Reduced Nerve Blood Flow Research Articles

Effect of bupivacaine and adjuvant drugs for regional anesthesia on nerve tissue oximetry and nerve blood flow.

BackgroundNerve blood flow has a critical role in acute and chronic pathologies in peripheral nerves. Influences of local anesthetics and adjuvants on tissue perfusion and oxygenation are deemed as relevant factors for nerve damage after peripheral regional anesthesia. The link between low tissue perfusion due to local anesthetics and resulting tissue oxygenation is unclear.MethodsCombined tissue spectrophotometry and laser-Doppler flowmetry were used to assess nerve blood flow in 40 surgically exposed median nerves in pigs, as well as nerve tissue oximetry for 60 min. After baseline measurements, test solutions saline (S), bupivacaine (Bupi), bupivacaine with epinephrine (BupiEpi), and bupivacaine with clonidine (BupiCloni) were applied topically.ResultsBupivacaine resulted in significant decrease in nerve blood flow, as well as tissue oximetry values, compared with saline control. Addition of epinephrine resulted in a rapid, but nonsignificant, reduction of nerve blood flow and extensive lowering of tissue oximetry levels. The use of clonidine resulted in a reduction of nerve blood flow, comparable to bupivacaine alone (relative blood flow at T60 min compared with baseline, S: 0.86 (0.67–1.18), median (25th–75th percentile); Bupi: 0.33 (0.25–0.60); BupiCloni: 0.43 (0.38–0.63); and BupiEpi: 0.41(0.30–0.54). The use of adjuvants did not result in any relevant impairment of tissue oximetry values (saturation values in percent at T60, S: 91.5 [84–95]; Bupi: 76 [61–86]; BupiCloni: 84.5 [76–91]; and BupiEpi: 91 [56–92]).ConclusionThe application of bupivacaine results in lower nerve blood flow, but does not induce relevant ischemia. Despite significant reductions in nerve blood flow, the addition of clonidine or epinephrine to bupivacaine had no significant impact on nerve tissue oximetry compared with bupivacaine alone. Nerve ischemia due to local anesthetics is not enhanced by the adjuvants clonidine or epinephrine.

Chapter 31 - Ischemia and diabetic neuropathy

In addition to hyperglycemia and ensuing metabolic changes, vascular abnormalities and ischemia driven by hyperglycemia and metabolic change plays a paramount role for the development of diabetic polyneuropathy. Endothelial dysfunction plays a key role in the initiation of cellular events evolving into the development of vascular complications of diabetes, and is the common denominator between the metabolic and vascular abnormalities detected in diabetes. Diminished production and function of endothelium-derived vasodilators, and the exaggerated production of vasoconstrictors, lead to endothelial dysfunction, resulting in elevated vascular tone, culminating in macro- and microvascular damage. There is microvascular pathology in human diabetic polyneuropathy: basement membrane thickening, pericyte degeneration, and endothelial cell hyperplasia in endoneurial microvessels. These vascular changes strongly correlate with clinical defects and nerve pathology. Studies in human and animal models have shown endoneurial hypoxia caused by a reduction in nerve blood flow and increased endoneurial vascular resistance. There is strong evidence that the nerve fiber degeneration and a loss of nerve fibers are ischemic in diabetic polyneuropathy. Diabetic nerves reveal a paradoxical contrast between their physiological resistance to ischemia and increased morphological susceptibility to ischemia. Diabetic nerves are particularly vulnerable to reperfusion injury. This chapter will review the response of diabetic nerves to ischemia and reperfusion injury, and the evidence of ischemia and hypoxia in diabetic neuropathies.

