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

New Findings What is the central question of this study?Does ageing augment muscarinic, nicotinic and/or ATP‐mediated cutaneous vasodilatation in women? What is the main finding and its importance?Ageing augments nicotinic and ATP‐induced, but not muscarinic, cutaneous vasodilatation in women. This will stimulate future studies assessing the pathophysiological significance of the augmented microvascular responsiveness in older women compared to their young counterparts. Abstract We previously reported that ageing attenuates adenosine triphosphate (ATP)‐induced, but not muscarinic and nicotinic, cutaneous vasodilatation in men, and that ageing may augment cutaneous vascular responses in women. In the present study, we evaluated the hypothesis that ageing augments muscarinic, nicotinic and/or ATP‐mediated cutaneous vasodilatation in healthy women. In 11 young (23 ± 5 years) and 11 older (60 ± 8 years) women, cutaneous vascular conductance was evaluated at three forearm skin sites that were perfused with (1) methacholine (muscarinic receptor agonist, 5 doses: 0.0125, 0.25, 5, 100, 2000 mm), (2) nicotine (nicotinic receptor agonist, 5 doses: 1.2, 3.6, 11, 33, 100 mm), or (3) ATP (purinergic receptor agonist, 5 doses: 0.03, 0.3, 3, 30, 300 mm). Each agonist was administered for 25 min per dose. Methacholine‐induced increases in cutaneous vascular conductance were not different between groups at all doses (all P > 0.05). However, a nicotine‐induced elevation in cutaneous vascular conductance at the lowest concentration (1.2 mm) was greater in older vs. young women (43 ± 15 vs. 26 ± 10%max, P = 0.04). ATP‐induced increases in cutaneous vascular conductance at moderate and high doses (3 and 30 mm) were also greater in older relative to young women (3 mm, 44 ± 11 vs. 28 ± 10%max, P = 0.02; 30 mm, 83 ± 14 vs. 64 ± 17%max, P = 0.05). Therefore, ageing augments nicotinic and ATP‐induced, but not muscarinic, cutaneous vasodilatation in women.

Section: Discussionmentioning

confidence: 98%

Ageing augments nicotinic and adenosine triphosphate‐induced, but not muscarinic, cutaneous vasodilatation in women

Fujii

McGarr

Sigal

et al. 2019

“…These authors reported that the reflex cutaneous vasoconstrictor response to graded skin cooling was ∼60% mediated by NA and ∼40% mediated by NPY. It was recently demonstrated that purinergic blockade attenuated the cutaneous vasoconstrictor response to body cooling, indicating that ATP might also contribute to the non-noradrenergic portion of reflex vasoconstriction (Lang, Krajek, & Smaller, 2017). Ang, angiotensin II; ATP, adenosine triphosphate; DRG, dorsal root ganglion; IML, intermediolateral cell column; MLC, myosin light chain; NA, noradrenaline; NPY, neuropeptide Y; P, phosphate; POA, preoptic area; RMR, rostral medullary raphe; ROCK, Rho-kinase.…”

Section: New Findingsmentioning

confidence: 99%

Cold‐induced cutaneous vasoconstriction in humans: Function, dysfunction and the distinctly counterproductive

Alba

Castellani

Charkoudian

2019

New Findings What is the topic of this review?This review presents an update and synthesis of normal mechanisms of human cutaneous vasoconstriction in response to cold stress. It then discusses conditions in which cutaneous vasoconstrictor responses are excessive or insufficient and cases in which cold‐induced vasoconstrictor responses become counter to maintaining thermal and haemodynamic homeostasis. What advances does it highlight?The review highlights our current understanding of the mechanisms that mediate alterations in cold‐induced cutaneous vasoconstriction in pathology and environmental extremes, which has important clinical implications for preventing cold‐ and cardiovascular‐related deaths. Abstract In humans, cold‐induced peripheral vasoconstriction is an essential element of body temperature regulation. Given that the thermoregulatory system responds rapidly to changes in skin temperature, sympathetically mediated cutaneous vasoconstriction represents a crucial ‘first line of defense’ against excessive reduction in body temperature. Sympathetic noradrenergic vasoconstrictor nerves cause a rapid decrease in skin blood flow, thus increasing the insulative capacity of the skin and decreasing heat loss from the body. Small changes in the activity of these nerves are also responsible for the subtle changes in skin blood flow that occur with normal daily activities or minor changes in environmental temperature. With ageing, hypertension and other conditions, the cutaneous reflex vasoconstrictor response can become excessive or insufficient. Healthy older adults have impaired reflex vasoconstriction, which may result in an impaired ability to defend body temperature in some circumstances. Hypertension is associated with augmented vasoconstriction, which could have pathological implications for left ventricular afterload in individuals already at risk for cardiovascular events. Finally, in some cases, the reflex vasoconstrictor response becomes distinctly counterproductive to its own goals of maintaining cardiovascular and thermoregulatory homeostasis. Examples include Raynaud's phenomenon, in which exaggerated vasoconstriction can produce ischaemia in the periphery, and the cutaneous vasoconstrictor response to therapeutic body cooling in severe hyperthermia, which can limit the heat exchange necessary to prevent serious heat illness.

“…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., ).…”

Section: Introductionmentioning

confidence: 99%

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

Fujii

Meade

McNeely

et al. 2018

The present study evaluated whether type 2 diabetes (T2D) attenuates muscarinic and/or nicotinic cutaneous vasodilatation and sweating as well as purinergic cutaneous vasodilatation. Cutaneous vascular conductance and sweat rate were evaluated in 12 healthy non-diabetic older adults (Control, 60 ± 8 years) and 13 older adults with T2D (62 ± 10 years) at three intradermal forearm skin sites perfused with the following: (i) methacholine (muscarinic receptor agonist, five doses: 0.0125, 0.25, 5, 100 and 2000 mm); (ii) nicotine (nicotinic receptor agonist, five doses: 1.2, 3.6, 11, 33 and 100 mm); or (iii) ATP (purinergic receptor agonist, five doses: 0.03, 0.3, 3, 30 and 300 mm). Each agonist was administered for 25 min per dose. At the end of the protocol, 50 mm sodium nitroprusside was administered to all skin sites to elicit maximal cutaneous vasodilatation. Cutaneous vascular conductance during methacholine and nicotine administration did not differ between groups (all P > 0.05). In contrast, cutaneous vascular conductance during administration of 30 mm (42 ± 28 versus 63 ± 26% maximum, P ≤ 0.05) and 300 mm ATP (56 ± 24 versus 71 ± 20% maximum, P ≤ 0.05) was attenuated in individuals with T2D in comparison to the Control participants. Furthermore, cutaneous vascular conductance during administration of 50 mm sodium nitroprusside was lower in individuals with T2D relative to Control subjects (P = 0.04). Methacholine- and nicotine-induced sweating was similar between groups (all P > 0.05). Thus, T2D attenuates purinergic cutaneous vasodilatation without affecting muscarinic and nicotinic cutaneous vascular and sweating responses.