Evidence of bidirectional flow in the sciatic vasa nervorum.

The purpose of this study was to determine whether bidirectional flow exists in the sciatic vasa nervorum. Images obtained using high-frequency color Doppler ultrasound in duplex imaging mode (Vevo 2100) were studied retroactively. In Fig. 1 (left panel; rat 1), the color Doppler signal and flow-velocity waveforms are indicative of pulsatile flow traveling towards (B) and away (C) from the probe. In the right panel (Fig. 1; rat 2), there appears to be three distinct vessels, reflective of non-pulsatile negative flow (D), and pulsatile positive (E) and negative (F) flows. These data confirm the presence of bidirectional arterial flow in the sciatic vasa nervorum. Investigating bidirectional flow in the intact whole nerve may be helpful in elucidating novel features of nerve blood flow control in healthy and diseased states.

Exercise training enhances insulin-stimulated nerve arterial vasodilation in rats with insulin-treated experimental diabetes.

Insulin stimulates nerve arterial vasodilation through a nitric oxide (NO) synthase (NOS) mechanism. Experimental diabetes reduces vasa nervorum NO reactivity. Studies investigating hyperglycemia and nerve arterial vasodilation typically omit insulin treatment and use sedentary rats resulting in severe hyperglycemia. We tested the hypotheses that 1) insulin-treated experimental diabetes and inactivity (DS rats) will attenuate insulin-mediated nerve arterial vasodilation, and 2) deficits in vasodilation in DS rats will be overcome by concurrent exercise training (DX rats; 75-85% VO2 max, 1 h/day, 5 days/wk, for 10 wk). The baseline index of vascular conductance values (VCi = nerve blood flow velocity/mean arterial blood pressure) were similar (P ≥ 0.68), but peak VCi and the area under the curve (AUCi) for the VCi during a euglycemic hyperinsulinemic clamp (EHC; 10 mU·kg(-1)·min(-1)) were lower in DS rats versus control sedentary (CS) rats and DX rats (P ≤ 0.01). Motor nerve conduction velocity (MNCV) was lower in DS rats versus CS rats and DX rats (P ≤ 0.01). When compared with DS rats, DX rats expressed greater nerve endothelial NOS (eNOS) protein content (P = 0.04). In a separate analysis, we examined the impact of diabetes in exercise-trained rats alone. When compared with exercise-trained control rats (CX), DX rats had a lower AUCi during the EHC, lower MNCV values, and lower sciatic nerve eNOS protein content (P ≤ 0.03). Therefore, vasa nervorum and motor nerve function are impaired in DS rats. Such deficits in rats with diabetes can be overcome by concurrent exercise training. However, in exercise-trained rats (CX and DX groups), moderate hyperglycemia lowers vasa nervorum and nerve function.

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.

The impact of aging on vasa nervorum, nerve blood flow and vasopressin responsiveness.

OBJECTIVE: Aging impacts microvessels in a number of tissue beds. Vasopressin acts as a vasoconstrictor in most blood vessels but may also cause vasodilation. We evaluated the role of aging and vasopressin in the regulation of nerve blood flow (NBF) in rat peripheral nerve. METHODS: We undertook a dose-response study to examine the impact of aging on resting NBF and its vasoreactivity to vasopressin. Nerve blood flow was measured using microelectrode hydrogen polarography. Arginine-vasopressin was administered both intra-arterially and topically. RESULTS: In young adult rats (two months old) topical epineurial application of arginine-vasopressin produced a concentration-dependent reduction of NBF (ED50 = 3.8 x 10(-5) mol/L). Intra-arterial arginine-vasopressin also reduced NBF. Nerve blood flow was lower in aged rats (12 months old) and less responsive to topically applied vasopressin. The aging group had significantly higher concentrations of vasopressin in plasma than did the younger group. CONCLUSIONS: The results suggest that vasopressin constricts vessels in peripheral nerve and that there is an age related decline in the vasoconstrictive response to vasopressin. There may be a reduction in receptor sensitivity in vascular smooth muscle cells in peripheral nerve with increasing age.

