Metoprolol Exerts A Non-Class Effect Against Ischaemia-Reperfusion Injury By Abrogating Exacerbated Inflammation

Aims Clinical guidelines recommend early intravenous beta-blockers during ongoing myocardial infarction; however, it is unknown whether all beta-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous beta-blockers.Methods and results Mice undergoing 45 min/24 h ischaemia-reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravitat microscopy. The effect of beta-blockers on the conformation of the beta 1 adrenergic receptor was studied in silico. Of the tested beta-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% +/- 0.03% for metoprolol vs. 35.9% +/- 0.03% for vehicle; P < 0.01]. Atenolot and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular beta 1 adrenergic receptor conformational changes when bound to metoprolol than to the other two beta-blockers.Conclusions Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of beta-blockers may be related to distinct conformational changes in the beta 1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous beta-blocker of choice for patients with on-going infarction.[GRAPHICS].