Elsevier

Microvascular Research

Volume 90, November 2013, Pages 106-111
Microvascular Research

The regional differences in the contribution of nitric oxide synthase to skin blood flow at forearm and lower leg sites in response to local skin warming

https://doi.org/10.1016/j.mvr.2013.10.003Get rights and content

Highlights

  • At baseline, NO plays a larger role in SkBF response of the legs than in the arms.

  • NO contribution to the SkBF effect to local heating stimulus is similar by region.

  • NO role at baseline seems to explain the observed changes amid leg and arm SkBF.

Abstract

We investigated the role of nitric oxide synthase (NOS) on regional cutaneous vascular function at rest (thermoneutral conditions) and during the vasodilator response to increased local skin temperature (Tloc). Dorsal forearm and lateral leg sites were instrumented with microdialysis fibers, local heaters, and laser-Doppler probes. All sites were heated from 33 °C to 42 °C. Each limb had 1 skin site treated with l-NAME to inhibit NOS, and 1 site infused with lactated Ringer's to serve as a control. Basal cutaneous vascular conductance (CVC) was measured at 33 °C, forearm sites averaged 14 ± 1%max and 17 ± 1%max at l-NAME and control sites, respectively (P = 0.26). CVC sites in the leg were different between l-NAME (17 ± 1%max) and control (27 ± 2%max) (P = 0.04). CVC between the forearm and the leg across control sites differed (P < 0.05). In contrast, at l-NAME treated sites, there was no difference between the forearm and leg sites (P = 0.23). When Tloc was increased to 42 °C, CVC at the control sites differed between the forearm 93 ± 1%max and leg 98 ± 1%max (P = 0.02). There were no differences between the arm and leg at l-NAME treated sites at 42 °C (P = 0.45). The findings of the current study were that the contribution of nitric oxide (NO) to the vasodilator response to an elevated Tloc is consistent between the arm and the leg, and, under thermoneutral conditions (33 °C), NO plays a larger role in the basal vascular function in the legs than that of the forearm. Accordingly, these data suggest, in part, that the differences in basal CVC between the forearm and leg are due to NOS activity.

Introduction

Thermal homeostasis is achieved primarily through an adjustment of the level of perfusion in the skin circulation. Under thermoneutral conditions, noradrenergic sympathetic innervation largely controls the circulation in nonglabrous (hairy) skin (Hodges and Johnson, 2009). Yet, in response to increased local skin temperature [Tloc; (i.e. no change in core temperature)] the resultant vasodilatation appears to be principally dependent on nitric oxide (NO) (Kellogg et al., 1999, Kellogg et al., 2008a). While significant contributions have been made regarding the control mechanisms of the human cutaneous circulation, the majority of the work has been performed in the forearm; this is likely due to the accessibility of the forearm compared to other parts of the body.

Despite the extant data detailing the involvement of NO during local skin warming, it remains unclear if there are regional body differences in the vasodilator response to a local warming stimulus. Previously, Kellogg et al., 1999, Kellogg et al., 2008a, Kellogg et al., 2008b, Kellogg et al., 2009 examined forearms while Stewart et al., 2003, Stewart et al., 2007, Stewart et al., 2011 examined legs, both of which came to different conclusions regarding the contributions of NO during the plateau phase of the hyperemic response to an increased Tloc. Kellogg et al. (1999) determined that 70% of the vasodilatation response to local heating was due to the production of NO, while Stewart et al. (2011) reported that roughly 88% of the thermal hyperaemia was due to NO production. The studies conducted by Kellogg et al. and Stewart et al. were methodologically different and the subjects examined differed, consequently, making direct comparisons among these studies difficult, if not impossible. Still, Bussell and Cable (2002), examined endothelium-dependent and -independent vasodilatation via acetylcholine and sodium nitroprusside iontophoresis, respectively, and reported that the contribution of the endothelium [primarily NO; (Kellogg et al., 2005)] to cutaneous vasodilatation did not differ between the forearm and leg skin. While differences were not observed, acetylcholine elicits vasodilatation not only via nitric oxide synthase (NOS), but also through prostaglandins, epoxyeicosatrienoic acids, and endothelial-derived hyperpolarizing factor, thus impairing our ability to reconcile the observed differences reported elsewhere. It is also important to note that this was achieved using pharmacological stimuli alone rather than through a physiological stimulus such as local skin warming.

Consequently, we sought to directly examine whether the contribution of NO to basal cutaneous vascular tone and to the vasodilator response to local skin warming differed between the forearm and the lower leg with and without NOS inhibition. To that end, we examined the effect of NOS inhibition with Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) (Hodges et al., 2006, Hodges et al., 2008, Kellogg et al., 1999, Kellogg et al., 2008a, Kellogg et al., 2009) under thermoneutral conditions (Tloc of 33 °C) and on the vasodilator response to local skin warming (Tloc of 42 °C) in the forearm and lower leg of young healthy humans. Based on the findings of Kellogg et al., 1999, Kellogg et al., 2008a, Kellogg et al., 2008b, Kellogg et al., 2009 who previously described the NO contribution in the forearm to be roughly 70% and Stewart et al., 2003, Stewart et al., 2007 who has previously determined that roughly 88% of the vasodilator response in the lower-leg to an elevated local temperature is due to the actions of NO, we hypothesized that the contribution of NO to 1) basal skin blood flow would be the same between regions, and 2) vasodilatation in response to an increased Tloc would be greater in the lower-leg compared to the forearm. Lastly, we hypothesized that the effect of l-NAME (NOS-inhibition) would be larger in the leg than that of the forearm.

Section snippets

Ethical approval

The current study was approved for completion by the local Institutional Review Board at The University of Alabama. The participants were fully informed of the experimental methods as well as the associated risks prior to their volunteering to be a participant. Verbal and written informed consent was obtained from each participant. The experimental protocol conformed to the guidelines set forth by the Declaration of Helsinki.

Participants

A power analysis indicated that 9 participants would be required with

Results

Fig. 1 shows responses in CVC, as a percentage of max, from a representative subject to 35 min of local skin warming at the two forearm and two leg sites. Each limb had a skin site treated with l-NAME and the other site left untreated (lactated Ringer's only). Note that at baseline, a Tloc of 33 °C, CVC at the leg (closed triangles) was higher when compared to the forearm (closed circles) and this difference was eliminated with l-NAME treatment. In response to an increase in Tloc at the 10-min

Discussion

The goal of the current study was to examine the relative contribution of NOS under resting thermoneutral (Tloc 33 °C) conditions and during the vasodilator response to local skin warming in the forearm and lower leg with and without NOS inhibition. The main findings of the current study are that: 1) the contribution of NO to the vasodilator response to increased Tloc is consistent between the arm and the leg; and 2) at rest, under thermoneutral conditions, NO plays a larger role in basal

Acknowledgments and disclosures

We thank the participants for their time and commitment to this study. This study was conducted by Andrew T. Del Pozzi in partial fulfillment of the requirements for the Doctor of Philosophy degree in the Department of Kinesiology at The University of Alabama. We extend gratitude to Drs. Phillip A. Bishop, Jonathan E. Wingo, Mark T. Richardson, and Stephen M. Secor for all of their help as doctoral dissertation committee members. Andrew T. Del Pozzi is currently at the New York Medical College.

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