Biomedical subjects

N E Cameron

Publications and source records attributed to N E Cameron.

At least 37 records · Page 2Linked to original sources

PubMed1997

Neurovascular effects of L-carnitine treatment in diabetic rats.

The aims were to ascertain whether L-carnitine could prevent nerve blood flow and conduction deficits in 1-month diabetic rats and to examine potential neurovascular mechanisms using co-treatment with the nitric oxide synthase inhibitor, NG-nitro-L-arginine. A 19.8% diabetic deficit in sciatic motor conduction velocity was 57.4% attenuated by L-carnitine treatment. Similarly, a 47.7% reduction in sciatic nutritive (capillary) endoneurial blood flow was 48.6% blocked by L-carnitine. Joint treatment with NG-nitro-L-arginine completely abolished the effects on nerve conduction and nutritive flow. However, L-carnitine treatment did not alter a 50.8% diabetic deficit in total sciatic endoneurial flow, which was further depressed (61%) by NG-nitro-L-arginine co-treatment. Thus, the effect of L-carnitine on nerve conduction in diabetic rats depends on changes in the endoneurial perfusion pattern by an action that may involve the nitric oxide system of vasa nervorum.

Animals↗

PubMed1997

Effects of alpha-tocopherol on nerve conduction velocity and regeneration following a freeze lesion in immature diabetic rats.

We investigated whether anti-oxidant treatment with alpha-tocopherol (1 g kg-1 day-1) could prevent the blunting of the normal maturational increase in motor and sensory nerve conduction velocity when diabetes is induced by streptozotocin in young rats. A further study in the same rats examined effects on myelinated fibre regeneration distance 14 days after a punctate sciatic nerve lesion by a liquid nitrogen cooled probe. In non-diabetic rats between 8 and 14 weeks of age, sciatic motor and saphenous sensory conduction velocity increased by approximately 28% (P < 0.001) and 21% (P < 0.001) respectively. Diabetes induced at 8 weeks blunted this maturational change by 65% for sciatic motor and almost completely for saphenous sensory fibres (P < 0.001). Treatment with alpha-tocopherol from diabetes induction totally prevented motor conduction velocity deficits (P < 0.001). For sensory saphenous nerve, conduction abnormalities were markedly attenuated (72%, P < 0.001) although a significant deficit remained compared to age-matched non-diabetic rats (P < 0.01). Sciatic nerve myelinated fibre regeneration distance, 14 days post lesion, was 15% reduced (P < 0.001) by untreated diabetes. However, in diabetic rats treated with alpha-tocopherol, regeneration distance was significantly improved (P < 0.001), being within the non-diabetic range. Thus, the data highlight the importance of reactive oxygen species in the aetiology of impaired nerve maturation and regeneration in experimental diabetes and indirectly support the view that anti-oxidant treatment could have a therapeutic role in patients.

Animals↗

PubMed1997

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats.

Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135706, (250 mg.kg-1.day-1) and an ARI, WAY-121509, (10 mg.kg-1.day-1) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6-8.2-fold) by WAY-135706 whereas WAY-121509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135706 and WAY-121509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9%, respectively with diabetes. These deficits were corrected by WAY-121509, but WAY-135706 was completely ineffective. A 48.6% diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121509, but was unaltered by WAY-135706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase.

Aldehyde Reductase↗

PubMed1997

Effects of dietary supplementation with arachidonic acid rich oils on nerve conduction and blood flow in streptozotocin-diabetic rats.