Calcitonin gene-related peptide and peripherin immunoreactivity in nerve sheaths.

The intrinsic innervation of rat sciatic nerve sheaths was studied by means of immunohistochemical labeling for calcitonin gene-related peptide (CGRP) and peripherin. CGRP immunoreactivity (CGRP-IR) and peripherin immunoreactivity (peripherin-IR) were found in fine nerve fibers independent of nerve sheath vasculature. These findings suggest that a subset of the nervi nervorum may have nociceptive functions, and that this subset is distinct from nerve fibers that innervate the blood vessels of the nerve sheaths.

Effects of nimodipine on sciatic nerve blood flow and vasa nervorum responsiveness in the diabetic rat.

Evidence is accumulating that impairment of nerve blood flow is a key factor in the pathogenesis of diabetic neuropathy. Nimodipine, a 1,4-dihydropyridine type Ca2+ channel antagonist, has been shown to ameliorate an existing neuropathy in the streptozotocin-induced diabetic rat. In the present study the effect of diabetes mellitus itself and the effect of chronic nimodipine treatment on the sciatic nerve blood flow of streptozotocin-induced diabetic rats were investigated. Nerve blood flow was assessed using laser-Doppler flowmetry. Nerve blood flow gradually decreased during the first 10 weeks of diabetes mellitus and remained relatively stable thereafter. Intervention with nimodipine significantly improved the flow deficit observed in the diabetic rats. Vasa nervorum adrenergic responsiveness was also investigated. Diabetic rats showed a postsynaptic adrenergic hyporesponsiveness. Treatment with nimodipine restored the reduced presynaptic responsiveness independent of the postsynaptic adrenergic hyporesponsiveness. It was concluded that, in addition to direct neuroprotective effects, nimodipine exerts beneficial effects on disturbed nerve blood flow and on reduced presynaptic adrenergic responsiveness of the vasa nervorum in experimental diabetic neuropathy.

Vasa nervorum constriction from substance P and calcitonin gene-related peptide antagonists: sensitivity to phentolamine and nimodipine.

Previous work has suggested that vasa nervorum are 'tonically' vasodilated by substance P (SP) and calcitonin gene-related peptide (CGRP) arising from perivascular afferent nerve fibers. Local application of specific receptor antagonists of SP or CGRP results in constriction of vasa nervorum. In this work, we examined the responsiveness of vasa nervorum to epineurial spantide and spantide II (SP antagonists) and hCGRP (8-37) (CGRP antagonist) using serial hydrogen clearance curves in the rat sciatic nerve. Vasoconstriction from spantide and hCGRP (8-37) was dose-dependent, and was slightly greater with spantide than hCGRP (8-37). Spantide II induced vasoconstriction comparable to that of spantide. The vasoconstrictive effects of both spantide and hCGRP (8-37) were eliminated by concurrent systemic treatment with with either phentolamine or nimodipine. The findings support the hypothesis that SP or CGRP blockade interrupts 'tonic' peptide vasodilatation and permits vasoconstriction, perhaps by unopposed adrenergic action mediated through calcium channels. The findings however do not exclude a unique direct vasoconstrictive action of the peptide antagonists.

Evidence that capsaicin hyperaemia of rat sciatic vasa nervorum is local, opiate-sensitive and involves mast cells.

