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

Stevens, Elizabeth; Tomlinson, David R.

doi:10.1111/j.1476-5381.1995.tb15888.x

Cited by 39 publications

(21 citation statements)

References 47 publications

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“…Moreover, nerve laser Doppler flux was reduced in the untreated diabetic rats, relative to control animals, in both experiments, confirming earlier reports of decreases in experimental diabetes (Stevens et al, 1993(Stevens et al, , 1994aKappelle et al, 1993;Yasuda et al, 1989;Maxfield et al, 1993;Karasu et al, 1995;Stevens and Tomlinson, 1995;Cameron et al, 1994a;Calcutt et al, 1994). Reductions of nerve blood flow in diabetic rats have also been found with other techniques, such as hydrogen clearance (Tuck et al, 1984;Cameron et al, 1991).…”

Section: Discussionsupporting

confidence: 88%

“…Support for a vascular mechanism is centred on clinical and experimen-tal studies, showing reduced endoneurial oxygen tension (Tuck et al, 1984;Newrick et al, 1986) and impaired nerve blood flow (Tuck et al, 1984;Cameron et al, 1991;Stevens et al, 1993;Kappelle et al, 1993;Tesfaye et al, 1993). Furthermore, treatment of diabetic rats with vasoactive agents can ameliorate both nerve blood flow and conduction velocitity deficits (for example, Stevens et al, 1993;Kappelle et al, 1993Kappelle et al, , 1994Yasuda et al, 1989;Maxfield et al, 1993;Cameron et al, 1994b;Karasu et al, 1995;Stevens and Tomlinson, 1995). The development of diabetic neuropathy in humans is associated with diabetes duration and metabolic control (Pirart, 1978a,b) and can be attenuated by intensive insulin treatment (The Diabetes Control and Complications Study Group, 1993;Amthor et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Insulin partially reverses deficits in peripheral nerve blood flow and conduction in experimental diabetes

Biessels¹,

Stevens²,

Mahmood³

et al. 1996

Journal of the Neurological Sciences

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Decreased nerve blood flow may be a pathogenetic factor in diabetic neuropathy. Previously it was shown that insulin treatment, commenced at the onset of streptozotocin-diabetes, prevents the development of a nerve blood flow deficit in the diabetic rat. The present study sought to determine the effect of short-term (one month) and acute (one hour) insulin reversal treatment on nerve blood flow deficits in streptozotocin-diabetes. Sciatic nerve blood flow was assessed using laser Doppler flowmetry. Treatment was initiated after one month of diabetes. One month of reversal insulin treatment ameliorated nerve laser Doppler flux (NDF) deficits; in untreated diabetic rats NDF was 51% of that in control animals (P < 0.01) in insulin-treated diabetic rats NDF was 85% of control values (P < 0.01 vs. untreated diabetic, P < 0.05 vs. control). In association with blood flow increases, we found a significant amelioration of motor (P < 0.05 vs. untreated diabetic) and sensory (P < 0.01 vs. untreated diabetic) nerve conduction velocities but not of exaggerated resistance to hypoxic conduction block. Insulin partially reversed hyperglycaemia and sciatic nerve polyol and sugar levels. In a second experiment, in rats with one month of diabetes, acute infusion of insulin led to a 47% (P < 0.001 vs. pre-insulin values) reduction of plasma glucose. This fall in plasma glucose was accompanied by a 38% (P < 0.05 vs. pre-insulin values) increase in NDF. Sensory nerve conduction velocity was marginally increased (6%, P < 0.05 vs. pre-insulin values) after insulin infusion, but motor conduction velocity was not. The data indicate that insulin can partially reverse deficits in nerve blood flow and conduction in diabetic rats.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Insulin partially reverses deficits in peripheral nerve blood flow and conduction in experimental diabetes

