ABSTRACT
The main determinant of myocardial necrosis following an acute myocardial infarction (AMI) is duration of ischemia. Infarct size is a strong independent predictor of postinfarction mortality. Interventions able to protect the myocardium (myocardial protection) from death during an ischemic event are urgently needed. Myocardial injury associated with reperfusion signicantly contributes to the nal necrotic size. Duration of ischemia is largely determined by availability of
6.1 Introduction .......................................................................................................................... 101 6.2 Regulation, Synthesis, and Metabolism of NO..................................................................... 102
6.2.1 Nitric Oxide .............................................................................................................. 102 6.2.2 Nitric Oxide Synthase Enzymes ............................................................................... 102 6.2.3 NOS-Independent Production of NO ........................................................................ 103 6.2.4 Mechanisms of NO in Myocardial Protection .......................................................... 104 6.2.5 NO in Ischemia/Reperfusion .................................................................................... 105
6.3 Regulation, Synthesis, and Metabolism of Arginine and ADMA........................................ 105 6.3.1 l-Arginine ................................................................................................................. 105 6.3.2 ADMA Metabolism .................................................................................................. 106 6.3.3 ADMA as a Risk Factor in Cardiovascular Disease ................................................ 107
6.4 Regulation, Synthesis, and Metabolism of BH4 .................................................................... 108 6.4.1 Tetrahydrobiopterin (BH4) ........................................................................................ 108 6.4.2 Redox Chemistry and Biology of BH4 ...................................................................... 108 6.4.3 Regulation and Synthesis of BH4 .............................................................................. 110 6.4.4 Salvage and Recycling Pathways of BH4 .................................................................. 110 6.4.5 Modulation of BH4, NOS Uncoupling, and ROS Generation ................................... 111 6.4.6 BH4 and Cardiac Pathophysiology ............................................................................ 112
6.5 NO and Cell Signaling/Cellular Communication ................................................................. 113 6.6 New Therapeutic Strategies .................................................................................................. 114
6.6.1 l-Arginine Supplementation and Treatments ........................................................... 114 6.6.2 BH4 Supplementation and Treatments ...................................................................... 114 6.6.3 Gene Therapy ........................................................................................................... 115 6.6.4 Pharmacological Agents ........................................................................................... 115
6.7 Summary and Conclusions ................................................................................................... 115 References ...................................................................................................................................... 116
emergency medical services and appropriate interventional policies within the hospital emergency medicine department. Thus, for a given duration of ischemia, myocardial loss can be limited by reducing reperfusion injury. However, despite investigational evidence in animal models of therapies demonstrated to reduce ischemic myocardial injury, translation to humans has been frustrating (Sanz-Rosa et al. 2012).
