Aldose reductase pathway inhibition improved vascular and C-fiber functions, allowing for pressure-induced vasodilation restoration during severe diabetic neuropathy.
Pressure-induced vasodilation, a neurovascular mechanism relying on the interaction between mechanosensitive C-fibers and vessels, allows skin blood flow to increase in response to locally nonnociceptive applied pressure that in turn may protect against pressure ulcers. We expected that severe neuropathy would dramatically affect pressure-induced vasodilation in diabetic mice, and we aimed to determine whether pressure-induced vasodilation alteration could be reversed in 8-week diabetic mice. Control and diabetic mice received no treatment or sorbinil, an aldose reductase inhibitor, or alagebrium, an advanced glycation end product breaker, the last 2 weeks of diabetes. Laser Doppler flowmetry was used to evaluate pressure-induced vasodilation and endothelium-dependent vasodilation after iontophoretic delivery of acetylcholine (ACh). We assessed the nervous function with measurements of motor nerve conduction velocity (MNCV) as well as the C-fiber-mediated nociception threshold. Pressure-induced vasodilation, endothelial response, C-fiber threshold, and MNCV were all altered in 8-week diabetic mice. None of the treatments had a significant effect on MNCV. Although sorbinil and alagebrium both restored ACh-dependent vasodilation, sorbinil was the sole treatment to restore the C-fiber threshold as well as pressure-induced vasodilation development. Therefore, the inhibition of aldose reductase pathway by sorbinil improved vascular and C-fiber functions that allow pressure-induced vasodilation restoration that could limit neuropathic diabetic cutaneous pressure ulcers.
Demiot
Claire
C
Laboratory of Physiology, CNRS, UMR6214, INSERM U771, Medical School, University of Angers, F-49045 Angers, France.
Tartas
Maylis
M
Fromy
Bérengère
B
Abraham
Pierre
P
Saumet
Jean Louis
JL
Sigaudo-Roussel
Dominique
D
D000109:Acetylcholine / Q000502:physiology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D048289:Imidazolidines / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D003668:Pressure Ulcer / Q000188:drug therapy; D014664:Vasodilation / Q000502:physiology*
D004791:Enzyme Inhibitors; D048289:Imidazolidines; D000449:Aldehyde Reductase; C026411:sorbinil; D000109:Acetylcholine