Biessels¹,

Stevens²,

Mahmood³

et al. 1996

Journal of the Neurological Sciences

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“…Moreover, sciatic nerve motor conduction deficits in diabetic rats were corrected by an ET A antagonist, in association with increases in sciatic nutritive endoneurial blood flow [55]. Non-selective ET A /ET B blockade failed, however, to evoke similar actions [56], indicating that the addition of ET B blockade might blunt the beneficial effects of ET A antagonism. Moreover, the addition of an angiotensin AT 1 receptor antagonist to diabetic rats already treated with an ET A antagonist conferred synergistic beneficial effects on nerve conduction [57].…”

Section: In Vivo Haemodynamic Studiesmentioning

confidence: 97%

Endothelin: emerging role in diabetic vascular complications

1999

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The endothelin (ET) family consists of three 21-amino acid peptides designated ET-1, 2]. The biological actions of the ETs are primarily mediated by two distinct, G-protein-coupled receptor subtypes designated ET A and ET B [2]. Endothelin A receptors have a higher affinity for ET-1 and ET-2 than ET-3 and the ET B receptor binds all three isoforms with equal affinity. Translation of preproET mRNA generates preproET, which is converted to big ET and finally cleaved by ET converting enzyme (ECE) to facilitate production of biologically active peptide. Endothelin-1 released by vascular endothelial cells exerts an autocrine influence by promoting vasodilatation, subsequent to activation of ET B receptors located on endothelial cells. It also exerts a paracrine effect on adjacent vascular smooth muscle cells (VSMC) in evoking vasoconstrictor and mitogenic actions by activation of both ET A and ET B receptors. The primary target of ET-1 is the vasculature where it evokes transient vasodilatation mediated by endothelial ET B receptors, followed by slow-onset and sustained contraction mediated by ET A and ET B receptors located on VSMC. The functional response to ET-1 varies throughout different tissues and vascular beds due to differences in distribution and expression of these two receptor subtypes. Endothelin-1 Diabetologia (1999) AbstractSince the discovery of endothelin-1 as the most potent endothelial-derived vasoconstrictor/mitogenic peptide a decade ago, considerable evidence has implicated this peptide in various cardiovascular disease states, including diabetes mellitus. Plasma and tissue concentrations of endothelin-1 as well as responses to the peptide are changed in various forms of the disease in humans and animals. Endothelin activity is also altered in atherosclerotic and ischaemic disease, nephropathy, retinopathy, erectile dysfunction, and neuropathy, many of the well-known complications of diabetes. Striking new evidence shows that antagonists of the endothelin system might beneficially affect and potentially overcome some of these complications. Despite this, lack of direct proof of causation makes this peptide's role in the disease uncertain. This review examines the current state of thought on the role of endothelin in diabetes and in the complications of the disease as well as the likely roles of altered metabolic variables in modulating endothelin-1 concentrations and its activity. It is concluded that although alterations in endothelin-1 release and action are clearly associated with the diabetic state, further studies using inhibitors of the endothelin system are warranted to determine its precise role in the complications of the disease. [Diabetologia (1999

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“…One hypothesis suggests that decreased nerve blood flow provokes the conduction impairment and this is supported by data from animal studies, including the parallel development of the two phenomena in diabetic rats; 8,9 the development of a similar conduction impairment in centrally hypoxaemic non-diabetic rats 10 and the prevention of the conduction deficit in diabetic rats by a range of drugs which share the capacity to increase peripheral blood flow as their only common denominator. [11][12][13][14][15] Direct endoneurial microinjection of drugs, which manipulate the production and effect of nitric oxide, indicates strongly that nerve blood flow in normal rats is heavily dependent on tonic nitric oxide production and that the latter is virtually absent in diabetic rats. 16 The conduction deficit in diabetic rats is prevented by inhibition of aldose reductase, the first enzyme of the polyol pathway.…”

Section: Introductionmentioning

confidence: 97%

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

et al. 1998

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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.

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

Cited by 39 publications

References 47 publications

Insulin partially reverses deficits in peripheral nerve blood flow and conduction in experimental diabetes

Insulin partially reverses deficits in peripheral nerve blood flow and conduction in experimental diabetes

Endothelin: emerging role in diabetic vascular complications

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

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