Selective stimulation of β3 adrenergic-receptor (β3AR) has been shown to reduce 
infarct size in a mouse model of myocardial ischemia/reperfusion. However, its 
functional long-term effect and the cardioprotective mechanisms at the level of 
cardiomyocytes have not been elucidated, and the impact of β3AR stimulation has 
not been evaluated in a more translational large animal model. This study aimed 
at evaluating pre-perfusion administration of BRL37344 both in small and large 
animal models of myocardial ischemia/reperfusion. Pre-reperfusion administration 
of the β3AR agonist BRL37344 (5 μg/kg) reduced infarct size at 2-and 24-h 
reperfusion in wild-type mice. Long-term (12-weeks) left ventricular (LV) 
function assessed by echocardiography and cardiac magnetic resonance (CMR) was 
significantly improved in β3AR agonist-treated mice. Incubation with β3AR 
agonist (BRL37344, 7 μmol/L) significantly reduced cell death in isolated adult 
mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility 
to deleterious opening of the mitochondrial permeability transition pore (mPTP), 
via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion 
BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, 
further implicating mPTP in the mechanism of protection. Large-white pigs 
underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 
45 days post-infarction. Pre-perfusion administration of BRL37344 (5 μg/kg) 
decreased infarct size and improved long-term LV contractile function. A 
single-dose administration of β3AR agonist before reperfusion decreased infarct 
size and resulted in a consistent and long-term improvement in cardiac function, 
both in small and large animal models of myocardial ischemia/reperfusion. This 
protection appears to be executed through inhibition of mPTP opening in 
cardiomyocytes.