title: 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.affiliation: Divison of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. adrian.gonon@ki.se
authors.forename: Adrian T
authors.initials: AT
authors.lastname: Gonon
authors.forename: Christian
authors.initials: C
authors.lastname: Jung
authors.forename: Abram
authors.initials: A
authors.lastname: Katz
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
authors.forename: Alexey
authors.initials: A
authors.lastname: Shemyakin
authors.forename: Per-Ove
authors.initials: PO
authors.lastname: Sjöquist
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.forename: John
authors.initials: J
authors.lastname: Pernow
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D009569:Nitric Oxide / Q000096:biosynthesis*; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D001119:Arginase