Nitric Oxide and the Surgical Patient

Abstract

It has been a decade since the elucidation of the key components of L-arginine to the nitric oxide (NO) pathway.1-3 Knowledge in this field has expanded at a dizzying pace such that it is clear that NO participates in some way in essentially every physiologic process. Just as important has been the characterization of roles of NO in the pathophysiological features of many disease processes. New findings appear in the scientific literature at a rate that overwhelms even the most dedicated NO researchers. The universal interest in the biomedical importance of this molecule recently became evident with the creation of the Nitric Oxide Society along with its peer-reviewed publication, Nitric Oxide: Biology and Chemistry. With this tremendous investment of research resources, the clinician cannot help but wonder, "What have we learned that is clinically relevant?" and "Where are the therapeutic dividends?" This article will provide some of the key observations made about NO relevant to the biological responses of surgical patients and discuss some of the therapies based on NO research on the horizon. First, we will summarize basic NO biochemistry. HOW IS NO MADE?Nitric oxide is produced from the amino acid L-arginine via 1 of 3 distinct NO synthases (NOSs) or enzymes (Figure 1 ).4"6 Each isoform differs considerably in its pat¬ tern of expression and regulation. In fact, the amount of NO produced at a specific site is determined primarily by the type of NOS isoform expressed. This is impor¬ tant because the biological consequences of NO are dependent to a considerable de¬ gree on its production rate, and essen¬ tially all of the NO-based therapies repre¬ sent efforts to either remove or supplement NO. Two of the isoforms, NOS-1 and NOS-3, are referred to as constitutive (cNOS) because they are typically ex¬ pressed in cells in the resting state. Nitric oxide synthase-1 was initially identified in neurons and NOS-3 in endothelial cells, hence, the alternative designations neu¬ ronal NOS for type 1 and endothelial NOS (eNOS) for type 3. These isoforms are regulated by calcium fluxes within the cell and produce small amounts of NO tran¬ siently when agonists trigger an eleva¬ tion in intracellular calcium. Agonists dif¬ fer for each cell type, and dysregulated constitutive NOS activity can result from either impaired cell signaling responses re¬ sulting in inadequate NO production or overstimulation resulting in enhanced NO production.In clear distinction from constitu¬ tive NOS, NOS-2, also known as the inducible or inflammatory NOS (iNOS), is active independent of increases in intra¬ cellular calcium and produces NO in a sus¬ tained manner. Although constitutive iNOS expression has been described, in most cell types iNOS expression requires exposure to signals such as cytokines, mi¬ crobes, or microbial products. Thus, one of the most important aspects of the regu¬ lation of iNOS activity is the level of gene expression. Tightly regulated iNOS gene expression is used by the host as an effec¬ tor mechanism during infect...

Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation

“…These effects of NO are probably dose-dependent, such that massive NO formation may be toxic, but lower, more physiological levels of NO may be protective. In addition, the source of NO and the relationship between NO and tissue injury 53 are important issues that need to be addressed in future research. Differences in the pathophysiological role of NO in different cell types may be explained by tissue-specific transcriptional regulation of the iNOS promoter/enhancer, as was reported recently in VSMCs and macrophages.…”

Nitric Oxide: A Review for Veterinary Surgeons

“…NO has direct and indirect actions 53 . Direct actions result from reactions of NO with transition metals, such as iron 53 .…”

“…NO has direct and indirect actions 53 . Direct actions result from reactions of NO with transition metals, such as iron 53 . Activation of soluble guanylate cyclase in smooth muscle cells, neurons, and other cells (by binding to a heme group within the enzyme) and increased levels of the second intracellular messenger, cyclic guanosine monophosphate (cGMP) occur by this mechanism 53 .…”

“…Direct actions result from reactions of NO with transition metals, such as iron 53 . Activation of soluble guanylate cyclase in smooth muscle cells, neurons, and other cells (by binding to a heme group within the enzyme) and increased levels of the second intracellular messenger, cyclic guanosine monophosphate (cGMP) occur by this mechanism 53 . The cGMP increase results in relaxation of smooth muscle cells by several different mechanisms that lead to a reduction of intracellular free calcium 53 .…”

“…Indirect actions of NO result from the formation of reactive products when NO reacts with oxygen or superoxide (O 2 − ) 53 . When NO combines with oxygen, N 2 O 3 is formed 53 .…”