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Biomedical subjects

N E Cameron

Publications and source records attributed to N E Cameron.

89 records · Page 5Linked to original sources
PubMed1989

Chronic low frequency electrical activation for one week corrects nerve conduction velocity deficits in rats with diabetes of three months duration.

This study examined the effect of chronic electrical activation on conduction velocity deficits after three months of streptozotocin-induced diabetes. There were 30% and 20% reductions in conduction velocity in diabetic animals for tibialis anterior and saphenous nerves, respectively (p less than 0.01). Unilateral electrical stimulation of the common peroneal nerve, which contains axons supplying tibialis anterior but not saphenous nerve, was carried out in a group of diabetic and a group of normal control rats. Stimulation was given over seven days, at 10 Hz for 8 h/day. Final experiments were carried out at least 17 h after the last stimulation session. In normal rats stimulation had no effect on conduction velocity in either nerve. In diabetic animals, however, tibialis anterior conduction was within the normal control range for the stimulated nerve. In contrast, the contralateral unstimulated nerve had reduced conduction velocity (p less than 0.001), which was within the unoperated diabetic control range. There were no effects on saphenous nerve conduction, comparing stimulated and unstimulated legs. We conclude that chronic increases in nerve electrical activation promote mechanisms that reverse conduction deficits in diabetic rats.

Animals↗
PubMed1989

Contractile properties of cardiac papillary muscle in streptozotocin-diabetic rats and the effects of aldose reductase inhibition.

This study examined the preventative effect of an aldose reductase inhibitor, ponalrestat, on contractile properties of heart left ventricular papillary muscles in rats having streptozotocin induced diabetes for 13 weeks. Both contraction and relaxation were slowed by diabetes. The time to reach peak twitch tension was increased by 21%, and the time to relax to half peak tension was increased by 29% (p less than 0.01, respectively compared to normal control animals). With ponalrestat treatment, the increase in contraction time was only 11%, and relaxation was only slowed by 4% (p less than 0.05 and p less than 0.01, respectively compared to diabetic controls). Diabetes also reduced maximum rates of contraction (13%) and relaxation (19%) and prolonged the time taken to reach peak relaxation rate (36%, p less than 0.01). Ponalrestat had no effect on maximum contraction rates but was particularly effective in normalising relaxation rates (p less than 0.01). Deficiencies with diabetes were noted over a range of stimulation frequencies (0.1-4.0 Hz), and ponalrestat treatment was beneficial except at the highest rates. Diabetes and ponalrestat effects were observed over a temperature range of 25-37 degrees C. Ventricular sorbitol levels showed a 17-fold increase with diabetes (p less than 0.01) and this was reduced by 67% with ponalrestat (p less than 0.01). There were no changes in ventricular myo-inositol. It is possible that ponalrestat treatment prevented a defect in sarcoplasmic reticulum calcium handling which could be responsible in part for the deficits in contraction ability and mainly for the deficits in relaxation ability in diabetic cardiomyopathy, although this remains to be tested directly.

Aldehyde Reductase↗
PubMed1989

Effects of long-term streptozotocin diabetes on the contractile and histochemical properties of rat muscles.

Contractile and histochemical properties of soleus (a slow-twitch muscle) and extensor digitorum longus (EDL, a fast-twitch muscle) were studied in mature rats after 3 months of streptozotocin-induced diabetes. Results were compared with age- and weight-matched controls. Diabetes produced profound wasting of fast muscles and particularly of the fast glycolytic (FG) fibres. Slow muscle fibres, both within the mixed EDL and in soleus, were less atrophied. Strength performance of EDL was reduced by diabetes, but maintained in soleus. Diabetes was without effect on the time to peak tension (TTP) and half-relaxation time (HRT) of EDL. However it produced profound slowing of soleus muscles, particularly of the relaxation phase. Part of the slowing effect of diabetes may be related to a histochemically demonstrable loss of fast oxidative glycolytic (FOG) fibres in soleus. Histochemical staining for the oxidative marker succinic dehydrogenase (SDH) revealed marked disruption of reaction product distribution in soleus, indicating an impairment of oxidative capacity.

Animals↗
PubMed1989

The effect of aldose reductase inhibition on the pattern of nerve conduction deficits in diabetic rats.

