The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

Diabetologia, Dec 1994

N. E. Cameron, K. C. Dines, M. A. Cotter

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The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

Diabetologia The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats N.E. Cameron 0 K. C. Dines 0 M.A. Cotter 0 0 Department of Biomedical Sciences,University of Aberdeen , Scotland , UK Summary Abnormal vascular endothelium function may contribute to the reduced nerve perfusion implicated in the aetiology of neuropathy in diabetes mellitus. The aim was to test the hypothesis that a powerful vasoconstrictor, endothelin-1, could be involved in nerve dysfunction in streptozotocin-diabetic rats. After 6 weeks of untreated diabetes, rats were implanted with osmotic minipumps which continuously delivered the endothelin-1 antagonist, BQ-123, to the circulation via a jugular vein cannula. Sciatic motor conduction velocity, monitored serially, was increased after 4 days, treatment (p = 0.028), and reached asymptote by 9-11 days (p = 0.0001), when the degree of amelioration was approximately 60 % of the initial diabetic deficit. Treatment of non-diabetic rats for 13 days with BQ-123 had no significant effect on motor conduction velocity. Sensory saphenous nerve conduction velocity was measured acutely after 20 days, BQ-123 treatment. The amelioration of a sensory deficit was approximately 80 % (p < 0.001); Neuropathy; nerve conduction; nerve blood flow; endothelin-1; vascular endothelium; hypoxia; streptozotocin; diabetic rat - 9 Springer-Verlag 1994 A n early reduction in peripheral nerve blood flow and consequent endoneurial hypoxia [ 1, 2 ] in experimental diabetes mellitus leads to the rapid developm e n t of diminished nerve conduction velocity (NCV) and increased resistance to ischaemic conducAbbreviations: EDs0, 50 % effective dose; EMG, electromyogram; ET, endothelin-1; NCV, nerve conduction velocity; NO, nitric oxide. the resultant conduction velocity value was not significantly different from that of a non-diabetic control group. After 20 days, treatment, sciatic nutritive endoneurial blood flow was measured by microelectrode polarography and hydrogen clearance. A 48 % deficit with untreated diabetes (p < 0.001) was 64 % ameliorated by BQ-123 treatment (p < 0.001). In non-diabetic rats, BQ-123 treatment had no effect on blood flow. We conclude that endothelin-1 does not seem to be involved in the control of nerve blood flow in non-diabetic rats; however, it makes a major contribution to the perfusion deficit in experimental diabetes. This has deleterious consequences for nerve conduction, and it is possible that endothelin-1 receptor blockade may have therapeutic potential in diabetic patients. [Diabetologia (1994) 37: 1209-1215] tion failure [ 3, 4 ]. Similar subclinical functional indicators are found in newly-diagnosed diabetic patients [ 5, 6 ]. Endoneurial hypoxia and reduced blood flow are also present in patients with established neuropathy [ 7-9 ]; therefore it is likely that neurovascular effects play a major role in the aetiology of this diabetic complication. Abnormalities of and damage to vascular endothelium contribute to diabetic microangiopathy [10. 16]. Thus, prostacyclin release is decreased in experimental diabetes [ 17 ] and in patients [ 18 ] because of reduced substrate availability as a consequence of impaired o)-6 essential fatty acid metabolism [ 19, 20 ]. In addition, the synthesis or action of nitric oxide (NO) is diminished [ 10-14 ], and activity in the c o a g u l a t o r y s y s t e m is i n c r e a s e d [21]. T o g e t h e r , these result in loss o f local v a s o d i l a t i o n , a n d i n c r e a s e d t h r o m b o s i s f o r m a t i o n w h i c h c o n t r i b u t e to n e r v e i s c h a e m i a [ 22 ]. I n c r e a s e d L D L a n d p a r t i c u l a r l y its oxidised a n d g l y c a t e d f o r m s m a y p l a y a m a j o r role in d a m a g i n g t h e e n d o t h e l i u m [ 23-25 ]. E n d o t h e l i a l d a m a g e a n d tissue h y p o x i a c a u s e i n c r e a s e d r e l e a s e o f a third factor, the p o t e n t v a s o c o n s t r i c t o r p e p t i d e , e n d o t h e l i n - 1 ( E T ) [ 26, 27 ]. P l a s m a E T levels are elev a t e d in several v a s c u l a r disease states, including t h o s e in d i a b e t i c p a t i e n t s a n d rats [ 28-30 ]. A l t h o u g h t h e c a r d i o v a s c u l a r significance o f e l e v a t e d p l a s m a E T is u n k n o w n , levels are p r o b a b l y t o o low t o e x e r t a p r o f o u n d g e n e r a l v a s c u l a r effect. H o w e v e r , p l a s m a E T is d e r i v e d f r o m a n " o v e r f l o w " effect, reflecting g r e a t l y e n h a n c e d synthesis at the local tissue level [27]. T h e r e is i n c r e a s e d E T r e l e a s e b y the e n d o t h e l i u m o f m e s e n t e r i c vessels in d i a b e t i c rats [ 29 ]. I f this also o c c u r s in n e r v e v a s c u l a r supply, the likely effect is vas o c o n s t r i c t i o n a n d r e d u c e d b l o o d flow. Thus, the aim was to e x a m i n e w h e (...truncated)


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N. E. Cameron, K. C. Dines, M. A. Cotter. The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats, Diabetologia, 1994, pp. 1209-1215, Volume 37, Issue 12, DOI: 10.1007/BF00399794