Diabetes mellitus is associated with defective essential fatty acid desaturation. In experimental models this contributes to characteristic reductions in peripheral nerve conduction velocity (NCV) and blood flow, which may be corrected by dietary supplementation with gamma-linolenic acid (GLA) rich oils to bypass the delta-6 desaturation deficit. There is debate about the mechanism of this improvement, including whether it depends on synthesis of series 1 prostanoids derived from di-homo GLA or series 2 prostanoids from arachidonic acid (ARA). The aim was to assess the efficacy of two ARA-rich (approximately 39% content) oils in correcting neurovascular dysfunction in streptozotocin-induced diabetic rats. After 6 weeks of untreated diabetes, rats were treated for a further 2 weeks with 1% dietary oil supplements before assessment of sciatic motor NCV and endoneurial blood flow. NCV was 19% reduced in diabetic rats and this was largely (approximately 86%) corrected by both oil treatments. A 48% deficit in endoneurial nutritive blood flow with diabetes was approximately 70% reversed by the two oils, vascular conductance being in the non-diabetic range. Thus, nerve conduction and perfusion deficits in diabetic rats are corrected by ARA-rich oil treatment. The magnitudes of these changes were similar to expectations based on previous studies of GLA-rich oils, therefore it is likely that the neurovascular effect of increased synthesis of series 2 prostanoids makes a major contribution to the beneficial action of n-6 essential fatty acids in experimental diabetic neuropathy.

Animals↗

PubMed1997

Metabolic and vascular factors in the pathogenesis of diabetic neuropathy.

Reduced nerve perfusion is an important factor in the etiology of diabetic neuropathy. Studies in streptozotocin-induced diabetic rats show that nerve conduction velocity (NCV) and blood flow deficits are corrected by treatment with vasodilator drugs, with angiotensin II and endothelin-1 antagonists being particularly important. The AT1 antagonist ZD7155 also prevents diabetic deficits in regeneration following nerve damage, indicating that hypoperfusion is an important limitation for nerve repair. Metabolic changes include high polyol pathway flux, increased advanced glycosylation, elevated oxidative stress, and impaired omega-6 essential fatty acid metabolism. Aldose reductase inhibitors (ARIs) restore NCV via their effects on perfusion. ARI action probably depends on blocking the conversion of glucose to sorbitol, thus preventing depletion of vasa nervorum glutathione, an important endogenous free radical scavenger. Free radicals cause vascular endothelium damage and reduced nitric oxide vasodilation. Inhibition of advanced glycosylation and autoxidation (autoxidative glycosylation), major sources of free radicals, by aminoguanidine or transition metal chelators, corrects neurovascular dysfunction. Evening primrose oil supplies gamma-linolenic acid (GLA) to improve vasodilator eicosanoid synthesis in diabetes, correcting nerve blood flow and NCV deficits. Interactions between some of these mechanisms have therapeutic implications. Thus, combined ARI and evening primrose oil treatment produced a 10-fold amplification of NCV and blood flow responses. Similarly, GLA effects are markedly enhanced when given in combination with ascorbate as ascorbyl-GLA. Thus, metabolic abnormalities combine to produce deleterious changes in nerve perfusion that make a major contribution to the etiology of diabetic neuropathy. The potential importance of multi-action therapy is stressed.

Animals↗

PubMed1996

Nerve function and regeneration in diabetic and galactosaemic rats: antioxidant and metal chelator effects.

Immature rats were made diabetic with streptozotocin or were fed a 40% galactose diet to stimulate the polyol pathway. Separate diabetic and galactosaemic groups were treated with butylated hydroxytoluene or trientine. After 4 weeks the sciatic nerve was freeze-lesioned. Two weeks later, the degree of myelinated fibre regeneration was assessed electrophysiologically and nerve conduction velocity was measured in the contralateral leg. Similar sciatic motor and saphenous sensory nerve conduction velocity deficits of approximately 18% and 19%, respectively, compared to age-matched control rats were found in both models. They were partially prevented by treatment (approximately 68% for butylated hydroxytoluene and 63% for trientine). There were 12% and 10% deficits in nerve regeneration distance with diabetes and galactosaemia respectively, which were markedly attenuated (approximately 80%) by both treatments. The data emphasise the importance of elevated, free radical activity for the aetiology of neural/neurovascular deficits in experimental diabetes and galactosaemia.

Animals↗

PubMed1996

Contraction and relaxation of aortas from diabetic rats: effects of chronic anti-oxidant and aminoguanidine treatments.

