Neurokinin‐1 receptor desensitization attenuates cutaneous active vasodilatation in humans

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Abstract
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 (NK1) receptors to active vasodilatation. Our experimental model exploited our previous findings that repeated microdialysis infusions of substance P desensitize the NK1 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 mm l-NAME to inhibit NO synthase. Site 3 received a 10 μm dose of substance P to desensitize the NK1 receptors prior to whole-body heating. Site 4 received a 10 μm dose of substance P combined with 10 mm 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 mm 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% CVCmax, which was significantly greater than for sites pretreated with substance P combined with l-NAME (27 ± 2% CVCmax; P < 0.001). During whole-body heating, CVC in control sites increased to 69 ± 3% CVCmax. Sites pretreated with substance P (48 ± 3% CVCmax) 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% CVCmax; 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% CVCmax) and was significantly reduced compared to the other three sites (all P < 0.001). These data suggest NK1 receptors contribute to active vasodilatation and that combined NK1 receptor desensitization and NO synthase inhibition further diminishes active vasodilatation.