Conduction deficits caused by 2-4 months diabetes were examined in one sensory and six motor nerve branches of mature rats. The effect of aldose reductase inhibitor (ponalrestat) treatment was assessed in preventative and reversal studies. The efficacy of 1% dietary myoinositol supplementation was also examined in a 2 month preventative group. Diabetes suppressed a maturation-related increase in conduction velocity in the interosseus nerve supplying foot muscles. This was unaffected by any treatment. Large conduction velocity reductions (22-29%) seen for fast nerves supplying four calf muscles and sensory saphenous nerves were prevented by ponalrestat treatment. In a reversal group, which had 2 months of diabetes followed by 2 months of treatment, restoration of conduction varied between nerves, ranging from 100% in sensory saphenous to 25% in soleus motor branches. Myo-inositol supplementation had little effect. Sciatic nerves accumulated the sugar alcohol sorbitol with diabetes. This was markedly reduced by treatment, and correlated with the conduction velocity improvement. There was a 40% reduction in nerve free myo-inositol levels after 2 months diabetes. Ponalrestat normalized myo-inositol in the short term but failed to do so in 4 month preventative and reversal groups. Myo-inositol treatment did not affect nerve levels. The data implicate the polyol pathway in the diabetic conduction velocity deficits seen in normally fast conducting motor and sensory nerves and suggest that aldose reductase inhibitor action does not depend on restoration of nerve myo-inositol levels.

Aldehyde Reductase↗
PubMed1986

The effects of sorbinil on peripheral nerve conduction velocity, polyol concentrations and morphology in the streptozotocin-diabetic rat.

This study examined the effects of an aldose reductase inhibitor, Sorbinil, on neuropathy over a 6-month period in streptozotocin-diabetic rats. Sorbinil treatment prevented the 10-fold increase in nerve sorbitol found with diabetes. It produced a 60% improvement in tibial nerve motor conduction velocity after 6 months. Morphometric profiles of nerves were also normalized. Axon area was reduced by 14% in untreated diabetic rats compared to age-matched controls, whereas Sorbinil-treated animals showed normal age-related axon growth. Myelin area was increased by 28% in untreated diabetic animals, but was the same as age-matched controls with Sorbinil treatment. Nerve myo-inositol levels were reduced by 45% after three months of untreated diabetes, but were normal after six months. Sorbinil treatment tended to restore myo-inositol levels toward normal over the shorter time period. It was concluded that axon growth retardation is the most likely cause of the conduction deficit seen in long-term experimental diabetes.

Age Factors↗
PubMed1986

Effect of diabetes on motor conduction velocity in different branches of the rat sciatic nerve.

Motor nerve conduction velocity was measured in six branches of the sciatic nerve in streptozotocin-diabetic rats. It was markedly reduced in nerves to the gastrocnemius, soleus, tibialis anterior, and extensor digitorum longus muscles. The branch to the plantaris muscle remained unaffected. In control rats none of these branches showed any evidence of conduction velocity maturation over the 2-month experimental period. Motor nerve conduction velocity to the interosseus muscles of the foot did show a normal maturation effect, which was halted by diabetes. We conclude that large-caliber motor fibers in mature nerves are particularly susceptible to diabetes.

Animals↗
PubMed1982

The photopic spectral sensitivity of a dichromatic teleost fish (Perca fluviatilis).

Spectral sensitivity curves for the freshwater perch were measured using an operant procedure. Sensitivity peaks were found at 530-560 nm and 660-680 nm. Compared with perch cone pigments (P530(2) and P617(2)), the red-shift of the maximum long wave length sensitivity suggested that opponent interactions between the cone types were responsible for the shape of the curve. The absorptions of the lens and yellow cornea were measured, and used to correct the sensitivity curve. It is suggested that the yellow cornea's function depends on its spectral selectivity. Like goldfish, perch show some aberrant high sensitivity around 400 nm.

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PubMedDate not supplied

Corpus cavernosum dysfunction in diabetic rats: effects of combined alpha-lipoic acid and gamma-linolenic acid treatment.

BACKGROUND: The effects of streptozotocin-induced diabetes on nitric oxide (NO)-mediated relaxation of rat corpus cavernosum smooth muscle to neurogenic and endothelial stimulation was examined. The aim was to assess the effects of treatment with low doses of the antioxidant, alpha-lipoic acid, and the omega-6 essential fatty acid, gamma-linolenic acid, either separately or in combination. METHODS: Treatment was preventive from diabetes induction or corrective over 4 weeks after 4 weeks of untreated diabetes. Corpus cavernosum responses were examined in vitro. RESULTS: Neither diabetes nor treatment affected contractile responses to transmural electrical field stimulation of noradrenergic nerves. Stimulation of phenylephrine precontracted cavernosa in the presence of guanethidine and atropine caused relaxation via the nitrergic innervation. Maximum relaxation responses were 40% and 46% decreased after 4 and 8 weeks of diabetes, respectively. alpha-Lipoic acid, gamma-linolenic acid combination treatment fully prevented this deficit, and partially (52%) corrected the effect of 4 weeks of untreated diabetes. Neither alpha-lipoic acid nor gamma-linolenic components alone had significant effects, which suggests that there were synergistic interactions between the drugs. Both 4 and 8 weeks of untreated diabetes reduced maximum endothelium-dependent relaxation of phenylephrine precontracted cavernosa to acetylcholine by approximately 40%. While alpha-lipoic acid or gamma-linolenic acid were ineffective, joint treatment fully prevented and corrected this diabetic endothelial deficit. Neither diabetes nor treatment affected endothelium-independent relaxation to the NO donor, sodium nitroprusside. CONCLUSION: The data show that alpha-lipoic acid and gamma-linolenic acid interact synergistically to improve NO-mediated neurogenic and endothelium-dependent relaxation of corpus cavernosum in experimental diabetes.

