Attenuated noradrenergic sensitivity during local cooling in aged human skin

Abstract

Reflex-mediated cutaneous vasoconstriction (VC) is impaired in older humans; however, it is unclear whether this blunted VC also occurs during local cooling, which mediates VC through different mechanisms. We tested the hypothesis that the sensitization of cutaneous vessels to noradrenaline (NA) during direct skin cooling seen in young skin is blunted in aged skin. In 11 young (18-30 years) and 11 older (62-76 years) men and women, skin blood flow was monitored at two forearm sites with laser Doppler (LD) flowmetry while local skin temperature was cooled and clamped at 24• C. Cutaneous vascular conductance (CVC; LD flux/mean arterial pressure) was expressed as percentage change from baseline (% ∆CVC base ). At one site, five doses of NA (10 −10 -10 −2 M) were sequentially infused via intradermal microdialysis during cooling while the other 24• C site served as control (Ringer solution + cooling). At control sites, VC due to cooling alone was similar in young versus older (−54 ± 5 versus −56 ± 3% ∆CVC base , P = 0.46). In young, NA infusions induced additional dose-dependent VC (10 −8 , 10 −6 , 10 −4 and 10 −2 M: −70 ± 2, −72 ± 3, −78 ± 3 and −79 ± 4% ∆CVC base ; P < 0.05 versus control). In older subjects, further VC did not occur until the highest infused dose of NA (10 −2 M: −70 ± 5% ∆CVC base ; P < 0.05 versus control). When cutaneous arterioles are sensitized to NA by direct cooling, young skin exhibits the capacity to further constrict to NA in a dose-dependent manner. However, older skin does not display enhanced VC capacity until treated with saturating doses of NA, possibly due to age-associated decrements in Ca 2+ availability or α 2C -adrenoceptor function.

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

“…Direct responses at the site of drug administration Intradermal administration of noradrenaline through microdialysis fibres induces vasoconstriction (Thompson et al, 2005). Nevertheless, blood flow increased at the site of iontophoresis of adrenergic agonists in the present study.…”

“…Adrenergic vasoconstriction (Drummond, 2002;Thompson et al, 2005) might intensify these effects by reducing the dispersal of inflammatory mediators.…”

Reflex vasoconstriction in aged human skin increasingly relies on Rho kinase-dependent mechanisms during whole body cooling

“…skin blood flow; aging; temperature regulation; norepinephrine PERIPHERAL CUTANEOUS VESSELS constrict in response to cold exposure through distinct reflex and locally regulated mechanisms. Localized cooling of skin induces vasoconstriction (VC) that is partly mediated by both stimulation of ␣ 2 -adrenoreceptors by norepinephrine (NE) (9, 11) and upregulation of the downstream intracellular messenger Rho kinase (ROCK) (30, 31), whereas reflex sympathetically mediated VC relies on NE (ϳ60% of the VC response) and other coreleased sympathetic neurotransmitters (ϳ40%) (29,34).In aged skin (Ͼ60 yr), the reflex VC response is not only blunted but relies entirely on an already compromised adrenergic mechanism (18,(32)(33)(34). Furthermore, the vascular signaling pathways that couple adrenoreceptor activation to VC may be altered (20,31).…”

“…In aged skin (Ͼ60 yr), the reflex VC response is not only blunted but relies entirely on an already compromised adrenergic mechanism (18,(32)(33)(34). Furthermore, the vascular signaling pathways that couple adrenoreceptor activation to VC may be altered (20,31).…”

Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin

“…Finally, a minimal concentration of ascorbate (1 mg/ml) was added as a preservative to prevent the degradation of NE. This concentration has been used in previous studies and did not alter the VC response (35,36).…”