Contribution of nitric oxide to cutaneous microvascular dilation in individuals with type 2 diabetes mellitus

Abstract

Sokolnicki LA, Roberts SK, Wilkins BW, Basu A, Charkoudian N. Contribution of nitric oxide to cutaneous microvascular dilation in individuals with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 292: E314 -E318, 2007. First published September 5, 2006; doi:10.1152/ajpendo.00365.2006.-Microvascular pathophysiology associated with type 2 diabetes mellitus (T2DM) contributes to several aspects of the morbidity associated with the disease. We quantified the contribution of nitric oxide (NO) to the cutaneous vasodilator response to nonpainful local warming in subjects with T2DM (average duration of diabetes mellitus 7 Ϯ 1 yr) and in age-matched control subjects. We measured skin blood flow in conjunction with intradermal microdialysis of N G -nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) or vehicle during 35 min of local warming to 42°C. Microdialysis of sodium nitroprusside (SNP) was used for assessment of maximum cutaneous vascular conductance (CVC). Resting CVC was higher in T2DM subjects at vehicle sites (T2DM: 19 Ϯ 2 vs. control: 11 Ϯ 3%maxCVC; P Ͻ 0.05); this difference was abolished by L-NAME (T2DM: 10 Ϯ 1 vs. control: 8 Ϯ 1%maxCVC; P Ͼ 0.05). The relative contribution of NO to the vasodilator response to local warming was not different between groups (T2DM: 46 Ϯ 4 vs. control: 44 Ϯ 6%maxCVC; P Ͼ 0.05). However, absolute CVC during local warming was ϳ25% lower in T2DM subjects (T2DM: 1.79 Ϯ 0.15 AU/mmHg; controls: 2.42 Ϯ 0.20 AU/mmHg; P Ͻ 0.01), and absolute CVC during SNP was ϳ20% lower (T2DM: 1.91 Ϯ 0.12 vs. control: 2.38 Ϯ 0.13 AU/ mmHg; P Ͻ 0.01). We conclude that the relative contribution of NO to vasodilation during local warming is similar between subjects with T2DM and control subjects, although T2DM was associated with a lower absolute maximum vasodilation. skin blood flow; vasodilation; local warming; thermoregulation THE PANDEMIC GROWTH of type 2 diabetes mellitus (T2DM) has made it increasingly important for clinicians and researchers to understand mechanisms of pathophysiology associated with the disease (19). A well-recognized area of dysfunction involves impaired microvascular control and reduced vasodilator responsiveness (2,10,16,18). For example, forearm vasodilator responses to brachial arterial infusion of endotheliumdependent or -independent vasodilators are diminished in patients with T2DM (18).It is unclear the extent to which vasodilator responsiveness in the cutaneous circulation is impaired in individuals with T2DM. Local application of ACh and nitroprusside in the skin caused less vasodilation [suggesting impaired nitric oxide (NO)-dependent vasodilation] in some groups of diabetic subjects (2), but not in others (16). In some studies, only individuals with T2DM involving significant peripheral neuropathy exhibited diminished cutaneous vasodilation (1, 16), whereas, in others (2, 17), T2DM subjects without signs of neuropathy showed decreased vasodilation in the skin. The diversity in results could reflect the variability inherent in the disease itself, inclu...

Aerobic training increases skin perfusion by a nitric oxide mechanism in type 2 diabetes

“…6 This underlying defect was present despite normal increases in interstitial NO in the foot dorsum under stimulated conditions, suggesting that NO is either ineffective or not significantly involved in this acute response. 3 A prior bout of acute maximal exercise also appears to improve responsiveness to local heating of the dorsal foot in active individuals with T2DM, but not in their sedentary counterparts. 7 These previous studies have suggested that participation in chronic aerobic training may regulate stimulated (heated) dorsal foot skin perfusion through alterations in either PG or EDHF pathways, given that interstitial cutaneous NO levels (measured via a subcutaneous probe) are not apparently significantly depressed by the presence of T2DM.…”

“…Among the vasodilators are nitric oxide (NO), prostacyclins, prostaglandins (PG), bradykinin, and endothelial-derived hyperpolarizing factor (EDHF), which appear to vary in importance depending on their cutaneal location. [1][2][3][4] Delivery of nutrients, removal of metabolic waste, temperature regulation, and healing are all affected by maintenance of skin perfusion, but when type 2 diabetes mellitus (T2DM) has an underlying presence, alterations in foot skin perfusion may result in a greater risk of ulceration and poor cutaneous healing. 3 Colberg et al Previously, it has been postulated that participation in chronic aerobic training (ie, regular exercise for longer than six months) improves stimulated dorsal foot skin perfusion through local release of vasodilatory compounds including NO, PG, and EDHF.…”

“…[1][2][3][4] Delivery of nutrients, removal of metabolic waste, temperature regulation, and healing are all affected by maintenance of skin perfusion, but when type 2 diabetes mellitus (T2DM) has an underlying presence, alterations in foot skin perfusion may result in a greater risk of ulceration and poor cutaneous healing. 3 Colberg et al Previously, it has been postulated that participation in chronic aerobic training (ie, regular exercise for longer than six months) improves stimulated dorsal foot skin perfusion through local release of vasodilatory compounds including NO, PG, and EDHF. 5,6 A prospective study reported a significantly lower skin perfusion during local heating to 44 o C in the dorsal feet of sedentary individuals with T2DM compared with active people without diabetes.…”

Exploring the oxygen challenge test as a microcirculation evaluation model

“…[3][4][5] Tem sido ainda utilizada como um modelo de investigação em vários estados patológi-cos como a diabetes do tipo II, [6] a doença vascular periférica [1] e a hipertensão [7] . No contexto clínico as variáveis microcirculatórias são utilizadas como ferramentas de prognóstico para avaliar a isquémia grave dos membros [8] , a evolução da ferida cutânea [9] e, até para determinar o nível de amputação.…”

“…[3][4][5] It has been used as a research model in various diseases such as type II diabetes [6] peripheral vascular disease [1] and hypertension. [7] Clinically, microcirculatory variables are also used as prognostic tools to assess severe limb ischemia, [8] wound outcome [9] and also to eventually determine the amputation level.…”