Topical methyl nicotinate-induced skin vasodilation in diabetic neuropathy Antonella Caselli a,b, *, Tarik Hanane a , Brady Jane a , Stephen Carter c , Lalita Khaodhiar a , Aristidis Veves a a Joslin-Beth Israel Deaconess Foot Center, Department of Surgery, Microcirculation Laboratory, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA, USA b Department of Internal Medicine, University of Tor Vergata, Rome, Italy c Biochemics Inc., Danvers, MA, USA Received 9 September 2002; received in revised form 6 November 2002; accepted 13 November 2002 Abstract Objective: To evaluate the vasodilation induced by topical application of methyl nicotinate (MN) and to compare it with the vasodilatory response to acetylcholine (ACh) and sodium nitroprusside (SNP) in healthy subjects and diabetic neuropathic patients. Research design and methods: Ten diabetic patients with peripheral neuropathy (DN) and 10 age- and sex-matched healthy control subjects (C) were enrolled. The vasodilatory response to topical application of 1% MN and a placebo emulsion at the forearm and dorsum of the foot skin at 5, 15, 30, 60 and 120 min was measured using Laser Doppler Perfusion Imaging. The vasodilatory response to iontophoresis of 1% ACh and 1% SNP solutions was also evaluated. Results: The maximal vasodilatory response to ACh, SNP and MN was similar at the forearm and foot level in the diabetic patients. In the control group, the responses to MN, ACh and SNP were similar on the forearm but in the foot, the MN vasodilatory response was higher when compared to the ACh and SNP responses. MN-related vasodilation was present 5 min after the application, reached its peak at 15 – 30 min and declined to pre-application levels 120 min afterward. Conclusions: Topical application of MN at the forearm and foot levels of diabetic neuropathic patients results in skin vasodilation that is comparable to the maximal vasodilation that can be induced by iontophoresis of ACh or SNP and lasts for less than 2 h. Further studies will be required to explore the potential of MN to increase blood flow and to prevent diabetic foot problems in clinical practice. D 2003 Elsevier Inc. All rights reserved. Keywords: Laser Doppler; Neuropathy; Smooth muscle cell; Microcirculation; Diabetic foot 1. Introduction Diabetes mellitus impairs the endothelium-dependent and -independent vasodilation, in both the macrocirculation and the skin microcirculation (Caballero et al., 1999; Mor- ris, Shore, & Tooke, 1995). Endothelial dysfunction is one of the primary pathways that leads to nerve hypoxia and to the development of diabetic neuropathy. Diabetic neuro- pathy itself has an additional detrimental effect on the foot microcirculation (Feldman, Stevens, & Greene, 1997; Veves et al., 1998). The final result of all the above changes is that the diabetic foot fails to mount a satisfactory hyperemic response to injury and is susceptible to ulceration and/or impaired wound healing (Arora, Pomposelli, LoGerfo, & Veves, 2002; Arora et al., 1998). Therapeutic interventions that can improve the skin microcirculation may have a great potential in preventing foot problems in diabetic patients (Mackool, Lowitt, & Dover, 1994). As most neuropathic diabetic patients need to use moisturizing cream for the dry skin of the lower extremity, the addition of a vasodilator that will increase the blood flow may prove of particular help (Pham, Exelbert, Segal-Owens, & Veves, 2002). The ideal vasodilator should provide results that last for a satisfactory period of time and should be devoid of any serious side effects. In the present study, we have tested the vasodilatory effect of methyl nicotinate (MN), an urticant that causes 1056-8727/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1056-8727(02)00256-8 * Corresponding author. Microcirculation Laboratory, Palmer 317, West Campus, One Deaconess Road, Boston, MA 02215, USA. Tel.: +1- 617-632-7075; fax: +1-617-632-7090. E-mail address: aveves@caregroup.harvard.edu (A. Caselli). Journal of Diabetes and Its Complications 17 (2003) 205 – 210