What is the central question of this study? In young adults, about half of the cold-related reduction in skin blood flow during cold exposure is mediated by noradrenaline, while the remainder is attributable to other substances co-released with noradrenaline that have yet to be identified. What is the main finding and its importance? Purinergic receptor blockade blunted the vasoconstriction response to whole-body cooling and to intradermal administration of tyramine. These results indicate that ATP is necessary to vasoconstrict blood vessels in the skin adequately and prevent heat loss in a cold environment. Noradrenaline is responsible for eliciting ∼60% of the reflex cutaneous vasoconstriction (VC) response in young adults, while the remainder is attributable to one or more unidentified co-released sympathetic adrenergic neurotransmitter(s). Inconsistent evidence has placed neuropeptide Y in this role; however, other putative cotransmitters have yet to be tested. We hypothesize that ATP contributes to the reflex cutaneous VC response. Two protocols were conducted in young adults (n = 10); both involved the placement of three microdialysis probes in forearm skin and whole-body cooling (skin temperature = 30.5°C). In protocol 1, the following solutions were infused: (i) lactated Ringer solution (control); (ii) 10 mm l-NAME; and (iii) purinergic receptor blockade with 1 mm suramin plus l-NAME. In protocol 2, the following solutions were infused: (i) lactated Ringer solution; (ii) suramin plus l-NAME; and (iii) suramin plus l-NAME plus adrenoreceptor blockade with 5 mm yohimbine plus 1 mm propranolol. Laser Doppler flux (LDF) was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP) and expressed as percentage changes from baseline (%ΔCVC ). l-NAME was used to block the vasodilatory influence of ATP and unmask the P X-mediated VC response to exogenous ATP infusion (-21 ± 6%ΔCVC ). During cooling, the VC response (control, -39 ± 8%ΔCVC ) was attenuated at the suramin site (-21 ± 4%ΔCVC ) and further blunted with combined adrenoreceptor blockade (-9 ± 3%ΔCVC ; P < 0.05). Compared with the control site (-22 ± 5%ΔCVC ), suramin inhibited pharmacologically induced VC to tyramine (-12 ± 6%ΔCVC ; P < 0.05), which displaces adrenergic neurotransmitters from axon terminals. These data indicate that ATP contributes to the cutaneous VC response in humans.

What is the central question of this study? Ageing is associated with altered sympathetic responses to stress, which are explained in part by reduced noradrenergic function. The impact of supplementation with oral l-tyrosine, the amino acid precursor for catecholamine synthesis, on the effector responses to cold and exercise stress has yet to be examined. What is the main finding and its importance? Oral l-tyrosine ingestion augmented the sympathetically mediated vasoconstriction response to cold exposure in aged skin. This suggests that l-tyrosine supplementation might improve thermoregulatory function in older adults. l-Tyrosine is the primary substrate for noradrenaline biosynthesis within sympathetic axon terminals. In stressful conditions requiring increased catecholamine production, the axonal l-tyrosine concentration may limit the full expression of the sympathetic effector response and this may be particularly evident in older adults. We hypothesize that oral l-tyrosine supplementation will increase the sympathetic response to whole-body cooling and muscle metaboreflex activation. In a randomized, double-blind design, 11 young (Y = 24 ± 1 years) and 11 older participants (O = 68 ± 4 years) ingested either 150 mg kg of l-tyrosine or placebo before commencing 30 min of whole-body cooling to induce a gradual decline in skin temperature from 34 to 30.5°C. Laser Doppler flux (LDF) was measured at the ventral forearm, and cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percentage change from baseline (%ΔCVC). Two minutes of static hand-grip exercise (35% maximal voluntary contraction) followed by 3 min of postexercise ischaemia were implemented before and toward the end of the cooling bout. l-Tyrosine supplementation did not affect blood pressure or heart rate responses to exercise or postexercise ischaemia. However, the blunted vasoconstriction response to whole-body cooling in older adults (placebo: Y = 39 ± 5%ΔCVC and O = 16 ± 2 %ΔCVC; P < 0.05) was augmented after l-tyrosine supplementation (l-tyrosine: Y = 40 ± 4%ΔCVC and O = 32 ± 5 %ΔCVC; P < 0.05). These results suggest that l-tyrosine bioavailability might limit thermoregulatory function in an older population.

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Norepinephrine is responsible for ~60% of the reflex cutaneous VC response in young individuals, whereas the remainder is due to a coreleased sympathetic adrenergic neurotransmitter(s) that has yet to be identified. There is conflicting evidence supporting neuropeptide Y in this role; however, other putative cotransmitters have yet to be tested in human skin. We hypothesize that ATP contributes to the reflex cutaneous VC response to whole‐body cooling (Tsk = 30.5 oC). Three microdialysis (MD) fibers were placed in the forearm skin of 7 (25 ± 1 years; 4 males, 3 females) individuals for infusion of 1) lactated Ringer's solution (control), 2) 10 mM L‐NAME, and 3) purinergic receptor blockade with 1mM suramin + L‐NAME. Laser Doppler flux (LDF) was measured over each MD site and cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percent change from baseline (%ΔCVC). L‐NAME was used to block the vasodilatory influence of ATP and unmask the P2X‐mediated VC response to exogenous ATP infusion (‐18 ± 2 %ΔCVC). This response was blocked in the suramin‐pretreated site (‐2 ± 1 %ΔCVC). During whole body cooling (Tsk = 30.5 oC), the VC response in the suramin site was attenuated (‐24 ± 3 %ΔCVC; p < 0.05) compared to the control site (‐35 ± 4 %ΔCVC). These data suggest that ATP has a contributory role in the reflex cutaneous VC response in humans during whole‐body cooling.**Funded by Iowa Osteopathic & Education Research Grant (IOER #03‐14‐01)