The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats.
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); 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.
Cameron
N E
NE
Department of Biomedical Sciences, University of Aberdeen, Scotland, UK.
Dines
K C
KC
Cotter
M A
MA
D000704:Analysis of Variance; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010525:Peripheral Nerves / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)