title: Neurokinin-1 receptor desensitization attenuates cutaneous active vasodilatation in humans.
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 (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 mM L-NAME to inhibit NO synthase. Site 3 received a 10 microm dose of substance P to desensitize the NK(1) receptors prior to whole-body heating. Site 4 received a 10 microm 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 microl min(-1) in sites 3 and 4, and skin blood flow was allowed to return to baseline (approximately 45-60 min). Subjects then underwent a period of whole-body heat stress to raise oral temperature 0.8-1.0 degrees 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.
authors.affiliation: Department of Human Physiology, 122 C Esslinger Hall, 1240 University of Oregon, Eugene, OR 97403, USA.
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Wong
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Minson
mesh_terms: D000328:Adult; D001794:Blood Pressure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes; D005260:Female; D006358:Hot Temperature; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply*; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology*; D013373:Substance P / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D018040:Receptors, Neurokinin-1; D009599:Nitroprusside; D013373:Substance P; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester