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

Kappelle, A.C.; Biessels, Geert Jan; Buren, T. van; Erkelens, D. W.; Wildt, Dick J. De; Gispen, Willem Hendrik

doi:10.1016/0014-2999(93)90619-s

Cited by 26 publications

(25 citation statements)

References 37 publications

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“…For the former, this agrees with previously reported measurements over a 4-h period [44]. The deficit in laser-Doppler flux with diabetes also agrees with several reports [6,8,43,[45][46][47][48]. It was further suggested that reduced blood flow in diabetic rats is only found when they are ketotic [49].…”

Section: Methodssupporting

confidence: 92%

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

et al. 1997

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Elevated polyol pathway activity has been implicated in the development of diabetic complications, including neuropathy [1]. In diabetic models, inhibitors of the first enzyme in the pathway, aldose reductase, prevent or correct nerve conduction velocity (NCV) and regeneration deficits [2][3][4][5][6][7][8][9][10][11][12][13]. Clinical trials of aldose reductase inhibitors (ARIs) have shown modest improvements in neurological symptoms, NCV, sensory measures, and an increase in nerve fibre regeneration [14-17] despite a less effective polyol pathway blockade than was found necessary for functional effects in animal studies [6,10,18].Several hypotheses have been advanced to explain the action of ARI. Some putative mechanisms are primarily dependent on the first half of the polyol pathway, conversion of glucose to sorbitol by aldose Diabetologia (1997) 40: 271-281 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 Summary 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-135 706, (250 mg ⋅ kg −1 ⋅ day −1 ) and an ARI, WAY-121 509, (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-135 706 whereas WAY-121 509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135 706 and WAY-121 509, 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-121 509, but WAY-135 706 was completely ineffective. A 48.6 % diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121 509, but was unaltered by WAY-135 706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135 706 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. [Diabetologia (1997) 40: ...

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Section: Methodssupporting

confidence: 92%

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

et al. 1997

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“…The deficit of approximately 50% in nerve laser Doppler flux in diabetic rats is consistent with results from other research groups who have either used Doppler flowmetry (Yasuda et al, 1989;Maxfield et al, 1993;Kappelle et al, 1993;Cameron et al, 1994b) or other methods Monafo et al, 1988;Cameron et al, 1991;Hotta et al, 1992) to estimate nerve perfusion in experimental diabetes. The validity of Doppler flowmetry as an index of nerve blood flow requires comment and, in the aforementioned papers (Stevens et al, 1993b;, we discussed the limitations and fidelity of the technique.…”

Section: Acute Bosentan Administrationsupporting

confidence: 87%

Effects of endothelin receptor antagonism with bosentan on peripheral nerve function in experimental diabetes

Stevens

Tomlinson

1995

British J Pharmacology

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1 The effects of the non-selective endothelin (ET) receptor (ETA/ETB) antagonist, bosentan, on sciatic nerve dysfunction in experimental diabetes were investigated. 2 Rats with 5-6 weeks untreated streptozotocin-diabetes exhibited characteristic slowed motor nerve conduction velocity (mean ± s.d., 36.6 ± 3.4 m s-') and nerve laser Doppler flux (197 ± 64 arbitrary units) compared to age-matched control animals (42.7 ± 2.4 m s-' and 398 ± 77 arbitrary units, respectively). Preventative treatment of diabetic rats with bosentan at 100 mg kg-' day-' p.o. attenuated both these deficits (39.7 ± 3.0 m s-' and 305 ± 56 arbitrary units, respectively) without affecting mean arterial pressure.3 In control and untreated diabetic rats, ET-1, 1 nmol kg-' i.v., caused an initial hypotension (duration, 30 ± 13 and 26 ± 9 s, respectively; change in mean arterial pressure, -27 ± 13 and -25 ± 7 mmHg, respectively) followed by prolonged hypertension (change in mean arterial pressure, 52 ± 18 and 31 ± 5 mmHg, respectively). Effectiveness of the chronic bosentan treatment was demonstrated by inhibition of the hypotensive response to ET-1 in treated diabetic rats (duration, 5 ± 2 s; change in mean arterial pressure, -4 + 2 mmHg) although the hypertension was unaltered (change in mean arterial pressure, 32 + 9 mmHg). 4