Effects of levobupivacaine and ropivacaine on rat sciatic nerve blood flow

Ischaemia is one of the causative mechanisms of peripheral nerve injury, a documented complication of regional anaesthesia. Local anaesthetics per se and/or vasopressor adjuvants may account for changes in peripheral nerve blood flow. The aim of this study was to test the effects of levobupivacaine and ropivacaine in a rat sciatic nerve model with respect to local blood flow and histopathological changes. Forty-eight female Sprague-Dawley rats were anaesthetized for left sciatic nerve exposure. After baseline nerve blood flow measurement with a laser Doppler flowmeter, 0.2 ml of one of the following solutions was applied topically to the nerve in a random fashion: saline 0.9%; lidocaine 10 mg ml(-1); levobupivacaine 2.5 mg ml(-1); levobupivacaine 5 mg ml(-1); levobupivacaine 7.5 mg ml(-1); ropivacaine 2 mg ml(-1); ropivacaine 7.5 mg ml(-1); and ropivacaine 7.5 mg ml(-1) plus epinephrine 5 microg ml(-1); all in saline 0.9%. Nerve blood flow was evaluated at 5-min intervals up to 30 min after local application of anaesthetic solution. Three animals per group were killed for histological evaluation 48 h later. Multiple one-way analyses of variance followed by Scheffé's post hoc test was used for statistical analysis. P<0.05 was considered significant. Local anaesthetics at all concentrations tested caused significant reduction in nerve blood flow. The combination of ropivacaine 7.5 mg ml(-1) plus epinephrine did not reduce nerve blood flow to a greater extent than ropivacaine 7.5 mg ml(-1) alone. Low concentrations of levobupivacaine (2.5 and 5 mg ml(-1)) reduced nerve blood flow to the same extent as lidocaine 10 mg ml(-1). No significant histological changes were observed at 48 h. Despite acute reductions in peripheral nerve blood flow, significant histopathological changes were not observed in this rat sciatic nerve model after topical application of levobupivacaine and ropivacaine at concentrations relevant to clinical practice.

Dexamethasone decreases blood flow in normal nerves and dorsal root ganglia.

An experimental physiologic and histologic study of dexamethasone effects on peripheral nerves. To characterize the effect of topically applied 0.4% dexamethasone on acute changes in nerve blood flow and subsequent histologic changes in rat sciatic nerve fibers. Dexamethasone is an anti-inflammatory glucocorticoid used clinically to reduce the neural consequences of inflammation. Several reports of accidental injury to nerves after steroid injections have raised questions about the mechanisms involved in dexamethasone-induced neurotoxic injury. Nerve blood flow studies using a laser Doppler flowmeter were conducted in animals with stable temperature and arterial pressure. Dexamethasone 0.4%, 0.1 mL was applied topically to rat sciatic nerve in the following protocol groups: 1) nerve blood flow recording every 5 minutes for 30 minutes, and 2) initial nerve blood flow recording and repeat recording at 4 hours. Three additional animals had 30-minute nerve blood flow recordings in which normal saline was substituted for dexamethasone; these animals were used for control and to assure that the experimental preparation was viable throughout the observational period. Additional groups of two animals each received dexamethasone but were used only for neuropathologic observation at 2, 4, and 6 days after treatment. Neuropathologic studies were conducted on glutaraldehyde-fixed, plastic-embedded tissue. Application of saline to the exposed sciatic nerves did not significantly change nerve blood flow from baseline values. Nerve blood flow values remained constant throughout the observational period. Dexamethasone, however, significantly reduced nerve blood flow in both the 30-minute and 4-hour groups. Some animals showed an initial transient increase in blood flow before nerve blood flow began to steadily decline to the final values reported. Neuropathologic changes were minimal and consisted only of edema and occasional subperineurial activation of Schwann cells. No demyelination or degeneration was seen. Dexamethasone causes statistically significant reductions in normal nerve blood flow at 30 minutes and 4 hours after topical application; however, the reduction is on average below the threshold for causing ischemic changes in the structure of peripheral nerve fibers.

