Original Article Aldose Reductase Pathway Inhibition Improved Vascular and C-Fiber Functions, Allowing for Pressure-Induced Vasodilation Restoration During Severe Diabetic Neuropathy Claire Demiot, 1,2 Maylis Tartas, 1,3 Be ´ renge ` re Fromy, 1 Pierre Abraham, 1,3 Jean Louis Saumet, 1,3 and Dominique Sigaudo-Roussel 1 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-in- duced vasodilation in diabetic mice, and we aimed to determine whether pressure-induced vasodilation alter- ation 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 vasodila- tion 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 va- sodilation, 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 func- tions that allow pressure-induced vasodilation restoration that could limit neuropathic diabetic cutaneous pressure ulcers. Diabetes 55:1478 –1483, 2006 D uring long-term diabetes, progressive microan- giopathy contributes to progressive loss of pe- ripheral neurological function, leading to the development of pressure-induced diabetic foot. However, the exact pathway leading to ulceration has not been fully identified, although it is recognized that ulcer- ation may result from microcirculatory failure (1). Up to now assessment of the circulation, the nervous control of sensation, and foot sensitivity to loading are performed to determine the risk of ulceration in the diabetic foot. In contrast, local measurement of the microvascular function is less routinely performed (2). We reported a novel relationship between nerves and vessels involving neural mechanosensitivity and cutane- ous vasodilation, referred to as pressure-induced vasodi- lation (3). The increase in cutaneous blood flow induced by local pressure application delays the occurrence of tissue ischemia, thus protecting the skin against pressure. The mechanism of pressure-induced vasodilation involves pressure sensing by specialized capsaicin sensory neurons that act at the endothelial level to synthesize and release endothelial factors, such as nitric oxide (NO) (3,4), that induce smooth muscle relaxation. Therefore, neurovascu- lar interaction is crucial for pressure-induced vasodilation development. More recently, we reported that pressure-induced vaso- dilation was altered in 1-week diabetic mice with only vascular dysfunction (5), which was correlated with dia- betic patients without neuropathy (6). At the point of clinical diabetes complication detection, significant im- pairments in nerve function may have already appeared and handicapped patients. Therefore, we expected that long-term diabetes in animals with severe neuropathy will dramatically aggravate pressure-induced vasodilation al- teration. In this condition, skin blood flow should drop down directly in response to local applied pressure, lead- ing to early ischemia, which could favor diabetic foot occurrence. Diabetes through hyperglycemia is widely known to be a major factor that leads to microvascular and nervous complications (7). Indeed, hyperglycemia-induced end- organ damage in diabetes is associated with increased flux of glucose through 1) the polyol metabolic pathway (8 –10) and 2) accumulation of advanced glycation end products (AGEs) (11,12), both participating to increase oxidative From the 1 Laboratory of Physiology, Unite ´ Mixte de Recherche (UMR)6214, National Center for Scientific Research (CNRS), Institut National de la Sante ´ et de la Recherche Me ´ dicale (INSERM) U771, Medical School, University of Angers, Angers, France; the 2 Faculty of Pharmaceutical Sciences, University of Angers, Angers, France; and the 3 Centre Hospitalier Universitaire (CHU), Laboratoire d’Explorations Vasculaires, Angers, France. Address correspondence and reprint requests to Dominique Sigaudo-Rous- sel, Laboratory of Physiology, CNRS, UMR6214, INSERM U771, Medical School, University of Angers, Angers, F-49045 France. E-mail: domroussel@ yahoo.fr. Received for publication 3 November 2005 and accepted in revised form 7 February 2006. ACh, acetylcholine; AGE, advanced glycation end product; ARI, aldose reductase inhibitor; MNCV, motor nerve conduction velocity; STZ, streptozo- tocin. DOI: 10.2337/db05-1433 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1478 DIABETES, VOL. 55, MAY 2006