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. © 2013 Elsevier Ireland Ltd.