Local Tetrahydrobiopterin Administration Augments Reflex Cutaneous Vasodilation Through Nitric Oxide-Dependent Mechanisms In Aged Human Skin

ASU Author/Contributor (non-ASU co-authors, if there are any, appear on document)
Caroline Smith, Assistant Professor (Creator)
Appalachian State University (ASU )
Web Site: https://library.appstate.edu/

Abstract: Functional constitutive nitric oxide synthase (NOS) is required for full expression of reflex cutaneous vasodilation that is attenuated in aged skin. Both the essential cofactor tetrahydrobiopterin (BH4) and adequate substrate concentrations are necessary for the functional synthesis of nitric oxide (NO) through NOS, both of which are reduced in aged vasculature through increased oxidant stress and upregulated arginase, respectively. We hypothesized that acute local BH4 administration or arginase inhibition would similarly augment reflex vasodilation in aged skin during passive whole body heat stress. Four intradermal microdialysis fibers were placed in the forearm skin of 11 young (22 ± 1 yr) and 11 older (73 ± 2 yr) men and women for local infusion of 1) lactated Ringer, 2) 10 mM BH4, 3) 5 mM (S)-(2-boronoethyl)-l-cysteine + 5 mM N?-hydroxy-nor-l-arginine to inhibit arginase, and 4) 20 mM NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced. After a 1.0°C rise in oral temperature (Tor), mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and expressed as a percentage of maximum (%CVCmax; 28 mM sodium nitroprusside and local heat, 43°C). Vasodilation was attenuated at the control site of the older subjects compared with young beginning at a 0.3°C rise in Tor. BH4 and arginase inhibition both increased vasodilation in older (BH4: 55 ± 5%; arginase-inhibited: 47 ± 5% vs. control: 37 ± 3%, both P < 0.01) but not young subjects compared with control (BH4: 51 ± 4%CVCmax; arginase- inhibited: 55 ± 4%CVCmax vs. control: 56 ± 6%CVCmax, both P > 0.05) at a 1°C rise in Tor. With a 1°C rise in Tor, local BH4 increased NO-dependent vasodilation in the older (BH4: 31.8 ± 2.4%CVCmax vs. control: 11.7 ± 2.0%CVCmax, P < 0.001) but not the young (BH4: 23 ± 4%CVCmax vs. control: 21 ± 4%CVCmax, P = 0.718) subject group. Together these data suggest that reduced BH4 contributes to attenuated vasodilation in aged human skin and that BH4 NOS coupling mechanisms may be a potential therapeutic target for increasing skin blood flow during hyperthermia in older humans.

Additional Information

Anna E. Stanhewicz, Rebecca S. Bruning, Caroline J. Smith, W. Larry Kenney, and Lacy A. Holowatz (2012). Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin. Journal of Applied Physiology, Vol. 112, No. 5. March 2012, pages 791-797. https://doi.org/10.1152/japplphysiol.01257.2011. Publisher version of record available at: https://www.physiology.org/doi/full/10.1152/japplphysiol.01257.2011
Language: English
Date: 2012
skin blood flow, aging, temperature regulation, tetrahydrobiopterin, nitric oxide synthase

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