1. In previous work, we identified a prolonged and intense hyperaemic response of rat sciatic endoneurial vasa nervorum produced by epineurial application of capsaicin. We postulated that this response, which was blocked by substance P (SP) or calcitonin gene-related peptide (CGRP) antagonists, was a result of local release of neuropeptides on the 'feeding' epineurial vascular plexus. 2. In the present study, we evaluated factors that might influence capsaicin-induced hyperaemia of the rat sciatic endoneurium as measured by hydrogen clearance: central afferent connections, the epineurial vascular plexus, the release of histamine and administration of opiates. 3. Interruption of central afferent connections by proximal nerve section or removal of the epineurial vascular plexus did not influence baseline endoneurial perfusion. Plexus removal, but not proximal section, prevented capsaicin hyperaemia. 4. The epineurial vascular plexus was desensitized to the effect of capsaicin by prior application of capsaicin. Capsaicin hyperaemia was also prevented by: topical treatment with Spantide II ((D-NicLys1,3-Pal3,D-Cl2Phe5,Asn6,D-Trp7,9,Nl e11) substance P) an SP antagonist, systemic pretreatment with a combination of H1 and H2 histamine receptor antagonists, systemic pretreatment with cromolyn sodium or systemic pretreatment with morphine. None of these pretreatments influenced baseline perfusion. When systemic morphine was given together with systemic naloxone, an opiate antagonist, capsaicin-induced hyperaemia was restored. 5. These findings indicate that the capsaicin hyperaemia of vasa nervorum is locally mediated, is independent of central afferent connections and is sensitive to a variety of interventions. It requires an intact epineurial plexus that 'feeds' endoneurial microvessels and the release of histamine by mast cells. Its inhibition by morphine suggests that there are local opiate receptors on epineurial perivascular peptidergic fibres.

[Vascularization of the common fibular nerve]. / Vascularisation du nerf fibulaire commun.

The vascularization of the common fibular nerve (CFN) let us suppose that one have to take anatomy and physiology of vasa nervorum in consideration in the genesis of neurologic lesions. This study is based on fresh cadavers dissections, with intra arterial injection of minimum colored latex. The results emphasize the causes of the CFN susceptibility while compression and stretching injury.

Influence of perivascular peptides on endoneurial blood flow and microvascular resistance in the sciatic nerve of the rat.

1. A variety of vasoactive peptides has been identified in the axon terminals innervating vasa nervorum but their function is unknown. In mesenteric arterioles, substance P (SP) and calcitonin gene-related peptide (CGRP) have been postulated to have a role in tonic vasodilatation. 2. We explored the effect of epineurial capsaicin, SP, CGRP, spantide (SP antagonist), and hCGRP (8-37) (CGRP antagonist) on blood flow (EBF) and microvascular resistance (EMR) in the endoneurial compartment of the rat sciatic nerve, as measured by hydrogen clearance. 3. Epineurial capsaicin induced a prompt, intense and prolonged increase in EBF and lowering of EMR as compared to epineurial application of the carrier alone in a separate animal group. The hyperaemic response was also confirmed by studying serial clearance curves in individual animals. 4. Multifibre sciatic-tibial motor conduction was not changed by epineurial capsaicin. 5. When co-administered with capsaicin, hCGRP (8-37) completely blocked the hyperaemic response and increased EMR above the pooled control range. Spantide also blocked the capsaicin response. 6. When administered alone, both epineurial hCGRP (8-37) and spantide lowered EBF below and increased EMR above the control measurements in the same animals. 7. At 10(-5) M epineurial CGRP, but not SP lowered EMR. Vasodilatation from intra-arterial administration of CGRP was much greater and was more prolonged compared with that induced by SP. hCGRP (8-37), but not spantide reduced the intra-arterial response to CGRP. 8. The findings suggest that epineurial peptidergic terminals mediate a vasodilatory response (particularly through CGRP) that increases blood flow in the 'downstream' endoneurial compartment. Physiological peptide release (blocked by SP and CGRP receptor antagonism) may be important in maintaining tonic vasodilatation.

Role of the blood-nerve barrier in experimental nerve edema.

