Sodium loading and cutaneous microvascular function: more than skin deep

For several years the human cutaneous circulation has been utilized as a representative vascular bed to assess microvascular function in clinical and pre-disease model populations. With relevance to hypertension, deficits in cutaneous microvascular function are related to impairment in indices of renal vascular function and target organ damage (Coulon et al. 2011). While the skin serves mainly thermoregulatory purposes, several skin-specific methodologies including both thermal and pharmacological stimuli and interventions have been successfully utilized to pharmacodissect underlying mechanisms of vascular dysfunction (Holowatz et al. 2008). The most commonly explored signalling pathways in human skin most relevant to globalized vascular dysfunction are nitric oxide synthase (NOS)-dependent vasodilatory mechanisms, and noradrenaline-mediated vasoconstrictor mechanisms. Moreover, specific pathology-relevant oxidant stress mechanisms have been explored using both specific and non-specific antioxidants including allopurinol, apocynin and ascorbate (Medow et al. 2011). In this issue of The Journal of Physiology, Greaney et al. (2012) published an elegant study examining the effects of dietary sodium loading on microvascular function, independent of an increase in blood pressure. This study is the first to show that dietary sodium loading in normotensive salt-resistant humans impairs cutaneous eNOS-dependent vasodilatation utilizing a local skin heating stimulus. Furthermore, when the non-specific antioxidant ascorbate was locally delivered, eNOS-dependent vasodilatation was restored. Together, the data from Greaney et al. show that dietary sodium-induces decrements in cutaneous microvascular function that occur through ascorbate-sensitive oxidant stress mechanisms. The results from this study bring to light several interesting points to consider from both a globalized vascular health perspective and for methodological reasons when examining the neurovascular regulation of skin blood flow. Human skin has been used as a model for examining decrements in vascular function with hypertension-induced vascular pathology for several decades. While as a regional circulation the compliant cutaneous circulation contributes minimally to the increase in systemic vascular resistance in comparison to more nutritive vascular beds, decrements in microvascular function are clearly apparent. Even before the technology was available to image or measure more precise changes in microcirculatory function through laser-Doppler or laser-speckle imagery, Carberry et al. (1992) utilized venous occlusion plethysmography and a whole limb heating technique to show that subjects with essential hypertension have lower forearm blood flows to increasing temperature and lower maximal blood flow, indicating a degree of endothelial dysfunction and inward vessel remodelling. Moreover, progressive decrements in vascular function to endothelium-dependent agonists with the severity of hypertensive disease have been consistently observed (Farkas et al. 2004). More recently with the development of skin-specific methodologies the underlying mechanisms of hypertension-induced vascular dysfunction are being extensively explored (Smith et al. 2011). The study by Greaney et al. adds another piece to the puzzle suggesting that dietary salt loading alone without increases in mean arterial pressure induces changes in vascular function that are consistent with a pre-clinical hypertensive vascular pathology state. From a methodological perspective, the results from Greaney et al. highlight the need for cautious experimental controls in all studies examining the neurovascular regulation of skin blood flow whether in healthy or clinical populations. Controlling or documenting sodium intake in human subjects may be a necessary experimental control especially when examining clinical populations. Finally, meaningful physiological interpretations of studies like that of Greaney et al. are not possible without tightly controlled mechanistic work in healthy populations. More of this work is necessary so that clinical test of microvascular function in the skin can be utilized on a broader scale (Minson, 2010).