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
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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)