Nerve edema is a common response to the nerve injury seen in many peripheral neuropathies and is an important component of Wallerian degeneration. However, independent pathologic effects of nerve edema that aggravate or induce nerve injury extend the role of edema beyond that of an epiphenomenon of injury. New insights into the mechanism and impact of nerve edema come largely from animal models. In the following review, we discuss the cause and consequences of nerve edema with particular reference to endoneurial fluid pressure and its relevance to the nerve microenvironment. Experimental models of nerve edema include conditions with increased vascular permeability such as lead poisoning, experimental allergic neuritis, and murine globoid leukodystrophy. Increased perineurial permeability induced by local anesthetics and neurolytic drugs can also induce nerve edema sufficient to increase endoneurial fluid pressure. Both perineurial and vascular permeability are increased after damage induced by crush, freeze, or laser injury. One of the most important forms of nerve edema is induced by external compression; the significance of this change is that edema has local compressive effects that persist after the external pressure has been relaxed. Nerve edema and increased endoneurial fluid pressure also occur in conditions in which vascular permeability appears to be unchanged such as experimental diabetic neuropathy and in hexachlorophene intoxication. In both of these conditions, reduced nerve blood flow has been demonstrated in rats and is viewed as a consequence of increased endoneurial fluid pressure. Whatever its mechanism, endoneurial edema has important structural and functional consequences for nerve fibers. A clear understanding of the underlying pathology of the nerve microenvironment may provide useful insights into treatment of clinical neuropathies.

Adrenergic innervation of the vasa nervorum in the cranial nerves and spinal roots in the subarachnoid space.

Fluorescence microscopy revealed that the innervation of the vasa nervorum of both cranial and spinal nerve roots in the subarachnoid space in the monkey is adrenergic in nature. The endoneurium of the cranial nerve roots contained free adrenergic nerve fibers which were not related to the vessel wall.

The noradrenergic innervation of the vasa nervorum in old rats: a fluorescence histochemical study.

The effect of ageing on the density and pattern of noradrenergic nerves in the perivascular nerve plexus supplying the vasa nervorum of the rat sciatic nerve was studied using combined catecholamine histofluorescence and quantitative image analysis techniques. The density of noradrenergic fibres around arteries and arterioles of the rat sciatic nerve vasa nervorum increased in the old animals. In contrast, no changes in perivascular nerve fibres supplying the veins and venules were found in the vasa nervorum of old rats. The increase in old age of noradrenergic innervation of arteries and arterioles of the vasa nervorum may be related to the pathogenesis of some peripheral nerve diseases.

A study on the critical mobilization length of peripheral nerves.

The transverse section of the sciatic, tibial and peroneal nerves in rabbits was followed by mobilization in a proximal and distal direction and a tension-free end-to-end suture of the cut surfaces. The proximal mobilization was performed up to eight different levels between 60 mm and 200 mm, i. e. 20.3% to 67.7% of the total nerve length. Histological findings and their statistical analysis indicated that the critical mobilization length, beyond which ischaemic parenchymal damages occur, is 70 mm or 24% of the total nerve length. Up to this level, the vascular "extrinsic system" of the mobilized nerve segments is completely compensated for by the "intrinsic system". When the mobilization length is increased, the degeneration distances were more pronounced than those of the ischaemic nerve distances. Some nerves showed no effects from the ischaemia.

Blood flow in peripheral nerves. Normal and post severance flow rates.

Regional blood flow has been measured in the sciatic nerve of cats utilizing the method of hydrogen polarography. The mean baseline flow of the sciatic nerve in cats was found to be 43 ml/100 g/min +/- 1.6 SD. Flow rates were somewhat erratic in both the proximal and distal segments of the nerve following nerve severance. The erratic flows were observed over the first 30 min following nerve cutting and by 1 hr had essentially stabilized at approximately the pre-severance flow level.

Absence of autoregulation in peripheral nerve blood flow.

Blood flow was measured in the sciatic nerve of cats utilizing the method of hydrogen polarography. The mean baseline blood flow for all animals was found to be 47.1 ml/100 g/min +/- 14.9 SD. The flow changes produced by lowering the blood pressure by exsanguination and elevation by the use of angiotensin were then evaluated. The highest (normal) levels of blood flow were observed between the mean blood pressures of 80-110 mm Hg. At mean systemic arterial pressures of less than 85, there was a marked decrease in peripheral nerve blood flow with no detectable flow being measured below mean systemic pressures of 50 mm Hg. Above 105 mm Hg mean arterial pressure, there was a very gradual and progressive decline in blood flow to the levels measured at 200 mm Hg. These findings indicate a complete absence of vascular autoregulation in the peripheral nerve trunks.