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Roles of nitric oxide synthase isoforms in cutaneous vasodilation induced by local warming of the skin and whole body heat stress in humans

Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs, South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital Division; and Division of Geriatrics and Gerontology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Submitted 29 June 2009 ; accepted in final form 9 September 2009

Nitric oxide (NO) participates in the cutaneous vasodilation caused by increased local skin temperature (Tloc) and whole body heat stress in humans. In forearm skin, endothelial NO synthase (eNOS) participates in vasodilation due to elevated Tloc and neuronal NO synthase (nNOS) participates in vasodilation due to heat stress. To explore the relative roles and interactions of these isoforms, we examined the effects of a relatively specific eNOS inhibitor, N-amino-L-arginine (LNAA), and a specific nNOS inhibitor, N-propyl-L-arginine (NPLA), both separately and in combination, on skin blood flow (SkBF) responses to increased Tloc and heat stress in two protocols. In each protocol, SkBF was monitored by laser-Doppler flowmetry (LDF) and mean arterial pressure (MAP) by Finapres. Cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). Intradermal microdialysis was used to treat one site with 5 mM LNAA, another with 5 mM NPLA, a third with combined 5 mM LNAA and 5 mM NPLA (Mix), and a fourth site with Ringer only. In protocol 1, Tloc was controlled with combined LDF/local heating units. Tloc was increased from 34°C to 41.5°C to cause local vasodilation. In protocol 2, after a period of normothermia, whole body heat stress was induced (water-perfused suits). At the end of each protocol, all sites were perfused with 58 mM nitroprusside to effect maximal vasodilation for data normalization. In protocol 1, at Tloc = 34°C, CVC did not differ between sites (P > 0.05). LNAA and Mix attenuated CVC increases at Tloc = 41.5°C to similar extents (P < 0.05, LNAA or Mix vs. untreated or NPLA). In protocol 2, in normothermia, CVC did not differ between sites (P > 0.05). During heat stress, NPLA and Mix attenuated CVC increases to similar extents, but no significant attenuation occurred with LNAA (P < 0.05, NPLA or Mix vs. untreated or LNAA). In forearm skin, eNOS mediates the vasodilator response to increased Tloc and nNOS mediates the vasodilator response to heat stress. The two isoforms do not appear to interact during either response.

skin; nitric oxide; nitric oxide synthase 1; nitric oxide synthase 3; microdialysis

Abbreviations: CVC, Cutaneous vascular conductance • eNOS, Endothelial nitric oxide synthase (NOS3) • iNOS, Inducible nitric oxide synthase (NOS2) • LDF, Laser-Doppler flowmetry • LNA, N-nitro-L-arginine • LNAA, N-amino-L-arginine • L-NAME, N-nitro-L-argininemethyl ester • L-NMMA, N-monomethyl-L-arginine • nNOS, neuronal nitric oxide synthase (NOS1) • N, N-nitro-L-arginine-2,4-L-diaminobutyric amide • NPLA, N-propyl-L-arginine • PR, Pulse rate • SkBF, Skin blood flow • Tloc, Local skin temperature • Tor, Oral temperature • Tsk, Skin temperature • 7-NI, 7-Nitroindazole