Nerve and ganglion blood flow in diabetes: An appraisal

Vasa nervorum, the vascular supply to peripheral nerve trunks, and their associated cell bodies in ganglia have unique anatomical and physiological characteristics. Several different experimental approaches toward understanding the changes in vase nervorum following injury and disease have been used. Quantative techniques most widely employed have been microelectrode hydrogen clearance palarography and [14C]iodoantipyrine autoradiographic distribution, whereas estimates of red blood cell flux using a fiber-optic laser Doppler probe offer real time data at different sites along the nerve trunk. There are important caveats about the use of these techniques, their advantages, and their limitations. Reports of nerve blood flow require careful documentation of physiological variables, including mean arterial pressure and nerve temperature during the recordings. Several ischemic models of the peripheral nerve trunk have addressed the ischemic threshold below which axonal degeneration ensues (< 5ml/100 g/min). Following injury, rises in local blood flow reflect acitons of vasoactive peptides, nitric oxide, and the development of angiogenesis. In experimental diabetes, a large number of studies have documented reductions in nerve blood flow and tandem corrections of nerve blood flow and conduction slowing. A significant proportions, however, of the work can be criticized on the basis of methodology and interpretation. Similarly, not all work has confirmed that reductions of nerve blood flow are an invariable feature of experimental or human diabetic polyneuropathy. Therefore, while there is disagreement as to whether early declines in nerve blood flow "account" for diabetic polyneuropathy, there is unquestioned eveidence of early microangiopathy. Abnormalities of vase nervorum and micorvessels supplying ganglia at the very least develop parallel to and together with changes in neurons, Schwann cells, and axons.

Protein kinase C changes in diabetes: Is the concept relevant to neuropathy?

Protein kinase C (PKC) comprises a superfamily of isoenzymes, many of which are activated by 1,2-diacylglycerol (DAG) in the presence of phosphatidylserine. In order to be capable of DAG activation, PKC must first undergo a series of phosphorylation at three conserved sites. PKC isoforms phosphorylate a wide variety of intracellular target proteins and have multiple functions in signal transduction-mediated cellular regulation. An elevation in DAG levels and an increase in composite PKC activity and/or certain isoforms occurs in several nonneural tissues from diabetic animals, including the vasculature. The ability of isoform-specific PKC inhibitors to antagonize diabetes-induced abnormalities has implicated altered PKC beta activity in the onset of several diabetic complications, In contrast to many other tissues, DAG levels fall in diabetic nerve and a consistent pattern of change in PKC activity has not been observed. Treatments that alter PKC activity affect nerve Na+, K+-ATPase activity, but the mechanism involved is not well understood, Inhibition of PKC beta in diabetic rats appears to correct reduced nerve blood flow and decreased nerve conduction velocity. These and other findings indicate that changes in the neurovasculature exert adverse effects during the pathogenesis of diabetic neuropathy. Still unresolved is a clear-cut role for PKC in the development of abnormalities in neural cell metabolism. Further progress will depend on a more complete understanding of the functions of individual PKC isoforms in nerve. Future investigation could focus profitably on biochemical processes in nerve cells that modulate PKC activity and that are altered in diabetes, such as vascular endothelial growth factor levels and production of reactive oxygen species arising from oxidative stress.

The effects of zenarestat, an aldose reductase inhibitor, on minimal F-wave latency and nerve blood flow in streptozotocin-induced diabetic rats

The effects of zenarestat, 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid, an aldose reductase inhibitor (ARI), on F-wave conduction abnormalities, nerve blood flow (NBF) reduction and sorbitol accumulation were studied in streptozotocin-induced diabetic rats. Two weeks after the induction of diabetes, zenarestat was given once a day for two weeks. In diabetic control rats, marked accumulation of sorbitol, reduction of NBF and prolongation of minimal F-wave latency (FWL) were observed as compared to normal rats. Zenarestat, at a dose of 32 mg/kg, inhibited sorbitol concentration to nearly the normal rat level and significantly improved not only NBF but also minimal FWL. At a dose of 3.2 mg/kg, sorbitol accumulation was inhibited by approximately 40% and there was a tendency to increase in NBF; however, minimal FWL was not improved at all. These data suggest that a highly inhibition of the nerve sorbitol accumulation is requisite for the treatment of diabetic peripheral neuropathy.

