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Clinical Trial
. 2008 Jul;295(1):H123-9.
doi: 10.1152/ajpheart.00082.2008. Epub 2008 May 9.

Endothelial nitric oxide synthase control mechanisms in the cutaneous vasculature of humans in vivo

Dean L Kellogg Jr  1 , Joan L Zhao, Yubo Wu
Affiliations
Clinical Trial

Endothelial nitric oxide synthase control mechanisms in the cutaneous vasculature of humans in vivo

Dean L Kellogg Jr et al. Am J Physiol Heart Circ Physiol. 2008 Jul.

Abstract

Nitric oxide (NO) participates in locally mediated vasodilation induced by increased local skin temperature (T(loc)) and in sympathetically mediated vasodilation during whole body heat stress. We hypothesized that endothelial NOS (eNOS) participates in the former, but not the latter, response. We tested this hypothesis by examining the effects of the eNOS antagonist N(G)-amino-l-arginine (l-NAA) on skin blood flow (SkBF) responses to increased T(loc) and whole body heat stress. Microdialysis probes were inserted into forearm skin for drug delivery. One microdialysis site was perfused with l-NAA in Ringer solution and a second site with Ringer solution alone. SkBF [laser-Doppler flowmetry (LDF)] and blood pressure [mean arterial pressure (MAP)] were monitored, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF / MAP). In protocol 1, T(loc) was controlled with LDF/local heating units. T(loc) initially was held at 34 degrees C and then increased to 41.5 degrees C. In protocol 2, after a normothermic period, whole body heat stress was induced (water-perfused suits). At the end of both protocols, 58 mM sodium nitroprusside was perfused at both microdialysis sites to cause maximal vasodilation for data normalization. In protocol 1, CVC at 34 degrees C T(loc) did not differ between l-NAA-treated and untreated sites (P > 0.05). Local skin warming to 41.5 degrees C T(loc) increased CVC at both sites. This response was attenuated at l-NAA-treated sites (P < 0.05). In protocol 2, during normothermia, CVC did not differ between l-NAA-treated and untreated sites (P > 0.05). During heat stress, CVC rose to similar levels at l-NAA-treated and untreated sites (P > 0.05). We conclude that eNOS is predominantly responsible for NO generation in skin during responses to increased T(loc), but not during reflex responses to whole body heat stress.

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Figures

Fig. 1.
Fig. 1.
Protocol 1: local skin warming. Two microdialysis sites were used: one was perfused with Ringer solution alone, and the other was perfused with 5 mM NG-amino-l-arginine (l-NAA) in Ringer solution (initiated at 0 min). During the initial phase, local temperature (Tloc) of microdialysis sites was held at 34°C. Local skin heating was then performed to raise Tloc to 41.5°C at both microdialysis sites. Finally, perfusates at both sites were changed to 56 mM sodium nitroprusside (SNP) to cause maximal vasodilation. An initial peak in cutaneous vascular conductance (CVC) was followed by a prolonged plateau at both sites. An initial peak was not observed in all studies.
Fig. 2.
Fig. 2.
Protocol 2: whole body heat stress. Two microdialysis sites were used. After an initial normothermic control period when both microdialysis sites were perfused with Ringer solution, perfusate at one site was changed to 5 mM l-NAA in Ringer solution (initiated at 5 min). Perfusion with Ringer solution alone was maintained at the other site. After ∼45 min of perfusion with l-NAA, skin temperature (Tsk) was decreased to induce whole body cold stress. Tsk was then increased to induce whole body heat stress, after which the subjects were cooled to normothermia. In this example, exogenous ACh was administered to both untreated and l-NAA-treated sites following heat stress to verify l-NAA effects. Finally, perfusates at both sites were changed to 56 mM SNP to cause maximal vasodilation.
Fig. 3.
Fig. 3.
Summary of CVC responses to local warming of the skin. With a Tloc of 34°C, CVC did not differ between sites perfused with Ringer solution alone and sites perfused with 5 mM l-NAA in Ringer solution (P > 0.05 between sites). With local heating to 41.5°C, CVC increased significantly at both sites (P < 0.05, 34°C vs. 41.5C); however, responses were significantly different (*P < 0.05 between sites); thus endothelial nitric oxide synthase (eNOS) antagonism attenuated vasodilation induced by local warming of the skin.
Fig. 4.
Fig. 4.
Summary of CVC responses to whole body heat stress. Under normothermic conditions, CVC did not differ between sites perfused with Ringer solution only and sites perfused with 5 mM l-NAA in Ringer solution (P > 0.05 between sites). During whole body cold stress, CVC fell at both sites (P < 0.05). Responses at the sites were not statistically different (P > 0.05 between sites). In response to whole body heating, CVC rose at both sites (P < 0.05). Responses at sites perfused with Ringer solution only and sites perfused with 5 mM l-NAA in Ringer solution were not statistically different (P > 0.05 between sites); thus eNOS antagonism did not attenuate cutaneous active vasodilator response to whole body heat stress.
Fig. 5.
Fig. 5.
Summary of CVC responses to exogenous ACh after whole body heat stress. Vasodilatory response to 1.0 mM ACh was significantly attenuated by 5 mM l-NAA, thus verifying eNOS antagonism. *P ≤ 0.05 between sites.
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