We examined whether chronic treatment with the free radical scavengers butylated hydroxytoluene (1 g kg-1 day-1) and N-acetyl-L-cysteine (250 mg kg-1 day-1), or the inhibitor of advanced glycosylation reactions, aminoguanidine (1 g kg-1 day-1), could prevent the development of relaxation and contraction abnormalities in aorta from 2 month streptozotocin-diabetic rats. Diabetes caused a 24% deficit in maximal endothelium-dependent relaxation to acetylcholine for phenylephrine precontracted aortas (P < 0.01). This was unaffected by tissue-bath glucose concentration (5.5 or 40 mM), or by addition of 1 mM L-arginine. Butylated hydroxytoluene, N-acetyl-L-cysteine and aminoguanidine treatments gave substantial protection, maximum relaxation remaining in the non-diabetic range. Neither diabetes nor treatment affected endothelium-independent relaxation to glyceryl trinitrate. To test the suggestion that aminoguanidine could act as an inhibitor of constitutive nitric oxide synthase, acute aminoguanidine effects on endothelium-dependent relaxation to acetylcholine were also examined. No inhibition was noted. A modest increase in phenylephrine sensitivity with diabetes (P < 0.05) was unaffected by butylated hydroxytoluene or N-acetyl-L-cysteine, but partially prevented by aminoguanidine (P < 0.05). The data, therefore, provide evidence for the involvement of reactive oxygen species and the advanced glycosylation process particularly for impaired endothelium-dependent relaxation in experimental diabetes.

Acetylcholine↗

PubMed1996

Comparison of the effects of ascorbyl gamma-linolenic acid and gamma-linolenic acid in the correction of neurovascular deficits in diabetic rats.

Essential fatty acid metabolism is impaired by diabetes mellitus and gamma-linolenic acid rich treatments such as evening primrose oil correct deficits in nerve conduction and endoneurial blood flow in diabetic rats. Other mechanistically unrelated treatments, such as antioxidants and aldose reductase inhibitors have a similar effect and there may be positive interactions with multiple treatments. Our aim was to compare the efficacy of a novel essential fatty acid derivative, ascorbyl gamma-linolenic acid, with that of gamma-linolenic acid in correcting diabetic neurovascular deficits. Eight weeks of diabetes caused 20.4 and 48.2% reductions in sciatic motor conduction velocity and nutritive endoneurial blood flow, respectively. Treatment was given for the last 2 weeks with gamma-linolenic acid (100 mg.kg-1.day-1) either in pure form or as ascorbyl gamma-linolenic acid, an equivalent dose of ascorbate (21 mg.kg-1.day-1) or jointly with ascorbate and gamma-linolenic acid. Conduction velocity was corrected by 39.8, 87.4, 13.2 and 66.8% with gamma-linolenic acid, ascorbyl gamma-linolenic acid, ascorbate and gamma-linolenic acid plus ascorbate, respectively. Corresponding ameliorations of the nutritive blood flow deficit were 44.0, 87.4, 87.4, 13.2 and 65.7%. For the gamma-linolenic acid plus ascorbate combinatin, and especially for ascorbyl gamma-linolenic acid, the magnitude of correction for conduction velocity and blood flow was greater than expected for simple addition of ascorbate and gamma-linolenic acid, indicating a synergistic interaction. Thus, with an efficacy 40 times that of evening primrose oil in rats, ascorbyl gamma-linolenic acid may be a suitable candidate for clinical trials of diabetic neuropathy.

Animals↗

PubMed1996

Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats.

Impaired omega-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, high-dose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Eight weeks of diabetes caused an 18.9% reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg.kg-1.day-1 and WAY121 509 (0.2 mg.kg-1.day-1 for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121 509 caused marked 71.5 and 82.4% corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8% with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121 509 (10 mg. kg-1.day-1 and primrose oil (10% dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg.kg(-1).day-1 and NG-nitro-L-arginine (10 mg.kg-1.day-1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived.

Acetanilides↗

PubMed1996

Rapid reversal by aminoguanidine of the neurovascular effects of diabetes in rats: modulation by nitric oxide synthase inhibition.

