Neurosurgery

Fig. 17.2. Diffusion and action of nitric oxide. Following its biosynthesis, NO rapidly diffuses to neighbouring cells. In vascular smooth muscle cells, NO activates guanylate cyclase which converts GTP to cGMP, thereby activating protein kinase G. This latter enzyme facilitates vasorelaxation both by facilitating the dephosphorylation of myosin light-chains and activating cell membrane potassium channels. Alternatively, NO can activate potassium channels directly, leading to membrane hyperpolarization and muscle relaxation. See Fig. 17.1 for abbreviations.

Fig. 17.2. Diffusion and action of nitric oxide. Following its biosynthesis, NO rapidly diffuses to neighbouring cells. In vascular smooth muscle cells, NO activates guanylate cyclase which converts GTP to cGMP, thereby activating protein kinase G. This latter enzyme facilitates vasorelaxation both by facilitating the dephosphorylation of myosin light-chains and activating cell membrane potassium channels. Alternatively, NO can activate potassium channels directly, leading to membrane hyperpolarization and muscle relaxation. See Fig. 17.1 for abbreviations.

by agonists or shear stress, or both (Fig. 17.1). In this light, important functional and spatial associations between NOS and HSP90 have recently been demonstrated in the cerebral vas-culature.

Three isoforms of NOS have now been identified, and their cDNAs isolated and sequenced. The nomenclature for any given isoform varies according to: (1) its order of discovery and characterization (i.e. Types I-III); (2) whether it is expressed by the cell type basally (i.e. at rest; "constitutive" cNOS) or inducibly under certain conditions (i.e. "inducible" iNOS); and (3) its tissue localization (i.e. endothelial eNOS vs smooth muscle inducible iNOS vs neuronal nNOS). For the purposes of this chapter, however, the last of these three nomenclatures will be used. Although these isoenzymes share a similar overall catalytic scheme as described above (Fig. 17.1), there are some important differences. First, eNOS and nNOS are constitu-tively active, unlike iNOS, whose expression and activity are induced (e.g. by bacterial lipopolysaccharide or proinflammatory cytokines such as interleukin-10). Second, although all three isoforms bind calmodulin, iNOS does not require the presence of intracellular calcium and is not modulated by it. Third, unlike the other two isoforms, iNOS, once activated, will continuously produce NO for the remainder of its enzymatic life - a feature likely to be important in the antimicrobial-cytotoxic role of NO

CEREBRAL BLOOD FLOW: PHYSIOLOGY AND MEASUREMENT TECHNIQUES

Fig. 17.3. Cross-section of a cerebral blood vessel. NO can be synthesized by the constitutive NOS isoforms present in endothelial cells (EC; eNOS) and (perivascular) nervi vasorum (NV; nNOS). In pathological conditions, the biosynthesis of NO by the inducible isoform of NOS (iNOS) can occur in smooth muscle cells (SMC), astrocytes (Ac) and activated macrophages (Mp) and neutrophils (Np). Finally, NOS isoforms such as eNOS may be transferred (tf) into adventitial fibroblasts (FB) under experimental conditions. See Fig. 17.1 for abbreviations.

Fig. 17.3. Cross-section of a cerebral blood vessel. NO can be synthesized by the constitutive NOS isoforms present in endothelial cells (EC; eNOS) and (perivascular) nervi vasorum (NV; nNOS). In pathological conditions, the biosynthesis of NO by the inducible isoform of NOS (iNOS) can occur in smooth muscle cells (SMC), astrocytes (Ac) and activated macrophages (Mp) and neutrophils (Np). Finally, NOS isoforms such as eNOS may be transferred (tf) into adventitial fibroblasts (FB) under experimental conditions. See Fig. 17.1 for abbreviations.

from macrophage iNOS and in the pathogenesis of toxic-septic shock. Fourth, the amount of iNOS expression not only varies between different cell types, but may also vary between similar cell types, e.g. microvascular vs macrovascular endothelial cells. Last, although beyond the scope of this review, it should be noted that knockout (gene-deleted) mice have been generated for the NOS isoforms in order to study their individual roles and the effects of their targeted deletions on physiological functions (including regulation of cerebroarterial tone) in intact animals.

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