sorbinil and Pressure-Ulcer

Pressure-induced vasodilation (PIV) allows skin blood flow to increase in response to locally applied pressure and may be protective against pressure ulcers. We previously showed that PIV was absent in 1-week diabetic mice exhibiting no neuropathy. Our aim was to determine whether the diabetes-induced PIV alteration could be prevented.. Diabetic mice received no treatment or a daily treatment with either sorbinil, alagebrium or alpha-lipoic acid (LPA) for 1 week. Laser Doppler flowmetry was used to evaluate PIV as well as endothelium-dependent vasodilation following iontophoretic delivery of acetylcholine (ACh). The effect of each treatment on oxidative stress was examined by plasma 8-isoprostane assay. LPA was the sole treatment to prevent both PIV and ACh vasodilation alterations, with a significant reduction of oxidative stress in diabetic mice. Both PIV and ACh-vasodilation were abolished in LPA-treated diabetic mice following injection of Nomega-nitro-L-arginine (p<0.05). In contrast, alagebrium and sorbinil prevented neither diabetes-induced PIV abolition nor endothelial alteration.. LPA treatment significantly reduced the oxidative stress and was able to preserve endothelial nitric oxide availability in the cutaneous microcirculation and then to preserve the PIV response in diabetic mice. LPA treatment could play a key role in limiting the risk of pressure-induced cutaneous ulcer during diabetes.

Topics: Acetylcholine; Aldehyde Reductase; Animals; Antioxidants; Biomarkers; Diabetes Mellitus; Dinoprost; Imidazolidines; Laser-Doppler Flowmetry; Male; Mice; Microcirculation; Nitric Oxide Synthase; Nitroarginine; Oxidative Stress; Pressure; Pressure Ulcer; Regional Blood Flow; Skin; Thioctic Acid; Vasodilation; Vasodilator Agents

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.

Topics: Acetylcholine; Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Imidazolidines; Male; Mice; Nerve Fibers; Pressure Ulcer; Vasodilation