Nitrates and nitrites in the treatment of ischemic cardiac disease

Abstract

The organic nitrite, amyl of nitrite, was initially used as a therapeutic agent in the treatment of angina pectoris, but was replaced over a decade later by the organic nitrate, nitroglycerin (NTG), due to the ease of administration and longer duration of action. The administration of organic nitrate esters, such as NTG, continues to be used in the treatment of angina pectoris and heart failure since the birth of modern pharmacology. Their clinical effectiveness is due to vasodilator activity in large veins and arteries through an as yet unidentified method of delivering nitric oxide (NO), or a NO-like compound. The major drawback is the development of tolerance with NTG, and the duration and route of administration with amyl of nitrite. Although the nitrites are no longer used in the treatment of hypertension or ischemic heart disease, the nitrite anion has recently been discovered to possess novel pharmacologic actions, such as modulating hypoxic vasodilation, and providing cytoprotection in ischemia-reperfusion injury. Although the actions of these 2 similar chemical classes (nitrites and organic nitrates) have often been considered to be alike, we still do not understand their mechanism of action. Finally, the nitrite anion, either from sodium nitrite or an intermediate NTG form, may act as a storage form for NO and provide support for investigating the use of these agents in the treatment of ischemic cardiovascular states. We review what is presently known about the use of nitrates and nitrites including the historical, current, and potential uses of these agents, and their mechanisms of action.

Figure 1

Endothelial nitric oxide synthase (eNOS) generates nitric oxide (NO^•) and L-citrulline from L-arginine. Circulating NO^• in the presence of oxygen (O₂) can be oxidized to form nitrite (NO_2⁻). Circulating NO_2⁻ can be reduced by deoxyhemoglobin to NO^• and methemoglobin under ischemic conditions. Modified from Lefer, D. (2006). Nitrite therapy for protection against ischemia-reperfusion injury.