Reduced Nerve Blood Flow In Diabetic Rats Is A Reflection Of Hindlimb Muscle Wasting

We examined the influence of muscle wasting, as a result of streptozotocin‐induced diabetes, on sciatic nerve laser Doppler flux (SNLDF), as an index of nerve blood flow, and conduction velocity (NCV). We compared dietary‐restricted weight‐reduced non‐diabetic rats with controls and with diabetic rats and we studied the effects of clenbuterol, an anabolic β‐adrenoceptor agonist, in control and diabetic rats. Dietary restriction reduced the weights of hindlimb muscles—extensor digitorum longus, soleus and gastrocnemius—half as much as did streptozotocin‐diabetes and clenbuterol increased muscle weights in control and diabetic rats. This gave a hierarchy of muscle weights in the order—clenbuterol‐controls, untreated controls, weight‐reduced non‐diabetics, clenbuterol‐diabetics and untreated diabetics. Diabetes without treatment reduced SNLDF by 51% (p &lt; 0.01); dietary restriction by 25% (p &lt; 0.01) and there were proportional increases associated with clenbuterol treatment. Combined muscle weights regressed closely with SNLDF (r2=0.69; p &lt; 0.001) and, when the latter was expressed relative to muscle weights, a similar value was obtained for all five groups—there were no significant differences. Thus, sciatic nerve blood flow is closely related to hindlimb muscle weight and the effect of diabetes on nerve blood flow may be secondary to muscle wasting. Sciatic/tibialis motor and sensory conduction velocities were also reduced by muscle wasting in the dietary restricted group of non‐diabetic rats, but, unlike nerve Doppler flux, it was unaffected by clenbuterol.

Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy.

Experimental diabetic peripheral neuropathy (DPN) is marked by impaired nerve conduction velocity (NCV), reduced nerve blood flow (NBF), and a variety of metabolic abnormalities in peripheral nerve that have been variously ascribed to hyperglycemia, abnormal fatty acid metabolism, ischemic hypoxia, and/or oxidative stress. Some investigators propose that NCV slowing in experimental DPN can be explained entirely on the basis of nerve energy depletion secondary to reduced NBF. This article reports highly selective effects of administration of the antioxidant DL-alpha-lipoic acid (LA) to streptozotocin-injected diabetic rats. LA improved digital sensory but not sciatic-tibial motor NCV, corrected endoneurial nutritive but not composite NBF, increased the mitochondrial oxidative state without correcting nerve energy depletion, and enhanced the accumulation of polyol pathway intermediates without worsening myo-inositol or taurine depletion. These studies implicate oxidative stress as an important pathophysiological factor in experimental DPN. They reveal complex interrelationships among nerve perfusion, energy metabolism, osmolyte content, conduction velocity, and oxidative stress that may reflect the heterogeneous and compartmentalized composition of peripheral nerve.

Altered vasoreactivity to angiotensin II in experimental diabetic neuropathy: role of nitric oxide.

We evaluated the effects of angiotensin II and an angiotensin-converting enzyme inhibitor (cilazapril) on nerve blood flow (NBF) and electrophysiology in control and diabetic rats. When applied locally to the sciatic nerve, the dose-response curve of angiotensin II was more potent in experimental diabetic neuropathy (EDN) than control rats. No difference existed in plasma angiotensin II levels between EDN and controls. The rats were given typical rat pellets or pellets treated with 10 mg/kg per day cilazapril for 4 weeks. Diabetes caused a significant reduction in NBF, nerve conduction velocity, and compound muscle action potential (CMAP) amplitudes. NBF was significantly increased in diabetic rats supplemented with cilazapril diet, and nerve conduction velocity and amplitudes of the CMAP were also improved after 4 weeks on this diet. Direct application 10(-3) mol/L cilazapril on sciatic nerve did not increase NBF in normal and EDN rats. We topically applied the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine, on sciatic nerve and observed reduced inhibition of NBF in EDN, which was correctable with a cilazapril diet. These results suggest that diabetic neuropathy may have an increasing vasopressor action with angiotensin II and this is likely to be the mechanism of NOS inhibition. Angiotensin II-converting enzyme inhibitors may have potential in the treatment of diabetic neuropathy.

