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
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.
References (45)
Comparison of laser speckle contrast imaging with laser Doppler for assessing microvascular function
Microvasc. Res.
(2011)Reproducibility of cutaneous thermal hyperaemia assessed by laser Doppler flowmetry in young and older adults
Microvasc. Res.
(2011)Endurance exercise training enhances cutaneous microvascular reactivity in post-menopausal women
Microvasc. Res.
(2012)Exercise training and the control of skin blood flow in older adults
J. Nutr. Health Aging
(2012)Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels
J. Physiol.
(2008)- et al.
Regional differences in the control of skin blood flow at forearm and calf sites
Med. Sci. Sports Exerc.
(2002) - et al.
Sensory and sympathetic nerve contributions to the cutaneous vasodilator response from a noxious heat stimulus
Exp. Physiol.
(2011) Influences of female reproductive hormones on sympathetic control of the circulation in humans
Clin. Auton. Res.
(2001)Body segment differences in surface area, skin temperature and 3D displacement and the estimation of heat balance during locomotion in hominins
PLoS One
(2008)Assessment of brachial artery blood flow across the cardiac cycle: retrograde flows during cycle ergometry
J. Appl. Physiol.
(2002)
Effect of exercise training on endothelium-derived nitric oxide function in humans
J. Physiol.
Obligatory role of hyperaemia and shear stress in microvascular adaptation to repeated heating in humans
J. Physiol.
Adrenergic control of the human cutaneous circulation
Appl. Physiol. Nutr. Metab.
The involvement of nitric oxide in the cutaneous vasoconstrictor response to local cooling in humans
J. Physiol.
The involvement of norepinephrine, neuropeptide Y, and nitric oxide in the cutaneous vasodilator response to local heating in humans
J. Appl. Physiol.
The effect of microdialysis needle trauma on cutaneous vascular responses in humans
J. Appl. Physiol.
The involvement of heating rate and vasoconstrictor nerves in the cutaneous vasodilator response to skin warming
Am. J. Physiol. Heart Circ. Physiol.
The effect of 48 weeks of aerobic exercise training on cutaneous vasodilator function in post-menopausal females
Eur. J. Appl. Physiol.
The human cutaneous circulation as a model of generalized microvascular function
J. Appl. Physiol.
Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin
J. Physiol.
Cardiovascular adjustments to heat stress
Cited by (30)
Analysis of phase interactions between heart rate variability, respiration and peripheral microhemodynamics oscillations of upper and lower extremities in human
2022, Biomedical Signal Processing and ControlRegional cutaneous vasodilator responses to rapid and gradual local heating in young adults
2021, Journal of Thermal BiologyCitation Excerpt :For the same response, the chest and arm were consistently higher than the lower limbs by ~10%, nearing the SMD threshold. Previous studies have consistently reported greater initial peak responses in the forearm compared to the leg during rapid LTH in the range of 9–19% (Del Pozzi et al., 2013; Del Pozzi and Hodges, 2015; Hodges et al., 2015). While we showed the same general trend, the magnitudes of these regional differences in the current study were much smaller, ranging from 3 to 7%.
Effect of sensory blockade and rate of sensory stimulation on local heating induced axon reflex response in facial skin
2021, Autonomic Neuroscience: Basic and ClinicalGlabrous and non-glabrous vascular responses to mild hypothermia
2019, Microvascular ResearchCitation Excerpt :The majority of the previous work examining the mechanisms of control of skin vasoconstriction have been performed on glabrous and non-glabrous skin of the hand and forearm (Johnson et al., 2014). It has been reported that there are differences in the contributions of endothelial and neural signals to the cutaneous vasomotor responses between different regions of the body (Del Pozzi et al., 2013; Del Pozzi and Hodges, 2015). Thus, any direct comparisons with prior work of different skin regions should be made with that caveat in mind.