Nitric Oxide: Friend and Foe in Myocardial Ischemia and Reperfusion

Summary

Nitric oxide (NO) may have beneficial as well as injurious effects on myocardial function following ischemia and reperfusion. The exact reason for this discrepancy is not clear, although it appears to be dependent on the model and end point for the assessment of ischemia/reperfusion injury. The friendly role of NO is attributable to the preservation of endothelial function, inactivation of -O¯₂ and attenuation of neutrophil accumulation following ischemia/reperfusion. The injurious effect of NO seems to be due to .OH radical generation via the peroxinitrite pathway, although to date the production of peroxynitrous acid in vivo during ischemia/reperfusion has not been demonstrated. Pearson et al. [1] reported that hypoxia enhances the production of an endothelial-derived constricting factor, which was proposed to be peroxynitrite. Further studies are required to resolve the controversial role of this important biologic messenger in myocardial ischemia/reperfusion.

Since the discovery by Furchgott and Zawadzki that endothelium modulates the response of blood vessels to acetylcholine (ACh) in vitro by releasing endothelium-dependent relaxing factor (EDRF), it has become apparent that EDRF participates in the regulation of blood flow through different organs under resting conditions and in the response to many humoral, neural, and mechanical stimuli [2–7]. Due to the identical pharmacologic properties of nitric oxide (NO) and EDRF, it is widely accepted that NO is one of the EDRF compounds. Both have a very short half-life (5–6 sec), can be inactivated by oxygen radicals [8], and cause heme-dependent stimulation of the cyclic GMP (cGMP) in vascular smooth muscle, leading to vasodilatation at both the arterial and venous ends. Nitric oxide is enzymatically synthesized in the presence of the nitric oxide synthase (NOS). Two types of NOS enzymes have been identified: 1) Ca²⁺ dependent which is found in vascular endothelium, brain, platelets, and adrenal glands; and 2) Ca²⁺ independent NOS, found in macrophages, neutrophils, liver parenchymal cells, and vascular endothelial and smooth muscle cells. Its wide distribution in the body implies its different physiologic functions.