hiPSC-CMs. hiPSC-CM incubated in the LPS-THP-1 media had a prolonged action potential. Cannabidiol (CBD: 5 μM), when included in the THP-1 incubation or perfused while recording from the hiSPC-CMs, rescued the right-shift in SSFI and reduced both the persistent current and AP prolongation. Our results suggest that CBD, through Nav1.5, may protect against sepsis-induced dysfunction in Nav1.5 gating and subsequent arrhythmias.