Aminoguanidine treatment prevents the development of nerve conduction velocity (NCV) deficits and some renal and retinal complications in diabetic rats. Pharmacological actions include inhibition of the formation of advanced glycosylation end products (AGEs) and nitric oxide (NO) synthase. The aims of the study were to determine the extent to which diabetic NCV and nerve blood flow deficits could be corrected by aminoguanidine in an intervention study, to assess the time course of drug action, and to examine the effects of cotreatment with the NO synthase inhibitor, NG-nitro-L-arginine (NOLA). A 19.3% +/- 0.9% reduction in sciatic motor NCV after 4 weeks of untreated diabetes was corrected 86.6% +/- 3.7% by aminoguanidine treatment for a further 4 weeks. Time-course studies showed that 50% of the maximal effect was attained within 6 days. Sciatic endoneurial capillary blood flow, reduced approximately 45% by diabetes, was corrected 85.6% +/- 12.1% by aminoguanidine treatment. The NCV and blood flow effects of aminoguanidine were completely blocked by cotreatment with NOLA. Thus, the data support a neurovascular mechanism for aminoguanidine involving improved NO action. The rapidity of aminoguanide's effect is consistent with inhibition of free radical production by autoxidative glycosylation or glycoxidation.

Animals↗

PubMed1996

Effectiveness of natural oils as sources of gamma-linolenic acid to correct peripheral nerve conduction velocity abnormalities in diabetic rats: modulation by thromboxane A2 inhibition.

Reduced nerve conduction velocity (NCV) in experimental diabetes can be prevented by evening primrose oil (EP), which is rich in gamma-linolenic acid (GLA). This study examined the efficacy of natural GLA sources, blackcurrant (BC), borage (BO) and fungal (FU) oils, compared with EP, in correcting motor and sensory NCV deficits in streptozotocin-diabetic rats, and any potential contribution of thromboxane (TX) A2 synthesis using the TX antagonist, ZD1542, alone and jointly with GLA-rich oils. Sciatic motor NCV, 20% reduced by 8 weeks of diabetes, was partially (16%) corrected by 2 weeks ZD1542 treatment. 1% BC, BO, FU and EP dietary supplementation caused 11%, 32%, 41% and 53% NCV ameliorations, respectively. A 2% EP diet, more closely matching the GLA intake from the other oils, caused 67% correction. Joint oil/ZD1542 treatment produced further motor NCV improvements for BC and, particularly, BO. A 13% sensory saphenous NCV deficit in diabetic rats was ameliorated by 31%, 24%, 49%, 81%, 70% and 94% for ZD1542, BC, BO, FU, EP and 2% EP, respectively. Joint ZD1542-oil treatment further improved NCV, particularly for BO. Therefore, efficacy against experimental diabetic neuropathy is not predictable from the GLA content of natural oils, EP consistently outperforming BC, BO and FU. Increased TXA2 with diabetes made a minor contribution to NCV deficits, but blockade improved the response to BO.

Animals↗

PubMed1996

Effects of the sulphydryl donor N-acetyl-L-cysteine on nerve conduction, perfusion, maturation and regeneration following freeze damage in diabetic rats.

Peripheral nerve conduction velocity deficits in diabetic rats depend on decreased nerve perfusion, which may be related to increased free radical activity and impaired endogenous protection by the glutathione redox cycle. We studied the effect of treatment with the glutathione precursor N-acetyl-L-cysteine on nerve conduction, blood flow, maturation and regeneration. Two months of diabetes in mature rats caused 20% and 48% deficits in sciatic motor conduction velocity and endoneurial blood flow, respectively, which were largely corrected by N-acetyl-L-cysteine treatment during the second month. In young nondiabetic rats, sciatic motor conduction velocity increased by 31% over 6 weeks. Diabetes halved the conduction velocity maturation rate, however N-acetyl-L-cysteine treatment allowed a normal pattern of development. After 1 month of treated or untreated diabetes, the sciatic nerve was lesioned by a liquid nitrogen-cooled probe. Myelinated fibre regeneration distance, determined electrophysiologically, was reduced by 12.2% with diabetes; this was prevented by N-acetyl-L-cysteine treatment. Thus, the data stress the importance of free radical-mediated changes in the aetiology of experimental diabetic neuropathy.

Acetylcysteine↗

PubMed1996

Interaction between oxidative stress and gamma-linolenic acid in impaired neurovascular function of diabetic rats.

