Endothelial nitric oxide synthase mediates cutaneous vasodilation during local heating and is attenuated in middle-aged human skin

Abstract

Local skin heating is used to assess microvascular function in clinical populations because NO is required for full expression of the response; however, controversy exists as to the precise NO synthase (NOS) isoform producing NO. Human aging is associated with attenuated cutaneous vasodilation but little is known about the middle aged, an age cohort used for comparison with clinical populations. We hypothesized that endothelial NOS (eNOS) is the primary isoform mediating NO production during local heating, and eNOS-dependent vasodilation would be reduced in middle-aged skin. Vasodilation was induced by local heating (42°C) and during acetylcholine dose-response (ACh-DR: 0.01, 0.1, 1.0, 5.0, 10.0, 50.0, 100.0 mmol/l) protocols. Four microdialysis fibers were placed in the skin of 24 men and women; age cohorts were 12 middle-aged (53 ± 1 yr) and 12 young (23 ± 1 yr). Sites served as control, nonselective NOS inhibited [N(G)-nitro-l-arginine methyl ester (l-NAME)], inducible NOS (iNOS) inhibited (1400W), and neuronal NOS (nNOS) inhibited (N(ω)-propyl-l-arginine). After full expression of the local heating response, l-NAME was perfused at all sites. Cutaneous vascular conductance was measured and normalized to maximum (%CVC(max): Nitropress). l-NAME reduced %CVCmax at baseline, all phases of the local heating response, and at all ACh concentrations compared with all other sites. iNOS inhibition reduced the initial peak (53 ± 2 vs. 60 ± 2%CVC(max); P < 0.001); however, there were no other differences between control, nNOS-, and iNOS-inhibited sites during the phases of local heating or ACh-DR. When age cohorts were compared, NO-dependent vasodilation during local heating (52 ± 6 vs. 68 ± 4%CVC(max); P = 0.013) and ACh perfusion (50 mmol/l: 83 ± 3 vs. 93 ± 2%CVC(max); 100 mmol/l: 83 ± 4 vs. 92 ± 3%CVC(max); both P = 0.03) were reduced in middle-aged skin. There were no differences in NOS isoform expression obtained from skin biopsy samples between groups (all P > 0.05). These data suggest that eNOS mediates the production of NO during local heating and that cutaneous vasodilation is attenuated in middle-aged skin.

Evidence of microvascular dysfunction in patients with cystic fibrosis

“…Postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh), in combination with laser technology, have each been used to evaluate microvascular function in humans. While PORH is partly dependent on prostanoids and NO has a less crucial role (21,58), the plateau phase of LTH is considered to be mediated principally by NO (27,28,44), and the response to ACh iontophoresis stimulates the activation of different factors, including NO, cyclooxygenase, prostanoids, and endotheliumderived hyperpolarizing factor-dependent pathways (6,20,33). Accordingly, the combination of these three protocols can provide a comprehensive assessment of microvascular function that includes evaluation of the microvascular hyperemic response by different mechanisms.…”

“…Cutaneous iontophoresis with ACh has previously been used to investigate microvascular function (47,49). The infusion of ACh across the skin and into the intradermal space using an electrical charge promotes the activation of NO, although the larger response seems to be mediated by prostanoids (6,20,33). Findings from the present study demonstrate that patients with CF exhibit a significantly reduced cutaneous vasodilation to ACh compared with control subjects (Table 3).…”

Autonomic thermoregulatory dysfunction in neurofibromatosis type 1

“…During body hyperthermia states, physiological peripheral vasodilation mediated by neural and local (endothelial function) factors shifts part of the cardiac output to the skin surface for heat dissipation. Therefore, skin blood flow has a key role in normal thermoregulation and any disruption in its neural or/and local control may lead to impaired thermoregulation 27,28,29 . It is possible that some degree of endothelial dysfunction observed in NF1 patients 30 could contribute to the NF1-reduced vascular thermal response in the present study.…”

Forearm cutaneous vascular and sudomotor responses to whole body passive heat stress in young smokers

“…Dry nitrogen gas was supplied through the capsule at a rate of 0.3 l/min. The absolute humidity (g/m 3 ) and ambient temperature from the effluent air of the capsule were monitored by a humidity and temperature sensor (HMT333; Vaisala, Woburn, MA), and local sweat rate (LSR; mg·cm Ϫ2 ·min Ϫ1 ) was calculated as LSR ϭ [(flow rate in mg 3 /min·absolute humidity in g/m 3 ) Ϭ (capsule surface area in cm…”