The Neurotoxicity of Drugs Given Intrathecally (Spinal)

The Neurotoxicity of Drugs Given Intrathecally (Spinal)

Effects of the Diacylglycerol Complexing Agent, Cremophor, on Nerve-Conduction Velocity and Perfusion in Diabetic Rats

The contribution of diacylglycerol (DAG) and protein kinase C (PKC) to diabetic complications has been the subject of debate. In vascular tissues, diabetes increases DAG content, which activates PKC and causes abnormal tissue perfusion. Reduced nerve blood flow has been implicated in the development of neuropathy. However, nerve DAG/PKC activity is not increased and may even be reduced by diabetes, which has also been implicated in neuropathy. The aim was to test whether 2 weeks of treatment with cremophor, an agent that complexes DAG and prevents PKC activation, could correct nerve-conduction velocity (NCV) deficits in rats with 6 weeks of untreated diabetes, as predicted on a vascular hypothesis, or whether this worsened the deficits, as predicted for a direct effect on nerve fibers. Diabetes caused 17.9 ± 0.9% (± SEM) and 15.5 ± 1.6% reductions in sciatic motor and saphenous sensory NCV, respectively, that were largely (79.6 ± 6.3% and 57.8 ± 11.5%) corrected by 100 mg · kg −1 · day −1 cremophor treatment. The effects of cremophor on motor and sensory NCV were completely attenuated by co-treatment with the nitric oxide synthase inhibitor, N G-nitro- l -arginine. In contrast, co-treatment with the cyclooxygenase inhibitor, flurbiprofen, had no effect on NCV. Sciatic nutritive and total endoneurial perfusion were 49.7 ± 3.4% and 51.8 ± 4.2% reduced by diabetes, respectively, and these deficits were 69.5 ± 7.4% and 79.0 ± 11.6% corrected by cremophor treatment. Thus the data suggest that an increased DAG/PKC vascular mechanism, perhaps linked to the nitric oxide system, contributes to the etiology of diabetic nerve dysfunction.

Reduced nerve blood flow in diabetic rats: relationship to nitric oxide production and inhibition of aldose reductase

This study examined links between impaired nitric oxide production in the sciatic endoneurium, nerve blood flow, and polyol pathway flux, to test the hypothesis that reduced nerve blood flow might be compromised by competition for NADPH between aldose reductase and nitric oxide synthase. Sciatic nerves of streptozotocin-diabetic rats showed reduced laser Doppler flux (by 51 % or 63 %; both p<0.05)—indicative of reduced nerve blood flow—and reduced motor nerve conduction velocity (17 % in two experiments; p<0.05). Acute interruption of nitric oxide production in the sciatic nerves of control rats, via endoneurial injection of Nω-nitro-D-arginine methyl ester ( L-NAME), caused a local reduction (of 64 %; p<0.001) in nerve Doppler flux. This was reversed by either L-arginine or sodium nitroprusside. The response to L-NAME was greatly reduced in diabetic rats (only 22 % reduction; p<0.01), though both L-arginine and SNP caused marked increases in flux. Chronic inhibition of aldose reductase in diabetic rats (with either sorbinil or imirestat at a range of doses) had little effect on resting sciatic nerve Doppler flux, though both inhibitors normalized conduction velocity. Both aldose reductase inhibitors reduced sorbitol pathway intermediates in a dose-related manner. These findings do not support the proposition that aldose reductase inhibitors normalise conduction velocity by mechanisms dependent upon either normalization of endoneurial nitric oxide or nerve blood flow. Instead, a mechanism based upon more direct effects on axon or Schwann cell function is favoured. © 1998 John Wiley & Sons, Ltd.

Reduced nerve blood flow in diabetic rats: relationship to nitric oxide production and inhibition of aldose reductase.

