Local arginase inhibition during early reperfusion mediates cardioprotection via increased nitric oxide production.

Abstract

Consumption of L-arginine contributes to reduced bioavailability of nitric oxide (NO) that is critical for the development of ischemia-reperfusion injury. The aim of the study was to determine myocardial arginase expression and activity in ischemic-reperfusion myocardium and whether local inhibition of arginase within the ischemic myocardium results in increased NO production and protection against myocardial ischemia-reperfusion. Anesthetized pigs were subjected to coronary artery occlusion for 40 min followed by 4 h reperfusion. The pigs were randomized to intracoronary infusion of vehicle (n = 7), the arginase inhibitor N-hydroxy-nor-L-arginine (nor-NOHA, 2 mg/min, n = 7), the combination of nor-NOHA and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 0.35 mg/min, n = 6) into the jeopardized myocardial area or systemic intravenous infusion of nor-NOHA (2 mg/min, n = 5) at the end of ischemia and start of reperfusion. The infarct size of the vehicle group was 80 ± 4% of the area at risk. Intracoronary nor-NOHA reduced infarct size to 46 ± 5% (P<0.01). Co-administration of L-NMMA abrogated the cardioprotective effect mediated by nor-NOHA (infarct size 72 ± 6%). Intravenous nor-NOHA did not reduce infarct size. Arginase I and II were expressed in cardiomyocytes, endothelial, smooth muscle and poylmorphonuclear cells. There was no difference in cytosolic arginase I or mitochondrial arginase II expression between ischemic-reperfused and non-ischemic myocardium. Arginase activity increased 2-fold in the ischemic-reperfused myocardium in comparison with non-ischemic myocardium. In conclusion, ischemia-reperfusion increases arginase activity without affecting cytosolic arginase I or mitochondrial arginase II expression. Local arginase inhibition during early reperfusion reduces infarct size via a mechanism that is dependent on increased bioavailability of NO.

• Authors: Adrian T Gonon, Christian Jung, Abram Katz, Håkan Westerblad, Alexey Shemyakin, Per-Ove Sjöquist, Jon O Lundberg, John Pernow
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e42038 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22860052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Enzyme Inhibitors
• Nitric Oxide
• Arginase

Topics

• Animals
• Arginase (antagonists & inhibitors)
• Blotting, Western
• Cardiotonic Agents (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Female
• Myocardial Reperfusion Injury (prevention & control)
• Myocardium (enzymology)
• Nitric Oxide (biosynthesis)
• Swine