The characteristics of the blood flow in nerve trunks and ganglia are unique and are distinguished from those of the central nervous system. Nerve trunks are supplied upstream by arterial branches of major limb vessels that share their supply with other limb tissues. At some sites, the overlapping vascular supply from several parent vessels renders zones of susceptibility to ischemia, or watershed zones. In the rat, and probably human sciatic nerve, a watershed zone can be found in the proximal tibial nerve (3). In some nerve trunks, the centrofascicular portion of the nerve trunk might be the most vulnerable to ischemia, accounting for corresponding centrofascicular patterns of axon damage. However, ischemic damage of large multifascicular nerve trunks is more commonly multifocal, with irregular zones of axon damage that depend on specific features of their perfusion and the exact vessels that are involved in causing ischemia (4,5). In general, nerve trunks are well-perfused from multiple anastamosing parent arteries that ultimately form a rich epineurial vascular plexus on it. Such a rich vascular supply explains why long segments of nerves can be "mobilized" by surgeons without major sequellae. Arteriovenous anastamoses are common in the epineurial plexus, but some might also exist in the endoneurium (6). Because of this rich complex of vessels, it can be surprisingly difficult to distinguish arterioles from venules in the epineurial plexus when they are directly visualized in vivo.
Spinal dorsal root ganglia are supplied from segmental radicular arteries and anastamoses with branches of spinal arteries (7). Unlike the peripheral nerve trunk, they do not have a prominent extracapsular plexus. Neuron perikarya that entrain higher metabolic requirements are most often located in the subcapsular space, whereas axons eventually entering roots are more frequently found in the core of the ganglia. Given this structure, microanatomic susceptibility of the ganglia to ischemia is probably even less predictable than that of nerve trunks.
Peripheral nerve trunks are supplied by blood vessels from two distinct compartments: the epineurial vascular plexus and the intrinsic endoneurial blood supply. Although, extrinsic epineurial blood flow is ultimately responsible for "downstream" blood flow in the endoneurial compartment, each compartment has distinct physiological and morphological characteristics. The epineurial plexus, as discussed, is well-perfused by arterioles, has prominent arteriovenous shunting, has innervation of its arterioles, discussed further below, and has a leaky blood-nerve barrier. This plexus supplies segmental arterioles that penetrate into the endoneurium directly or that arrive there from a remote origin traveling in a longitudinal centrofascicular pattern. Although not an absolute rule, the endoneurium is largely supplied by noninnervated capillaries that respond passively to changes in blood flow. Pericytes, smooth musclelike contractile cells, are associated with some endoneurial capillary segments, but how they influence local blood flow is uncertain. Endoneurial capillaries might also be somewhat larger than those of other tissue beds (8).
Epineurial arterioles are innervated by sympathetic adrenergic unmyelinated axons that mediate local vasoconstriction and peptidergic (Substance P, calcitonin gene-related peptide [CGRP]) sensory axons that in turn mediate local vasodilatation (9,10). CGRP is a highly potent vasodilator, capable of relaxing vascular smooth muscle through both nitric oxide (NO)-dependent and -independent pathways (11,12). An interesting feature of both the adrenergic and peptidergic vascular innervation is that both types of axons appear to arise from their parent nerve trunk (13). Moreover, there is evidence that this innervation is tonically active, influencing the ambient caliber of arterioles of the epineurial plexus. Ongoing sympathetic and concurrent peptidergic "tone" of the epineurial vascular plexus, thus, can direct downstream endoneurial capillary blood flow. Sympathetic blockade or sympathectomy to block ongoing adrenergic tone in the normal vasa nervorum consequently is associated with rises in endoneurial nerve blood flow, whereas blockade of peptidergic innervation is associated with declines in nerve blood flow (14-16). Among neuropeptides that influence vascular caliber, CGRP is likely the most potent candidate identified, although it has been observed that both Substance P (SP) and CGRP antagonists were associated with constriction of vasa nervorum (16). Although not explored in peptidergic perivascular axons, the adrenergic innervation of epineurial arterioles is probably nonuniform and segmental, suggesting the presence of discrete zones of vascular regulation that might control "downstream" endoneurial capillary flow (14). Hypercarbia might be associated with mild rises in epineurial plexus blood flow, but appears to have less impact on endoneurial blood flow (17,18). There is very little evidence of autoregulation in peripheral nerve trunks, but instead there is a near linear passive relationship between mean arterial pressure and endoneurial blood flow (18).
Quantitative hydrogen clearance (HC) or autoradiographic [14C] iodoantipyrene measures of normal endoneurial blood flow yield values in the range of 15-20 mL/100 g per minute (18,19).
Dorsal root ganglia, and probably sympathetic ganglia have higher levels of blood flow measuring approximately 30-40 mL/100 g per minute (20,21). These higher values likely reflect higher metabolic demands of perikarya in ganglia than stable axons and Schwann cells in the nerve trunk. Similarly, oxygen tension values measured in ganglia are shifted to lower values, implying increased oxygen extraction. Such measures have been carried out using oxygen sensitive microelectrodes and polarog-raphy, an approach that constructs histograms of oxygen tension values in tissues to circumvent the variability of single estimates of oxygen tension (22,23). Neither nerve trunks nor ganglia are as well perfused as spinal cord gray matter that ranges approximately 50-60 mL/100 g per minute or cortex ranging more than 100 mL/100 g per minute depending on the measurement approach (24). Unlike peripheral nerve trunks, there is some evidence of partial autoregulation of ganglion blood flow, but a lesser influence of adrenergic input (25). Hypercarbia does not appear to influence ganglion blood flow (20).
Although newer imaging approaches might be capable of providing blood flow measures within nerve, published measures have concentrated on a few approaches: quantitative microelectrode HC polarography, laser doppler flowmetry (LDF), [14C]
idioantipyrene distribution or autoradiography, and microsphere embolization. Detailed appraisal of the methodology and its pitfalls is given elsewhere (2,26) and is only briefly highlighted here. Ancillary approaches have included direct live videoangiographic imaging of epineurial vessels (14), morphometric measures of fixed or unfixed peripheral nerves (27,28), and measures of indicator transit times (29). Combining approaches to address primarily the epineurial plexus (LDF) and the endoneurium (HC) is a powerful way to confirm and supplement findings as both compartments have strong linkages as discussed earlier. HC requires rigorous physiological support and characterization, and locally manufactured linearly sensitive hydrogen microelectrodes with small diameter tips of 3-5 ^m. Some publications have used very large microelectrodes that might excessively disrupt sampled nerves (30-34). HC and autoradiographic [14C] idioantipyrene distribution both offer quantitative measures of selective endoneurial blood flow, but only the former can offer serial studies. LDF is sensitive to real time changes in erythrocyte flux, but vigorous care and controls in its use are required: lighting conditions, multiple sampling, micromanipulator use, and (like all techniques) strict control of near nerve temperature. Because LDF measures can vary widely depending on the exact placement of the sampling probe, single measures are likely to be highly unreliable. For instance a small movement of the probe might shift its sampling sphere to a nearby superficial vessel, substantially altering the read out. Kalichman and Lalonde (35) pointed out the importance of obtaining multiple samples of LDF along the nerve trunk to provide meaningful measures. Microsphere embolization measures have yielded somewhat lower blood flow values in peripheral nerve trunks, and this might be a technical limitation of the approach (36-38). Arteriovenous (AV) shunts might allow passage rather than capture of indicator microsphere, underestimating their distribution. Other isotope distribution techniques have used [3H] desmethylimipramine and [14C] butanol (39,40).
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