Nitric Oxide Synthases

Nitric oxide is generated from the metabolism of l-arginine by nitric oxide synthase (NOS). Functionally, NOS can be separated into constitutive and inducible isoforms. The constitutive isoforms of NOS [endothelial NOS (eNOS) and neuronal NOS (nNOS)] appear to be active under basal conditions and can be stimulated by receptor-mediated increases in intracellular calcium. These isoforms of NOS (eNOS and nNOS) produce small quantities of nitric oxide for relatively short periods of time. In addition to the constitutive isoforms of NOS, an inducible isoform of NOS (iNOS) was first identified in macrophages. Unlike that found for the constitutive isoforms of NOS, iNOS is calcium-independent, and when stimulated can produce large, unregulated quantities of nitric oxide for relatively long periods of time.

Many cell types contained within the brain may be responsible for the synthesis/release of nitric oxide under physiologic and pathophysiologic conditions. It appears that a small portion of parenchymal neurons stain for NADPH diaphorase (a marker for nNOS), and thus may be capable of releasing nitric oxide during the activation of nNOS. Since these neurons may be adjacent to cerebral blood vessels, nitric oxide produced during activation of these neurons may influence vascular tone and the transport of molecules across the blood-brain barrier (Figure 1). Endothelium contained within cerebral blood vessels have been shown to express eNOS, and in some instances iNOS. In vivo and in vitro studies of cerebral blood vessels have shown that nitric oxide released by cerebral endothelium contributes to basal tone, agonist-induced changes in diameter of cerebral blood vessels and in reactivity of cerebral blood vessels in response to physiologic stimuli. Thus, the synthesis/release of nitric oxide by activation of eNOS is important in the control of diameter of cerebral blood vessels, and could conceivably be important in the regulation of permeability of the blood-brain barrier (Figure 1). Glial cells (astrocytes, microglia, and oligodendrocytes) are the predominant cell types in the brain and have been shown to release nitric oxide by activation of iNOS. Astrocytes, for example, not only appear to express a constitutive form of NOS in response to a number of vasoactive agonists including neurotransmitters, but also are capable of the synthesis/release of nitric oxide from iNOS in response to lipopolysaccharide and a number of other important cytokines (Figure 1).

Thus, it is conceivable that the synthesis/release of nitric oxide by these cells contained within the brain could have a major impact on the basal integrity of the blood-brain barrier and on increases in permeability of the blood-brain barrier during brain trauma. Unfortunately, very few studies have examined the role of these cellular elements and the various isoforms of NOS on the regulation of permeability of the blood-brain barrier.

Figure 1 Schematic showing possible sources of nitric oxide (NO) in the brain. NO can be synthesized/released by cerebral endothelium, neurons, astrocytes, and microglia. Activation of glutamate receptors on neurons and stimulation of astrocytes and microglia can stimulate nNOS and/or iNOS, causing local production of NO that could diffuse to cerebral endothelium and influence the permeability of the blood-brain barrier via activation of a number of cellular pathways. Endothelial generated NO from L-arginine (L-arg) in response to inflammatory mediators also may stimulate a number of cellular pathways to influence the permeability of the blood-brain barrier.

Figure 1 Schematic showing possible sources of nitric oxide (NO) in the brain. NO can be synthesized/released by cerebral endothelium, neurons, astrocytes, and microglia. Activation of glutamate receptors on neurons and stimulation of astrocytes and microglia can stimulate nNOS and/or iNOS, causing local production of NO that could diffuse to cerebral endothelium and influence the permeability of the blood-brain barrier via activation of a number of cellular pathways. Endothelial generated NO from L-arginine (L-arg) in response to inflammatory mediators also may stimulate a number of cellular pathways to influence the permeability of the blood-brain barrier.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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