Acetylcholine↗
PubMedDate not supplied

Reversal of defective peripheral nerve conduction velocity, nutritive endoneurial blood flow, and oxygenation by a novel aldose reductase inhibitor, WAY-121,509, in streptozotocin-induced diabetic rats.

The main aim was to investigate whether 1 month of aldose reductase inhibitor treatment could correct a deficit in sciatic nerve nutritive blood flow following 1 month of untreated streptozotocin-induced diabetes in rats. Treatment was with two doses of WAY-121,509, both of which completely blocked neuronal sorbitol accumulation. The high dose fully corrected a motor conduction velocity deficit, whereas the low dose caused 51.3% amelioration. Nutritive endoneurial blood flow, monitored by hydrogen clearance, was 43.4% reduced after 1 month of diabetes. This was completely corrected by the high dose of WAY-121,509. In addition, vascular conductance was supranormal and there was a decrease in arteriovenous shunt flow. Low dose treatment caused a 55.6% improvement of the nutritive endoneurial blood flow deficit, paralleling the conduction velocity effect. WAY-121,509 did not alter nerve perfusion in nondiabetic rats. Data from multiple sciatic nerve penetrations by oxygen sensitive microelectrodes revealed a 42.0% deficit in mean endoneurial oxygen tension with diabetes, whereas tensions were in the nondiabetic range for high dose WAY-121,509 treatment. Thus, the data highlight neurovascular actions of aldose reductase inhibition, and suggest that neuronal polyol pathway metabolite levels are a poor predictor of functional efficacy.

Aldehyde Reductase↗
PubMedDate not supplied

Diabetes causes an early reduction in autonomic ganglion blood flow in rats.

Impaired blood flow to peripheral nerve trunks makes a major contribution to the neuropathic complications of diabetes mellitus. Comparatively little attention has been paid to perfusion abnormalities for the cell bodies of origin of the autonomic and sensory nerves, although they are severely affected in diabetic neuropathy. The aim was to examine the time course of changes in superior cervical ganglion (SCG) perfusion in streptozotocin-induced diabetic rats. Ganglion blood flow, measured by hydrogen clearance microelectrode polarography, was approximately 70 ml min(-1) 100 g(-1). One week of diabetes caused a 46% perfusion deficit, which was maintained (54%) over 24 weeks. Thus, an early, profound, and long-lived reduction in ganglion perfusion may deleteriously affect neural cell body function and could contribute to autonomic neuropathy.

Aging↗
PubMedDate not supplied

Effects of diabetes on reactivity of sciatic vasa nervorum in rats.

The aim was to investigate the effects of 2 months of streptozotocin-induced diabetes mellitus in rats on the responses of sciatic vasa nervorum to vasoactive drugs. Changes in perineural blood flow were monitored by laser-Doppler flowmetry during drug superfusion in vivo. Laser-Doppler flux was reduced by 53.3% after 2 months of diabetes. A 38-fold increase in norepinephrine sensitivity was found in diabetic compared to nondiabetic rats. Co-superfusion of norepinephrine and a high dose (100 microM) of the nitric oxide synthase inhibitor, NG-nitro-L-arginine, resulted in 116-fold and 3.6-fold increases in norepinephrine sensitivity in nondiabetic and diabetic rats, respectively, such that dose-response curves for changes in vascular conductance were superimposed. This suggests that the increased norepinephrine sensitivity in diabetes was caused by defective endothelial nitric oxide production or action. After norepinephrine preconstriction, acetylcholine caused dose-dependent increases in vascular conductance, sensitivity being 8.1-fold greater in nondiabetic than diabetic rats. In contrast, endothelium-independent responses to the nitrovasodilator, glyceryl trinitrate, were relatively unaffected by diabetes. Thus, diabetes causes a deficit in nitric oxide mediated endothelium-dependent relaxation of vasa nervorum, resulting in increased vasoconstrictor sensitivity which is likely to impair perfusion and contribute to the pathogenesis of neuropathy.

