Stimulation of the Beta2 adrenergic receptor at reperfusion limits myocardial reperfusion injury via an interleukin-10-dependent anti-inflammatory pathway in the spleen

Background: In addition to the airway-relaxing effects, β₂ adrenergic receptor (β₂AR) agonists are also found to have broad anti-inflammatory effects. The current study was conducted to define the role of β₂AR agonists in limiting myocardial ischemia/ reperfusion injury (IRI). Methods and Results: Adult male wild-type (WT) and interleukin (IL)-10 knockout (KO) mice underwent a 40-min left coronary artery ligation and 60-min reperfusion. A selective β₂AR agonist, Clenbuterol, at doses of 0.1 μg or 1 μg/g weight i.v. 5 min before reperfusion, significantly reduced myocardial infarct size (IS) by 28% and 39% (vs. control, P<0.05) in WT mice respectively, but had no protective effect in IL-10 KO mice. Inhalational therapy with nebulized Clenbuterol, Albuterol, Salmeterol or Arformoterol immediately before ischemia significantly reduced IS (P<0.05) in WT mice. Splenectomy similarly reduced IS as Clenbuterol-treated mice, but intravenous Clenbuterol did not further reduce IS in splenectomized mice. In splenectomized WT mice, acute transfer of isolated splenocytes, not the Clenbuterol-pretreated splenocytes, restored the myocardial IS to the level of intact mice. Intravenous Clenbuterol significantly increased splenic protein levels of β₂AR, phosphorylated Akt and IL-10 and plasma IL-10, and inhibited the expression of pro-inflammatory mRNAs. Conclusions: Both intravenous and inhalational β₂AR agonists exert a cardioprotective effect against IRI by activating the anti-inflammatory β₂AR-IL-10 pathway.