B1-adrenergic blockers provide cardiac protection through extracellular traps inhibition during widespread inflammation

Abstract

Sepsis is one of the leading causes of death worldwide, and no therapy is available other than intensive care treatments. Drug development attempts have mainly focused on controlling inflammation or treating dysfunction, without significant improvement in the last decades. Recently, interest has emerged in β1-adrenergic blockade, which has proved beneficial to both parameters. Unfortunately, the specific underlying mechanisms have not been addressed yet. Our study aimed to investigate on mice (adult Swiss male, 30-45g) lipopolyssacharide or cecal ligature and puncture models the effects of atenolol, a β1-adrenergic blocker, currently used in intensive care units for hypertension and arrhythmia. The results demonstrated a beneficial effect of treatment on survival and a preservation of cardiac function including left ventricular ejection fraction (33±2,8% in sepsis group versus 55±5,1% in sepsis-treated group, p<0,05) at a concentration reducing heart rate by approximately 10%.We wondered if beneficial results obtained with atenolol could be due to a modulation of extracellular traps. These components are essential in pathogen spreading control and are increased during sepsis. However, an excess of their production induces vascular occlusions and acute heart injuries.We demonstrated that neutrophils extracellular traps were increased in heart and blood during sepsis and decreased significantly following atenolol administration (blood: 1.1±0,3% in control group, 13,4±1.8% in sepsis group, 6.9±1.2% in sepsis-treated group). This beneficial effect of atenolol was not associated with other modulations of neutrophil function such as their ability to phagocyte (33,6±3,9% in sepsis group versus 25.6±3.6% in sepsis-treated group, p>0,05), to undergo apoptosis (Annexin V+/ L/D-: 13,2±2.1% in sepsis group versus 14.1±2.9% in sepsis-treated group, p>0,05) or to degranulate. Blood neutrophil phenotypes associated with their maturation state (expression of CD62L and CXCR2) or ability to migrate into tissue (expression of adhesion molecules PSGL1, LFA1, VLA4, PECAM1) was also similar between LPS and LPS-treated groups. Although, the modulation of extracellular traps production by atenolol was also observed in other immune cells population able to extrude chromatin fibers in extracellular space such as macrophages. These results suggest a specific beneficial effect of ß1-adrenergic blockers on extracellular traps formation associated with cardiac function preservation and ultimately survival without detrimental effect on heart rate during widespread inflammation. This work was supported by funding from INSERM and Paris-Saclay University-UVSQ. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.