This study examined links between impaired nitric oxide production in the sciatic endoneurium, nerve blood flow, and polyol pathway flux, to test the hypothesis that reduced nerve blood flow might be compromised by competition for NADPH between aldose reductase and nitric oxide synthase. Sciatic nerves of streptozotocin-diabetic rats showed reduced laser Doppler flux (by 51% or 63%; both p<0.05)-indicative of reduced nerve blood flow-and reduced motor nerve conduction velocity (17% in two experiments; p<0.05). Acute interruption of nitric oxide production in the sciatic nerves of control rats, via endoneurial injection of N omega-nitro-D-arginine methyl ester (L-NAME), caused a local reduction (of 64%; p<0.001) in nerve Doppler flux. This was reversed by either L-arginine or sodium nitroprusside. The response to L-NAME was greatly reduced in diabetic rats (only 22% reduction; p<0.01), though both L-arginine and SNP caused marked increases in flux. Chronic inhibition of aldose reductase in diabetic rats (with either sorbinil or imirestat at a range of doses) had little effect on resting sciatic nerve Doppler flux, though both inhibitors normalized conduction velocity. Both aldose reductase inhibitors reduced sorbitol pathway intermediates in a dose-related manner. These findings do not support the proposition that aldose reductase inhibitors normalise conduction velocity by mechanisms dependent upon either normalization of endoneurial nitric oxide or nerve blood flow. Instead, a mechanism based upon more direct effects on axon or Schwann cell function is favoured.

Diabetic neuropathy: pathogenesis and current treatment perspectives

Peripheral neuropathy is a major late complication of diabetes mellitus. The pathogenesis is multifactorial. Changes in polyol pathway flux, oxidative stress, non-enzymatic protein glycation, endothelial dysfunction leading to reduced nerve blood flow, disturbed calcium homeostasis and deficits in neurotrophic factors probably all contribute to the clinical and neurophysiological findings in the diabetic patient with neuropathy. The present review focuses on animal models that are currently used to evaluate these pathophysiological mechanisms, and on the possibility of therapeutic pharmacological intervention. © 1997 John Wiley & Sons, Ltd.

Extreme vasoreactivity of rat epineurial arterioles to vasopressin.

Vasopressin is a potent vasoconstrictor to most blood vessels but is a vasodilator to some. The role of vasopressin in the regulation of nerve blood flow (NBF) is not known. We undertook a dose-effect study of vasopressin on NBF and evaluated its interactions with alpha-adrenoreceptors and its effect on ischemic conduction failure. NBF was measured using microelectrode hydrogen polarography. Vasopressin was administered topically (to epineurium). Topical epineurial application of vasopressin caused a concentration -dependent reductin of NBF (EC 50 = 6.6 x 10(-9) M; asymptote = 73.9% NBF reduction). The topical application of subthreshold concentrations of vasopressin and norepinephrine alone resulted in no change in NBF, but combined application resulted in a dramatic reduction in NBF (72.3%). The ratio of amplitudes of muscle compound action potential evoked on proximal to distal stimulation was used as an index of the presence of an ischemic conduction block. This ratio was significantly reduced following the combined topical application of supramaximal concentrations of vasopressin and norepinephrine. These findings suggest that vasopressin is a potent neural vasoconstrictor and that vasoconstriction caused by combined vasopressin and norepinephrine can produce partial conduction block of sciatic-tibial nerve [corrected].

Presynaptic deficit of sympathetic nerves: a cause for disturbed sciatic nerve blood flow responsiveness in diabetic rats

Reduced nerve blood flow is thought to play an important role in the pathogenesis of diabetic neuropathy. This disturbance in nerve blood flow might be the consequence of either microangiopathy or an impaired autonomic innervation of the vasa nervorum. In order to differentiate between a vascular or an adrenergic-autonomic defect as the underlying cause of the disturbed nerve blood flow, we investigated the effects of the adrenocorticotropic hormone [ACTH]-(4–9) analogue Org 2766 on sciatic nerve blood flow under basal and adrenergic-stimulated conditions. Org 2766 has neuroprotective effects without cardiovascular effects. Treatment with Org 2766 was started 6 weeks after the induction of experimental diabetes mellitus. At week 12 the sciatic nerve blood flow, measured by laser-Doppler flowmetry, was reduced to 60% of the non-diabetic level; blood pressure was unchanged in diabetic rats compared to non-diabetic rats. Basal haemodynamic values were not affected by Org 2766 treatment. Vasa nervorum adrenergic responsiveness to tyramine (presynaptic) and phenylephrine (postsynaptic) was investigated. Diabetic rats showed adrenergic hyporesponsiveness. Treatment with Org 2766 restored the reduced presynaptic response to tyramine without affecting the reduced postsynaptic response to phenylephrine. It is concluded that a presynaptic-sympathetic deficit of nervi vasorum causes a disturbed flow responsiveness in diabetic rat sciatic nerve and that adrenergic autonomic disturbances in the vasa nervorum have only a small role in the reduced basal nerve blood flow of diabetic rats.

