Arginase inhibition reduces infarct size via nitric oxide, protein kinase C epsilon and mitochondrial ATP-dependent K+ channels.

Reduced bioavailability of nitric oxide (NO) contributes to the development of myocardial ischemia-reperfusion (I/R) injury. Increased activity of arginase is a potential factor that reduces NO bioavailability by competing for the substrate L-arginine. The aim of the study was to test the hypothesis that inhibition of arginase after coronary artery occlusion protects from I/R injury and to explore possible mechanisms behind this effect. Male Sprague-Dawley rats subjected to 30 min of coronary artery ligation and 2h reperfusion were given i.v. before the reperfusion: 1) saline; 2) the arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA); 3) nor-NOHA with the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA); 4) nor-NOHA with the mitochondrial ATP-dependent K(+) (mitoKATP) channel blocker 5-hydroxydecanoic acid (5-HD); 5) nor-NOHA with the protein kinase C epsilon (PKCε) inhibitor ε-V1-2 or 6) ε-V1-2 alone. Infarct size in the control groups was 61±3% and it was reduced to 47±3% (P<0.01) by nor-NOHA. The cardioprotective effect was blocked by the NOS inhibitor L-NMMA. PKCε expression was reduced by I/R and this reduction was attenuated by nor-NOHA. Furthermore, the PKCε inhibitor ε-V1-2 abolished the protective effect of nor-NOHA (infarct size 69±6%). In addition, the cardioprotective effect of nor-NOHA was also abolished following blockade of the mitoKATP channel (infarct size 62±1%). Inhibition of arginase before reperfusion protects the heart from I/R injury via a NOS-dependent pathway, increased expression of PKCε and activation of mitoKATP channels.