Myocardial protection by co-administration of L-arginine and tetrahydrobiopterin during ischemia and reperfusion.
Tratsiakovich Y., Gonon AT., Kiss A., Yang J., Böhm F., Tornvall P., Settergren M., Channon KM., Sjöquist PO., Pernow J.
BACKGROUND: Reduced 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. METHODS: Sprague-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 5 min before reperfusion. Pigs received infusion of vehicle, L-arginine, BH4 or L-arginine+BH4 into the left main coronary artery for 30 min starting 10 min before reperfusion. RESULTS: Infarct 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). CONCLUSION: Administration 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.