Intradermal administration of ATP does not mitigate tyramine-stimulated vasoconstriction in human skin

Abstract

Cutaneous vasodilation associated with whole-body heat stress occurs via withdrawal of adrenergic vasoconstriction and engagement of cholinergic "active" vasodilation, the latter of which attenuates cutaneous vasoconstrictor responsiveness. However, the precise neurotransmitter(s) responsible for this sympatholytic-like effect remain unknown. In skeletal muscle, ATP inhibits adrenergically mediated vasoconstriction. ATP also may be responsible for attenuating cutaneous vasoconstriction since it is co-released from cholinergic neurons. The effect of ATP on cutaneous vasoconstrictor responsiveness, however, has not been investigated. Accordingly, this study tested the hypothesis that ATP inhibits adrenergically mediated cutaneous vasoconstriction. To accomplish this objective, four microdialysis probes were inserted in dorsal forearm skin of 11 healthy individuals (mean +/- SD; 35 +/- 11 years). Local temperature at each site was clamped at 34 degrees C throughout the protocol. Skin blood flow was indexed by laser-Doppler flowmetry and was used to calculate cutaneous vascular conductance (CVC; laser-Doppler-derived flux/mean arterial pressure), which was normalized to peak CVC achieved with sodium nitroprusside infusion combined with local skin heating to approximately 42 degrees C. Two membranes were perfused with 30 mM ATP, while the other two membranes were flow matched via administration of 2.8 mM adenosine to serve as control sites. After achieving stable baselines, 1 x 10(-4) M tyramine was administered at all sites, while ATP and adenosine continued to be infused at their respective sites. ATP and adenosine infusion increased CVC from baseline by 35 +/- 26% CVC(peak) units and by 36 +/- 15% CVC(peak) units, respectively (P = 0.75). Tyramine decreased CVC similarly (by about one-third) at all sites (P < 0.001 for main effect and P = 0.32 for interaction). These findings indicate that unlike in skeletal muscle, ATP does not attenuate tyramine-stimulated vasoconstriction in human skin.

Purinergic Signaling and Blood Vessels in Health and Disease

“…Intradermal administration of ATP does not attenuate tyramine-stimulated vasoconstriction in human skin, in contrast to skeletal muscle vessels (Wingo et al, 2010). Changes in purine receptor expression (increase in P2Y 1 , P2Y 2 , and P2X 5 , decrease in P2X 7 ) on human lower leg epidermal keratinocytes were shown in chronic venous insufficiency (Metcalfe et al, 2006).…”

Evidence for a functional vasoconstrictor role for ATP in the human cutaneous microvasculature

“…Although several P 2 receptor subtypes have been identified, this receptor class is divided into P 2X ligand-gated ion channels and P 2Y G-protein-coupled receptor families (Burnstock & Kennedy, 1985;Burnstock, 2012Burnstock, , 2012. Intravascular sources of ATP, such as that released from endothelial cells or offloaded from red blood cells, elicit vasodilatation by acting on P 2 receptors located on the endothelium to increase vasoactive factors, such as nitric oxide (Duff et al 1954;Rongen et al 1994;Wingo et al 2010;Fujii et al 2015b). However, ATP co-released from perivascular axon terminals binds to P 2X receptors to increase the intracellular calcium concentration and contract vascular smooth muscle (Burnstock, 1988(Burnstock, , 2008.…”

“…Furthermore, skin sympathetic nerve activity is reduced for a given cooling stimulus (Grassi et al 2003;Greaney et al 2015b). Exogenous intradermal infusion of ATP resulted in a dose-dependent VD that was mediated in part by nitric oxide (Wingo et al 2010;Fujii et al 2015b). Recent work in human skin has revealed that ATP also has a vasodilatory influence.…”

Type 2 diabetes specifically attenuates purinergic skin vasodilatation without affecting muscarinic and nicotinic skin vasodilatation and sweating

“…However, no study to date has evaluated whether T2D modulates the cutaneous vascular response to purinergic receptor activation elicited by ATP. In human skin, low concentrations of ATP may cause vasoconstriction (Lang, Krajek, & Smaller, ), whereas high concentrations have been shown to induce a dose‐dependent vasodilatation (Fujii et al., , ; Kalsi et al., ; Wingo et al., ) without affecting sweat rate (Fujii et al., , ). Furthermore, previous work has demonstrated that ATP‐induced vasodilatation in forearm conduit arteries is impaired in individuals with T2D (Thaning et al., ).…”