Nerve conduction and perfusion deficits in diabetic rats depend on increased oxidative stress and impaired n-6 essential fatty acid metabolism, which are corrected by free radical scavenger and gamma-linolenic acid (GLA)-rich oil treatments, respectively. We investigated the interaction between these mechanisms on conduction velocity and endoneurial blood flow by use of low-dose antioxidant (BM15.0639) and GLA treatments, alone and in combination. After 8 wk of streptozotocin-induced diabetes, sciatic motor conduction velocity was 20.9% reduced. Treatment with GLA or BM15.0639 for the final 2 wk corrected this deficit by 18.5 and 20.0%, respectively; however, joint treatment caused 71.5% improvement, corresponding to a 7.5-fold amplification of individual drug effects. A 48.3% deficit in sciatic nutritive endoneurial blood flow was corrected by 34.8 and 24.8% with GLA and BM15.0639 treatments, respectively. With joint treatment, the flow improvement of 72.5% was greater than expected from individual drug effects, indicating a facilitatory interaction. Thus the synergistic effect of combined antioxidant and n-6 essential fatty acid treatment could potentially provide increased therapeutic power against diabetic neuropathy.

Animals↗

PubMed1996

Effects of a nonpeptide endothelin-1 ETA antagonist on neurovascular function in diabetic rats: interaction with the renin-angiotensin system.

The aims of this study were to assess whether high-dose treatment with an endothelin 1 (ET1) ETA antagonist could correct deficits in peripheral nerve conduction and blood flow in streptozotocin-diabetic rats and to examine interactions between ET1 and the renin-angiotensin system using low-dose single and combined treatments with ETA and AT1 antagonists. After B wk of diabetes, sciatic motor nerve conduction velocity (NCV) was approximately 20% reduced. High-dose ETA antagonist treatment for 2 wk corrected NCV to the extent of 84%. A approximately 48% diabetic deficit in nutritive endoneurial blood flow was also 88% corrected by the ETA antagonist. Combined treatment with low-doses of ETA and AT1 antagonists, selected to give approximately 20% amelioration of diabetic NCV deficits on their own, resulted in 66% correction. This was greater than expected for a simple additive effect between the antagonists, demonstrating a synergistic interaction. From NCV dose-response curves, the combined treatment effect was equivalent to a 4.2- to 8.9-fold dose increase for the individual antagonists. In parallel, joint treatment markedly improved sciatic nutritive endoneurial perfusion. Thus, the data strongly implicate ET1, acting via ETA receptors in the etiology of neurovascular dysfunction in experimental diabetic neuropathy. Furthermore, they demonstrate synergistic interactions between ET1 and renin-angiotensin systems that, if present in neuropathic patients, could potentially be used to obtain a therapeutic advantage.

Angiotensin Receptor Antagonists↗

PubMed1995

Impaired myelinated fiber regeneration following freeze-injury in rats with streptozotocin-induced diabetes: involvement of the polyol pathway.

This study examined the effects of streptozotocin-induced diabetes mellitus and aldose reductase inhibitor (ZD5522) treatment on myelinated fiber regeneration in rats. After 2 months of diabetes, with or without ZD5522 treatment (10 mg.kg-1.day-1) from induction, sciatic nerve degeneration was initiated by a punctate lesion using a liquid N2 cooled probe. Regeneration was studied over a subsequent 14-day period using in vitro electrophysiological techniques. There was a 21.4% (P < 0.001) deficit in the maximum fiber regeneration distance in diabetic rats, 14 days postlesion. This was partially (64.9%, P < 0.01) prevented by aldose reductase inhibitor treatment, the resultant regeneration distance being not significantly different from that of age-matched nondiabetic control rats. The regeneration rate, assessed from data collected 4, 9 and 14 days postlesion, was 23.7% (P < 0.001) reduced by diabetes and ZD5522 treatment provided 73.1% protection (P < 0.01). We conclude that polyol pathway activity is involved in impaired regeneration in experimental diabetes, potential pathophysiological mechanisms involving a reduction in neurotrophic support and impaired endoneurial blood supply.

Acetanilides↗

PubMed1995

Nerve function in galactosaemic rats: effects of evening primrose oil and doxazosin.

