Neurokinin-1 receptor desensitization attenuates cutaneous active vasodilatation in humans

• Published in: The Journal of physiology Vol. 577; no. 3; pp. 1043 - 1051
• Main Authors: Wong, Brett J., Minson, Christopher T.
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15.12.2006; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Adult; Blood Pressure; Enzyme Inhibitors - pharmacology; Erythrocytes; Female; Hot Temperature; Humans; Integrative; Laser-Doppler Flowmetry; Male; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Nitroprusside - pharmacology; Receptors, Neurokinin-1 - drug effects; Receptors, Neurokinin-1 - metabolism; Regional Blood Flow - drug effects; Skin - blood supply; Stress, Physiological - metabolism; Stress, Physiological - physiopathology; Substance P - pharmacology; Vasodilation - drug effects
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2006.112508

To date, the neurotransmitter(s) and pathways involved in cutaneous active vasodilatation are not fully understood. The purpose of this study was to determine the potential involvement of neurokinin-1 (NK 1 ) receptors to active vasodilatation. Our experimental model exploited our previous findings that repeated microdialysis infusions of substance P desensitize the NK 1 receptors and that substance P-induced vasodilatation contains a substantial nitric oxide (NO) component. Eleven subjects were equipped with four microdialysis fibres on the ventral forearm. Site 1 served as a control and received a continuous infusion of Ringer solution. Site 2 received a continuous infusion of 10 m m l -NAME to inhibit NO synthase. Site 3 received a 10 μ m dose of substance P to desensitize the NK 1 receptors prior to whole-body heating. Site 4 received a 10 μ m dose of substance P combined with 10 m m l -NAME. Red blood cell (RBC) flux was measured via laser-Doppler flowmetry, and cutaneous vascular conductance (CVC) was calculated as RBC flux/mean arterial pressure and normalized to maximal vasodilatation via 28 m m sodium nitroprusside. Substance P was infused for 15 min at 4 μl min −1 in sites 3 and 4, and skin blood flow was allowed to return to baseline (∼45–60 min). Subjects then underwent a period of whole-body heat stress to raise oral temperature 0.8–1.0°C above baseline. Pretreatment with substance P increased CVC to 48 ± 2% CVC max , which was significantly greater than for sites pretreated with substance P combined with l -NAME (27 ± 2% CVC max ; P < 0.001). During whole-body heating, CVC in control sites increased to 69 ± 3% CVC max . Sites pretreated with substance P (48 ± 3% CVC max ) were significantly reduced compared to control sites ( P < 0.001). The CVC response to whole-body heat stress in l -NAME sites was significantly reduced (32 ± 3% CVC max ; P < 0.001) compared to both control sites and sites pretreated with substance P. The CVC response to whole-body heating was nearly abolished in sites pretreated with substance P combined with l -NAME (20 ± 2% CVC max ) and was significantly reduced compared to the other three sites (all P < 0.001). These data suggest NK 1 receptors contribute to active vasodilatation and that combined NK 1 receptor desensitization and NO synthase inhibition further diminishes active vasodilatation.