The Aetiology of Diabetic Neuropathy: the Combined Roles of Metabolic and Vascular Defects

A combination of metabolic and vascular defects have been implicated in the pathogenesis of diabetic neuropathy. Animal studies have demonstrated that a reduction in nerve blood flow may be an important early defect and that vasodilators can prevent or ameliorate nerve dysfunction. The potential factors contributing to nerve ischaemia include structural defects in the endoneurial microvasculature together with rheological abnormalities, abnormalities in vasoactive agents which regulate nerve blood flow including nitric oxide and the eicosanoids, and alterations in tone of the autonomic innervation of the nerve vasculature. The principle metabolic defects which have been implicated include disruption of the polyol pathway, altered lipid metabolism, advanced glycosylated end-product formation, increased oxidative stress, and diabetes-induced defects in growth factors. The demonstration that activation of the polyol pathway in experimental diabetes may affect nerve blood flow, and conversely that vasoactive agents appear to be important in regulating some aspects of nerve metabolism, has highlighted the interdependence of the metabolic and vascular defects in the pathogenesis of this condition. Thus, selective intervention aimed at a key defect early in this cascade may subsequently correct a number of later abnormalities offering therapeutic hope in this chronic debilitating complication.

Effects of cocaine on blood flow and prostaglandin metabolites in rat sciatic nerve.

To better understand the mechanisms of local anesthetic-reduced nerve blood flow and nerve blood flow regulation, the effects of cocaine on blood flow and vasoactive prostaglandins were tested in the sciatic nerve of anesthetized rats. After 30 min, nerve blood flow was significantly reduced from baseline by perineural injection of 160 mM cocaine [-29.4 +/- 4.0 (SD) laser-Doppler flow units (P < 0.001)] but not saline (1.6 +/- 11.3). These same nerves were removed and assayed for the stable metabolites 6-ketoprostaglandin F1 alpha and thromboxane B2 of the vasoactive eicosanoids prostacyclin and thromboxane A2, respectively. Both metabolites were reduced, but the ratio of thromboxane B2 to 6-ketoprostaglandin F1 alpha was greater (P < 0.05) in nerves pretreated with cocaine (6.1 +/- 3.2 vs. 2.4 +/- 1.1) and was inversely correlated (P < 0.01) with nerve blood flow. In a separate experiment, perineural injection of the prostaglandin synthesis inhibitor indomethacin (0.5 mg in 0.5 ml of either saline or 50% ethanol) reduced nerve blood flow as well (P < 0.05). These results are consistent with the proposal that cocaine inhibits nerve blood flow by effects on nerve prostaglandin metabolites.

Experimental nerve thermal injury.

Thermal injury to rat sciatic nerve was produced by local heating (47 and 58 degrees C) and studied physiologically and morphologically. Unmyelinated nerve fibres showed a greater direct vulnerability to hyperthermia; first manifest as a reversible conduction block of C fibre action potentials and at higher temperatures by immediate and selective axonal degeneration. By contrast, lower grade nerve thermal injury resulted in delayed, selective loss of myelinated fibres. Evidence from this study suggests that this is secondary to a heat-induced angiopathy, immediately and diffusely manifest in the vasa nervorum and giving rise to a progressive and ultimately severe reduction in nerve blood flow. The relative sparing of unmyelinated fibres is likely to be a result of their greater resistance to ischaemia. The pathological vulnerability of unmyelinated fibres to thermal injury, coupled with the susceptibility of large myelinated nerve fibres to secondary ischaemia, largely resolves previous contradictions in the literature.