Although bradykinin has been demonstrated to protect the heart at reperfusion, 
the detailed cellular and molecular mechanisms that mediate the protection 
remain elusive. Here we aimed to determine whether bradykinin protects the heart 
at reperfusion by modulating the mitochondrial permeability transition pore 
(mPTP) opening through glycogen synthase kinase 3beta (GSK-3beta). Bradykinin 
given at reperfusion reduced infarct size in isolated rat hearts subjected to 30 
min regional ischemia followed by 2 h of reperfusion. The infarct-limiting 
effect of bradykinin was reversed by atractyloside, an opener of the mPTP, 
suggesting that bradykinin may protect the heart at reperfusion by modulating 
the mPTP opening. In support of this observation, bradykinin prevented the 
collapse of mitochondrial membrane potential (DeltaPsi(m)), an index of the mPTP 
opening. Bradykinin increased GSK-3beta phosphorylation at reperfusion, and the 
selective inhibitor of GSK-3beta SB216763 reduced infarct size and prevented the 
loss of DeltaPsi(m) by mimicking the effect of bradykinin. The effect of 
bradykinin on GSK-3beta phosphorylation was blocked by wortmannin and LY294002, 
and bradykinin increased Akt phosphorylation at reperfusion. Further experiments 
showed that the MEK inhibitor PD98059 prevented the effect of bradykinin on 
GSK-3beta. However, the mTOR/p70s6K pathway inhibitor rapamycin did not alter 
bradykinin-induced GSK-3beta phosphorylation and bradykinin failed to alter 
phosphorylation of either mTOR or p70s6K at reperfusion. Taken together, these 
data suggest that bradykinin protects the heart at reperfusion by modulating the 
mPTP opening through inhibition of GSK-3beta. The PI3-kinase/Akt pathway and 
ERK, but not the mTOR/p70s6K pathway account for the suppression of GSK-3beta by 
bradykinin.