Graded sympatholytic effect of exogenous ATP on postjunctional α‐adrenergic vasoconstriction in the human forearm: implications for vascular control in contracting muscle

Abstract

Recent evidence suggests that adenosine triphosphate (ATP) can inhibit vasoconstrictor responses to endogenous noradrenaline release via tyramine in the skeletal muscle circulation, similar to what is observed in contracting muscle. Whether this involves direct modulation of postjunctional α-adrenoceptor responsiveness, or is selective for α 1 -or α 2 -receptors remains unclear. Therefore, in Protocol 1, we tested the hypothesis that exogenous ATP can blunt direct postjunctional α-adrenergic vasoconstriction in humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses to local intra-arterial infusions of phenylephrine (α 1 -agonist) and dexmedetomidine (α 2 -agonist) during moderate rhythmic handgrip exercise (15% maximum voluntary contraction), during a control non-exercise vasodilator condition (adenosine), and during ATP infusion in eight young adults. Forearm hyperaemia was matched across all conditions. Forearm vasoconstrictor responses to direct α 1 -receptor stimulation were blunted during exercise versus adenosine ( FVC = −11 ± 3% versus −39 ± 5%; P < 0.05), and were abolished during ATP infusion (−3 ± 2%). Similarly, vasoconstrictor responses to α 2 -receptor stimulation were blunted during exercise versus adenosine (−13 ± 4% versus −40 ± 8%; P < 0.05), and were abolished during ATP infusion (−4 ± 4%). In Prototol 2 (n = 10), we tested the hypothesis that graded increases in ATP would reduce α 1 -mediated vasoconstriction in a dose-dependent manner compared with vasodilatation evoked via adenosine. Forearm vasoconstrictor responses during low dose adenosine (−38 ± 3%) and ATP (−33 ± 2%) were not significantly different from rest (−40 ± 3%; P > 0.05). In contrast, vasoconstrictor responses during moderate (−22 ± 6%) and high dose ATP (−8 ± 5%) were significantly blunted compared with rest, whereas the responses during adenosine became progressively greater (moderate = −48 ± 4%, P = 0.10; high = −53 ± 6%, P < 0.05). We conclude that exogenous ATP is capable of blunting direct postjunctional α-adrenergic vasoconstriction, that this involves both α 1 -and α 2 -receptor subtypes, and that this is graded with ATP concentrations. Collectively, these data are consistent with the conceptual framework regarding how muscle blood flow and vascular tone are regulated in contracting muscles of humans.

Blood temperature and perfusion to exercising and non‐exercising human limbs

“…2004; Kirby et al . 2008). To gain insight into this mechanism, we measured plasma ATP, blood oxygenation and plasma noradrenaline in the subclavian and femoral veins and in the brachial artery at rest and during combined steady‐state leg and arm exercise.…”

“…2004; Kirby et al . 2008). Comparison of the strength of the relationships between [ATP] versus T B and [ATP] versus oxyhaemoglobin provides information about two potential mechanisms leading to increases in intravascular [ATP].…”

The Age-Old Tale of Skeletal Muscle Vasodilation: New Ideas Regarding Erythrocyte Dysfunction and Intravascular ATP in Human Physiology

“…Together, these data are of the first to identify that aging per se results in less than optimal tissue oxygen delivery during states of substantial hemoglobin deoxygenation and further, that these states are associated with a lack of increase in the plasma levels of the powerful vasoactive molecule ATP. 3 To our knowledge, we are unaware of any other study demonstrating an inability to elevate plasma ATP in any at-risk clinical population under such conditions. As stated, it is not the validity of these data that the authors of the Editorial take caution with, but rather the approach of integrating our in vitro data with the in human findings.…”

Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

“…First, in vitro evidence suggests that within the same vasculature, low-dose ATP-induced vasodilation is sensitive to NO and PG inhibition, whereas higher doses are not (30,33). This latter finding is of interest when considering the dual properties of ATP in the human vasculature whereby it not only evokes direct vasodilation but also can limit sympathetic ␣-adrenergic vasoconstriction (20,29). In this context, our laboratory has demonstrated 1) that NO and PGs are not obligatory to observe the normal blunting of sympathetic vasoconstriction in contracting muscle (10), and 2) that the unique ability of ATP to blunt sympathetic vasoconstriction is graded with ATP concentrations, where high levels are sympatholytic but low levels are not (20).…”