THE PIVOTAL ROLE OF L-ARGININE IN THE ISCHEMIC HEART PRECONDITIONING - A NANOMEDICAL APPROACH
Tadeusz Malinski, Ph.D., Dr.h.c.m., Ohio University, Athens, OH, USA
Ischemic preconditioning with a short coronary artery occlusion has been shown to protect the heart against a subsequent myocardial infarction. Although several endogenous molecules have been implicated in the heart adaptation to an ischemic event, its mechanism is not well understood. A nanomedical approach was used to study, in vivo and ex vivo, the concentration changes of small molecules in the heart during preconditioning. Catheter-protected nanosensors, with a diameter of 300nM, were implanted into the left ventricular wall of the heart of New Zealand white rabbits, in order to measure the concentration of nitric oxide (NO), peroxynitrite (ONOO-), superoxide (O2-), and carbon monoxide (CO), as well as, tetrahydrobiopterin and L-arginine. Ischemia triggered fast release of NO level, which peaked at 1.2±0.2 micromol/L, after 5 minutes. The release of NO was accompanied by the generation of superoxide, which reached maximum concentration after 7±1 minutes, and peroxynitrite which peaked after 17±2 minutes. At 15 minutes of ischemia, equal concentrations (0.8± micromole/L) of NO, O2-, and ONOO- were measured. After 19 minutes, the cytoprotective NO significantly decreased and the cytotoxic ONOO- increased. Therefore, the ratio of NO/ONOO- decreased to 0.05±0.03 from the preischemic ratio of 7:1. Ischemic preconditioning was achieved by an episode of 4-7 minutes of occlusion, followed by 15-60 minutes of reperfusion prior to the 60 minute occlusion. L-arginine content in the heart was measured during different stages of ischemic preconditioning, reperfusion and ischemia. The content of L-arginine increased significantly, from 14 nmol/L per mg protein by 10-50%, after preconditioning. The increase in L-arginine content after preconditioning correlated directly with the decrease of infarct size (25±6%) when compared to the control (48±5%). These results support the hypothesis that the cardioprotective effect of ischemic preconditioning is dependent on L-arginine availability.