This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The ability to vasoconstrict and conserve heat during cold exposure is reduced in aged men and women. Cutaneous vasoconstriction (VC) in response to whole-body cooling in young, human skin is controlled by noradrenergic (~60% of the response) and sympathetic co-transmitter (~40%) mechanisms. Moreover, cotransmitter-mediated vasoconstriction (VC) during whole-body cooling is functionally lost in older humans and adrenergic responsiveness to norepinephrine (NE) is reduced. Putative mechanisms through which reflex VC may be attenuated with age include 1) increased oxidant stress resulting in a reduction in an essential co-factor in catecholamine production, tetrahydrobiopterin (BH4), or 2) dimished responsiveness of vascular smooth muscle to co-transmitter binding post-junctionally. These mechanisms will be assessed using in vivo analysis of cutaneous vascular conductance using laser-doppler flometry coupled with intradermal microdialysis to introduce specific pharmacological agents. After pharmacological agents have begun perfusing skin, whole-body skin cooling will commence. Forearm skin blood flow will be measured continuously over each microdialysis site using laser Doppler flowmetry while mean skin temperature is decreased from 34 to 30.5oC over a 30-min period and clamped for an additional 10-min at 30.5oC using a water-perfused suit.. Cutaneous vascular conductance will be calculated as the ratio of laser Doppler flux to mean arterial pressure and expressed as percent change from baseline. Our proposed studies intend to systematically investigate neuronal and vascular mechanisms of sympathetic neurotransmitter storage, release, and receptor binding in human skin. Also, we intend to supplement BH4 and ascorbate exogenously in aged subjects to potentially ameliorate vasoconstrictor function. The proposed studies will be pilot work used for an upcoming competitive NIH R01 renewal.
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