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The ability to modulate sympathetic α-adrenergic vasoconstriction in contracting muscle is impaired with age. In young adults, adenosine triphosphate (ATP) has been shown to blunt sympathetic vasoconstrictor responsiveness similar to exercise. Therefore, we tested the hypothesis that modulation of postjunctional α-adrenergic vasoconstriction to exogenous ATP is impaired in ageing humans.We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) to intra-arterial infusions of phenylephrine (α₁-agonist) and dexmedetomidine (α₂-agonist) during rhythmic handgrip exercise (15% MVC), a control non-exercise vasodilator condition (adenosine), and ATP infusion in seven older (64 ± 3 years) and seven young (22 ± 1 years) healthy adults. Forearm hyperaemia was matched across all vasodilatating conditions. During adenosine, forearm vasoconstrictor responses to direct α₁-stimulation were lower in older compared with young adults (ΔFVC=-25 ± 3% vs. -41 ± 5%; P <0.05), whereas the responses to α₂-stimulation were not different (-35±6% vs. -44 ± 8%; NS). During exercise, α₁-mediated vasoconstriction was significantly blunted compared with adenosine in both young (-9 ± 2% vs. -41 ± 5%) and older adults (-15 ± 2% vs. -25 ± 3%); however, the magnitude of sympatholysis was reduced in older adults (32 ± 13 vs. 74 ± 8%; P <0.05). Similarly, α₂-mediated vasoconstriction during exercise was significantly blunted in both young (-15 ± 4% vs. -44 ± 8%) and older adults (-26 ± 3% vs. -35 ± 6%), however the magnitude of sympatholysis was reduced in older adults (19 ± 8% vs. 60 ± 10%; P <0.05). During ATP, both α₁- and α₂-mediated vasoconstriction was nearly abolished in young and older adults (ΔFVC ∼ -5%), and the magnitude of sympatholysis was similar in both age groups (∼85-90%). Our findings indicate that the ability to modulate postjunctional α-adrenergic vasoconstriction during exercise is impaired with age, whereas the sympatholytic effect of exogenous ATP is preserved. Thus, if impairments in vascular control during exercise in older adults involve vasoactive ATP, we speculate that circulating ATP is reduced with advancing age.

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 alpha-adrenoceptor responsiveness, or is selective for alpha(1)- or alpha(2)-receptors remains unclear. Therefore, in Protocol 1, we tested the hypothesis that exogenous ATP can blunt direct postjunctional alpha-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 (alpha(1)-agonist) and dexmedetomidine (alpha(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 alpha(1)-receptor stimulation were blunted during exercise versus adenosine (DeltaFVC = -11 +/- 3% versus -39 +/- 5%; P< 0.05), and were abolished during ATP infusion (-3 +/- 2%). Similarly, vasoconstrictor responses to alpha(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 alpha(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 alpha-adrenergic vasoconstriction, that this involves both alpha(1)- and alpha(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.

Muscle sympathetic vasoconstrictor nerve activity increases with advancing age, but does not result in elevated forearm vasoconstrictor tone because of a selective reduction in alpha1-adrenoceptor responsiveness. In contrast, the leg circulation of older adults is under greater tonic sympathetic vasoconstriction, but it is unclear whether alpha-adrenoceptor responsiveness is altered with age. In the present study, we tested the hypothesis that postjunctional alpha-adrenergic vasoconstrictor responsiveness is reduced in the leg circulation with age. We measured femoral blood flow (Doppler ultrasound) and calculated the femoral vascular conductance (FVC) responses to alpha-adrenoceptor stimulation during local blockade of beta-adrenoceptors in 12 young (24 +/- 1 year) and seven healthy older men (62 +/- 2 year). Whole-leg vasoconstrictor responses to local intrafemoral artery infusions of tyramine (evokes noradrenaline (NA) release), phenylephrine (alpha1-agonist) and dexmedetomidine (alpha2-agonist) were assessed. Consistent with previous data, resting femoral blood flow and FVC were approximately 30% lower in older compared with young men (P < 0.05). Maximal vasoconstrictor responses to tyramine (-30 +/- 3 versus -41 +/- 3%), phenylephrine (-25 +/- 4 versus -45 +/- 5%), and dexmedetomidine (-22 +/- 4 versus -44 +/- 3%) were all significantly lower in older compared with young men (all P < 0.05). Our results indicate that human ageing is associated with a reduction in leg postjunctional alpha-adrenoceptor responsiveness to endogenous NA release, and this reduction is evident for both alpha1- and alpha2-adrenoceptors. However, given that basal leg vascular conductance is reduced with age and is primarily mediated by sympathetic vasoconstriction, impaired alpha-adrenoceptor responsiveness does not negate the ability of the sympathetic nervous system to evoke greater tonic vasoconstriction in the leg vasculature of older men.

Muscle sympathetic vasoconstrictor nerve activity increases with advancing age, but does not result in elevated forearm vasoconstrictor tone due to a selective reduction in α1-adrenergic receptor responsiveness. In contrast, the leg circulation of older adults is under greater tonic sympathetic vasoconstriction, but it is unclear whether leg α-receptor responsiveness is altered with age. We tested the hypothesis that α-adrenergic receptor responsiveness is not reduced in the leg circulation with age. In 12 young (24±1 yrs) and 7 healthy older men (62±2 yrs), we measured femoral blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses to alpha-adrenergic receptor stimulation via intra-femoral artery infusions of tyramine (evokes endogenous NE release), phenylephrine α1-agonist), and dexmedetomidine (α2-agonist) during local blockade of β-adrenergic receptors. At rest, femoral blood flow and vascular conductance were ∼30% lower in older compared with young men. Maximal vasoconstrictor responses (%ΔFVC) to tyramine (-30±3 vs -41±3%), phenylephrine (-25±4 vs -45±5%), and dexmedetomidine (-22±4 vs -44±3%) were significantly reduced in older compared with young men (all P<0.05). We conclude that aging is associated with impaired leg α-adrenergic receptor responsiveness at rest, and that this involves both α1- and α2-adrenergic receptors. [ABSTRACT FROM AUTHOR]