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Unlocking the secrets of skin blood flow

Although few of us recognize the fact, the skin is the largest organ in the body. As such it possesses a remarkable range of functions and adaptations that include waterproofing and forming a barrier from infection, a site of vasoconstriction during orthostasis and a heat exchanger with the environment. The latter role arises from its position on the surface of the body and its capacious volume for blood flow allowing rapid heat loss. Indeed, it has been estimated that during whole body heating maximal skin blood flow may reach 7–8 l min−1. Only skeletal muscle has the potential to receive a greater blood flow. However, despite much empirical work investigating the possible neural and local control of skin blood flow, the precise mechanisms that mediate the increase in cutaneous flow during local heating were until relatively recently unknown. 
 
In the non-glabrous skin of the trunk and limbs, cutaneous blood flow is controlled by the noradrenergic vasoconstrictor system and an active vasodilator system, as well as local factors. The skin blood flow response to rapid local heating is biphasic in nature, with an initial rapid increase in skin blood flow, followed by a more prolonged plateau phase. The initial phase is thought to be mediated by an axon reflex and the secondary hyperaemia largely (70%) governed by the endothelial release of nitric oxide (NO) (Kellogg et al. 1999; Minson et al. 2001). 
 
The initial axon reflex is suggested to be neurally mediated by C-fibre antidromic vasodilatation via the release of the neuropeptides substance P and calcitonin gene-related peptide (CGRP), as their infusion causes increased cutaneous flow, whereas their depletion by capsaicin causes a reduced blood flow response to local heating. In this issue of The Journal of Physiology, Houghton et al. (2006) have extended these observations by examining for the first time the precise contribution of NO and noradrenaline to the rapid increase in skin blood flow mediated by this axon reflex. The authors have used an elegant design to address this topic. Subjects were exposed to a localized heating protocol that raised skin temperature from 30 to 40°C at a rate of 0.1°C min−1 with the concomitant infusion of (i) NG-nitro-l-arginine methyl ester (l-NAME) for complete NO synthase inhibition, (ii) l-NAME with low dose sodium nitroprusside (SNP) to determine the effect of exogenous NO during blockade, and (iii) low dose SNP to determine the effect of exogenous SNP without blockade of endogenous release on the axon reflex. In addition a similar protocol was followed using bretylium tosylate to block presynaptic adrenoceptors, followed by blockade with low dose noradenaline and infusion of low dose adrenaline alone. This latter protocol effectively assayed the contribution of noradrenaline to the axon-mediated increase in flow during local heating. 
 
The study reported that during NO inhibition, the axon reflex was either absent or shifted to a higher temperature threshold, a response that was not restored with exogenous NO. In addition, the axon reflex was also abolished during adrenergic blockade and the threshold temperature for axon response was shifted to a lower value during infusion of noradrenaline alone. These results clearly demonstrate that both NO and noradrenaline play an obligatory role in mediating the axon reflex during progressive local heating. Furthermore, given that NO aids the release of CGRP in the skin and contributes to substance P-mediated dilatation, the authors suggest that NO may be essential for the sensitization of the axon reflex, which ultimately releases these neuropeptides causing antidromic vasodilatation. In addition, NO may also enhance the sensitivity of α1-adrenoreceptors to stimulation by noradrenaline. 
 
Although the exact role of nitric oxide in mediating this initial phase of the hyperaemic response remains to be elucidated, the paper of Houghton et al. (2006) is an excellent first step in documenting this response and in developing our understanding of the role of NO in the cutaneous hyperaemic response. Collectively, this paper and the previous work of Kellogg et al. (1999) and Minson et al. (2001) demonstrate that NO contributes to both the initial peak hyperaemic and the secondary plateau hyperaemic response to local heating. 
 
Recently there has been much interest in the effect of various pathologies on the maximal hyperaemic response seen in the skin in response to local heating. For example it is known that there is an impaired maximum hyperaemic response in both type 1 and type 2 diabetic patients. Interestingly, this reduced capacity for maximal flow can be detected in populations before the onset of diabetes, as it is observed in individuals with elevated fasting blood glucose and in 3-month-old infants of low birth weight. It is known that these diabetic populations suffer impaired endothelial function, a fact supported by their reduced maximum cutaneous blood flow during local heating. It would therefore be fascinating to examine whether the axon reflex-mediated increase in blood flow is impaired in prediabetic, diabetic, and other diseased populations. The techniques utilized by Houghton et al. (2006) allow this question to be addressed and furthermore allow characterization of the role of NO in this response. 
 
So yes, our knowledge of the reflex control of the cutaneous microcirculation has been significantly enhanced. However, we now are not only chasing the answers to the empirical control questions during both heating and exercise, but also coming to realize that the measurement of skin blood flow (which is non-invasive and technically simple) can provide a unique insight into the mechanisms of disease. Indeed such assessment of the microcirculation of our largest and most accessible organ may provide an early detection system for the development and progress of endothelial dysfunction and related pathology. It is therefore vital that our understanding of the exact mechanisms for altered cutaneous blood flow in health and disease are fully understood.