Rats were fed for 6 weeks with a 40% galactose diet to chronically stimulate the polyol pathway. Sciatic motor and saphenous sensory nerve conduction velocity deficits of 22% and 14% respectively developed. Treatment with evening primrose oil or doxazosin from galactosaemia induction partially (approximately 60%) prevented the development of reduced motor and sensory conduction, the former treatment being more successful than the latter. Sciatic nerve resistance to hypoxic conduction failure was 49% increased by galactosaemia. This abnormality was 27% and 43% prevented by doxazosin and evening primrose oil respectively. Galactosaemic sciatic nerves had a 10% increase in water content and endoneurial capillary density was 24% reduced. While neither treatment affected water content, both caused angiogenesis, elevating capillary density by approximately 16%. The data support the hypothesis that, as in experimental diabetes mellitus, the main effect of polyol pathway activation on peripheral nerve function occurs indirectly via a neurovascular action.

Animals↗

PubMed1995

Neuroprotective effects of carvedilol in diabetic rats: prevention of defective peripheral nerve perfusion and conduction velocity.

The effects of carvedilol (10 mg kg-1 day-1), a peripheral vasodilator and oxygen free radical scavenger, on nerve conduction and blood flow were examined in streptozotocin-diabetic rats. Rats were treated from induction of diabetes for 1 month in a preventive experiment; effects of treatment in non-diabetic rats were also examined. Diabetes caused a 20.0% (P < 0.001) reduction in sciatic motor conduction and a 14.7% (P < 0.001) deficit in saphenous sensory conduction. Diabetic rats given carvedilol treatment had motor and sensory conduction velocities which did not differ significantly from those of non-diabetic controls, but were greater than for untreated diabetes (P < 0.001). Carvedilol treatment did not significantly alter nerve conduction in non-diabetic rats. The nutritive (capillary) component of sciatic endoneurial blood flow, measured by microelectrode polarography and hydrogen clearance, was 45.8% (P < 0.001) reduced by diabetes. This was completely corrected (P < 0.001) by carvedilol treatment in diabetic rats, flow being in the upper half of the non-diabetic range. In non-diabetic rats, carvedilol caused a 30.6% (P < 0.05) elevation in blood flow. Hydrogen clearance data also revealed a shift away from non-nutritive (arterio-venous anastomotic) towards nutritive flow in treated diabetic rats (P < 0.05). We conclude that the data support a neurovascular hypothesis of diabetic neuropathy. Carvedilol, via vasodilator and anti-oxidant actions, prevents the nutritive blood flow changes that lead to nerve dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Reversal of peripheral nerve conduction and perfusion deficits by the free radical scavenger, BM15.0639, in diabetic rats.

We examined the ability of the oxygen free radical scavenger, BM 15.0639 (400 mg kg-1 day-1), to correct existing sciatic motor nerve conduction velocity and endoneurial blood flow deficits in streptozotocin-diabetic rats. Rats were treated for 1 month following 1 month of untreated diabetes. Effects of treatment in non-diabetic rats were also examined. A further experiment determined the dose-response relationship for correction of conduction velocity abnormalities by BM15.0639. Diabetes caused 20.9% and 22.7% deficits in motor conduction velocity after 1 and 2 months respectively (both P < 0.001). Rats treated with BM15.0639 after the first month of untreated diabetes had conduction velocity values that were not significantly different from those for non-diabetic controls, but were significantly elevated compared to 1 or 2 months untreated diabetes (both P < 0.001). The ED50 for correction of nerve conduction velocity was approximately 36 mg kg-1 day-1. Sciatic nutritive endoneurial blood flow was 46.5% and 50.5% decreased by 1 and 2 months diabetes respectively (both P < 0.001). This was more than corrected by BM15.0639 treatment of diabetic rats, flow being approximately 33% greater than normal (P < 0.05). In contrast, 1 month BM15.0639 treatment had no effect on blood flow or conduction velocity in non-diabetic rats. Co-treatment of BM15.0639-treated diabetic rats with the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (10 mg kg-1 day-1) largely abolished the anti-oxidant effect on conduction velocity and blood flow. Thus, the data highlight the importance of oxygen free radical activity for the neurovascular deficits in experimental diabetes which are at least in part caused by impaired NO production or release.

Analysis of Variance↗