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“…Thus, nerve ischaemia and endoneurial hypoxia have been reported in association with diabetic neuropathy in patients (see Tesfaye et al, 1994, for a recent review). The phenomenon has been modelled in diabetic rats and most studies on nerve blood flow or its indirect estimation via laser Doppler velocimetry report a reduction of about 50% in the sciatic nerves of rats with either streptozotocin-induced (Tuck et al, 1984;Monafo et al, 1988;Cameron et al, 1991;Kappelle et al, 1993;Stevens et al, 1993b) or genetic (Stevens et al, 1994) diabetes mellitus.…”

Section: Introductionmentioning

confidence: 99%

Deficient nitric oxide responsible for reduced nerve blood flow in diabetic rats: effects of L‐NAME, L‐arginine, sodium nitroprusside and evening primrose oil

Omawari

Dewhurst

et al. 1996

British J Pharmacology

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1 This study examined the potential role of impaired nitric oxide production and response in the development of endoneurial ischaemia in experimental diabetes. Rats were anaesthetized (Na pentobarbitone 45 mg kg-', diazepam 2 mg kg-') for measurement of sciatic nerve laser Doppler flux and systemic arterial pressure. Drugs were administered into the sciatic endoneurium via a microinjector attached to a glass micropipette. 2 In two separate studies comparing diabetic rats (streptozotocin-induced; 8-10 wk duration) with controls, nerve Doppler flux in diabetic rats (Study 1, 116.6+40.4 and Study 2, 90.1+34.7 (s.d.) in arbitrary units) was about half that measured in controls (219.6+52.4 and 212.8+95.5 respectively; P<0.005 for both). There were no significant differences between the two in systemic arterial pressure. 3 Inhibition of nitric oxide production by microinjection of 1 nmol L-NAME into the endoneurium halved flux in controls (to 126.3+41.3 in Study 1 and 102.1+38.9 in Study 2; both P<0.001), with no significant effect in diabetic rats, indicating markedly diminished tonic nitric oxide production in the latter. D-NAME was without effect on nerve Doppler flux. 4 L-Arginine (100 nmol), injected after L-NAME, markedly increased flux in controls (by 65.8% (P<0.03) and 97.8% (P<0.01) in the two studies) and by proportionally similar amounts in diabetic rats [75.8% (P<0.001) and 60.2% (P<0.02)]. The nitro-donor, sodium nitroprusside (SNP; 10 nmol) had similar effects to L-arginine in both groups (increases of 66.0% in controls and 77.5% in diabetics; both P<0.002). 5 A second diabetic group, treated with evening primrose oil performed exactly like control rats in respect of responses to L-NAME, L-arginine and SNP. At the end of all measurements blood was collected for plasma glucose measurement by a glucose oxidase assay kit, as defined elsewhere (Stevens & Tomlinson, 1993;Karasu et al., 1995). Endoneurial drug administrationA glass micropipette (tip diameter 10-15 im) was advanced into the endoneurium of the sciatic nerve using a X-Y-Z micropositioner; this pipette was connected to a Drummond Microdispenser (Laser Labs, Southampton, U.K.). The sciatic nerve was impaled about 1-2 mm proximal to the site at which LDF was monitored. Resting cardiovascular parameters were then recorded in steady-state. In some rats, saline (1 ml) was injected to demonstrate that the physical effect of injection was insignificant and short-lasting (<5 min). Infusion of L-NAME (1 nmol in 1 Ml) was made over 5 min to inhibit the production of nitric oxide. Approximately 30 min later L-arginine (100 nmol in 1 Ml) was infused in some of the rats to reverse the effect of L-NAME. In the remaining animals, L-NAME was followed after about 30 min with sodium nitroprusside (10 nmol in 1 Ml) to examine the response of the guanyl cyclase system to a nitro-donor. Both of these infusions were also made over 5 min. Statistical analysisAll data are presented as means + 1 standard deviation. Acute drug effects were evaluated by comparison withi...

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

Cited by 26 publications

References 37 publications

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

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

Effects of endothelin receptor antagonism with bosentan on peripheral nerve function in experimental diabetes

Deficient nitric oxide responsible for reduced nerve blood flow in diabetic rats: effects of L‐NAME, L‐arginine, sodium nitroprusside and evening primrose oil

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