Animals↗
PubMedDate not supplied

Effect of the aldose reductase inhibitor tolrestat on nerve conduction velocity, Na/K ATPase activity, and polyols in red blood cells, sciatic nerve, kidney cortex, and kidney medulla of diabetic rats.

Long-term prospective studies comparing the effects of conventional and intensive insulin therapy have linked diabetic hyperglycemia to the development of diabetic retinopathy, nephropathy, and neuropathy. The mechanisms through which glucose metabolism leads to the development of these secondary complications, however, are incompletely understood. In animal models of diabetic neuropathy, the loss of nerve function in myelinated nerve fibers has been related to a series of biochemical changes. Nerve glucose, which is in equilibrium with plasma glucose levels, rapidly increases during diabetic hyperglycemia because glucose entry is independent of insulin. This excess glucose is metabolized in large part by the polyol pathway. Increased flux through this pathway is accompanied by the depletion of myo-inositol, a loss of Na/K ATPase activity and the accumulation of sodium. Supportive evidence linking these biochemical changes to the loss of nerve function has come from studies in which aldose reductase inhibitors block polyol pathway activity, prevent the depletion of myo-inositol and the accumulation of sodium and preserve Na/K ATPase activity, as well as nerve function. The kidney and red blood cells (RBCs) are two additional sites of diabetic lesions that have been reported to develop biochemical changes similar to those in the nerve. We observed that polyol levels in the kidney cortex, medulla, and RBCs increased two- to ninefold in rats following 10 weeks of untreated diabetes. Polyol accumulation was accompanied by a 30% decrease in myo-inositol levels in the kidney cortex, but no change in RBCs or the kidney medulla. Na/K ATPase activity was decreased by 59% in RBCs but was unaffected in the kidney cortex or medulla. Aldose reductase inhibitor treatment that preserved myo-inositol levels, Na/K ATPase, and conduction velocity in the sciatic nerve also preserved Na/K ATPase activity in RBCs. Our results suggest that the pathophysiologic mechanisms underlying diabetic neuropathy are different from those of diabetic nephropathy. Our results also suggest that RBCs maybe a surrogate tissue for the assessment of diabetes-induced changes in nerve Na/K ATPase activity.

Aldehyde Reductase↗
PubMedDate not supplied

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 x kg(-1) x 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.

Animals↗
PubMedDate not supplied

Correction of nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition.

Increased p38 mitogen-activated protein kinase (MAPK) in response to stress stimuli, including hyperglycemia, contributes to diabetic somatic neuropathy. However, effects on autonomic nerve and vascular function have not been determined. The aim of this study was to investigate the effects of the p38 MAPK inhibitor, LY2161793, on penile neurovascular function in streptozotocin-induced diabetic mice. Diabetes duration was 6 weeks and intervention LY2161793 treatment was given for the final 2 weeks. In vitro measurements on phenylephrine-precontracted corpus cavernosum revealed a 32% reduction in maximum nitrergic nerve-mediated relaxation with diabetes that was 74% corrected by LY2161793 treatment. Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was 42% attenuated by diabetes and 88% restored by LY2161793. Moreover, treatment partially corrected a diabetic deficit in endothelium-independent relaxation to a nitric oxide donor. Thus, p38 MAPK inhibition corrects nitric oxide-dependent indices of diabetic erectile autonomic neuropathy and vasculopathy, a therapeutic approach potentially worthy of consideration for clinical trials.

Animals↗
PubMedDate not supplied

Potential therapeutic approaches to the treatment or prevention of diabetic neuropathy: evidence from experimental studies.

Recent investigations using experimental models of diabetes mellitus have emphasized the importance of impaired blood flow for the development of nerve dysfunction. Other observations suggest that this may also be the case for patients. A number of studies have revealed that several types of vasodilators can prevent or successfully treat early conduction abnormalities in diabetic rodents. These include alpha 1-adrenoreceptor antagonists, calcium channel blockers, agents that inhibit the renin-angiotensin system, and vasomodulator prostanoids. Other treatments applied to animal models, such as omega-6 essential fatty acids, aldose reductase inhibitors, aminoguanidine which prevents the formation of advanced glycation end-products, and anti-oxidants all appear to have vascular-related effects that lead to improvements in nerve conduction. These findings suggest that endothelial dysfunction and oxidative stress could be important factors in the aetiology of diabetic neuropathy. Studies have also focused on deficits in axon growth and regeneration, their relation to impaired neuronal synthesis and transport of growth-related chemicals, and neuronotrophic abnormalities. Taken together, the data give rise to the notion that an optimal therapeutic strategy could consist of improving the microenvironment of damaged nerve fibres by manipulating nerve blood flow while concurrently encouraging repair with trophic agents.

Aldehyde Reductase↗