Myocardial protection by co-administration of l-arginine and tetrahydrobiopterin during ischemia and reperfusion

Abstract

BackgroundReduced bioavailability of nitric oxide (NO) is a key factor contributing to myocardial ischemia and reperfusion injury. The mechanism behind the reduction of NO is related to deficiency of the NO synthase (NOS) substrate l-arginine and cofactor tetrahydrobiopterin (BH4) resulting in NOS uncoupling. The aim of the study was to investigate if the combination of l-arginine and BH4 given iv or intracoronary before reperfusion protects from reperfusion injury. MethodsSprague–Dawley rats and pigs were subjected to myocardial ischemia and reperfusion. Rats received vehicle, l-arginine, BH4, l-arginine+BH4 with or without the NOS-inhibitor L-NMMA iv 5min before reperfusion. Pigs received infusion of vehicle, l-arginine, BH4 or l-arginine+BH4 into the left main coronary artery for 30min starting 10min before reperfusion. ResultsInfarct size was significantly smaller in the rats (50±2%) and pigs (54±5%) given l-arginine+BH4 in comparison with the vehicle groups (rats 65±3% and pigs 86±5%, P<0.05). Neither l-arginine nor BH4 alone significantly reduced infarct size. Administration of L-NMMA abrogated the cardioprotective effect of l-arginine+BH4. Myocardial BH4 levels were 3.5- to 5-fold higher in pigs given l-arginine+BH4 and BH4 alone. The generation of superoxide in the ischemic-reperfused myocardium was reduced in pigs treated with intracoronary l-arginine+BH4 versus the vehicle group (P<0.05). ConclusionAdministration of l-arginine+BH4 before reperfusion protects the heart from ischemia–reperfusion injury. The cardioprotective effect is mediated via NOS-dependent pathway resulting in diminished superoxide generation.