Nitric oxide

NO has been the most investigated gasotransmitter. The role of endogenously derived NO has been studied using pharmacological inhibitors against NOS and by genetic modifications of each NOS. The role of exogenously derived NO has been studied through the administration of NO in the form of authentic NO gas, NO donors, and more recently nitrite and nitrate. Perhaps the most clear-cut evidence for a protective role of endogenously derived NO in the setting of myocardial injury comes from studies aimed at investigating eNOS. Studies that have employed the use of mice deficient in eNOS (eNOS^-/-) have overwhelmingly shown that these mice experience exacerbated infarct sizes and increased myocardial dysfunction in response to myocardial ischemia. In contrast, the overexpression of eNOS has been shown to reduce the size of myocardial infarction and increase myocardial function in the same experimental models of injury. Early studies reported that a deficiency of nNOS or iNOS did not affect infarct size in response to acute myocardial ischemia. However, more recent evidence suggests that nNOS plays a crucial role in preventing adverse left ventricular remodeling and ventricular arrhythmias and maintaining myocardial β-adrenergic reserve after myocardial infarction. Likewise, new evidence has emerged to suggest that gene transfer of iNOS affords cardioprotection against myocardial I/R injury. Taken together, these studies clearly demonstrate that endogenously produced NO has the ability to protect the heart from I/R injury.

Inhaled NO gas just before or during coronary artery reperfusion has been shown to be effective and accumulates NO metabolites in blood and tissues and to provide protection against myocardial I/R injury, because it improved microvascular perfusion and decreased tissue injury in a porcine model. Additionally, the class of drugs known as NONOates, which release NO in a pH-dependent, first order process have repeatedly been reported to provide cardioprotection in experimental models of myocardial I/R injury. NONOates are not the only pharmacological agents that can provide protection by increasing the bioavailability of NO, as it has clearly been shown that statins, metformin, adiponectin, and estrogen provide cardioprotection by increasing the production of NO from eNOS. The use of NO as a therapeutic agent in the treatment of myocardial I/R injury has not been without some controversy, as there have been some studies to report negative effects. The cause for discrepancies between the opposing findings can be explained by dosing inconsistencies, as it is suggested that physiological levels (i.e., nanomolar) of NO promote cytoprotection, while suprapharmacological levels (i.e. high micromolar and milimolar) mediate cellular necrosis and apoptosis.