title: Noradrenaline and neuropeptide Y contribute to initial, but not sustained, vasodilatation in response to local skin warming in humans.
abstract: What is the central question of this study? Previous work has produced the counterintuitive finding that the vasoconstrictor neurotransmitters noradrenaline and neuropeptide Y are involved in vasodilatation. We aimed to discover whether sympathetic neurotransmitters are required for the sustained vasodilatation in response to local skin warming, as has been previously suggested, and to determine whether noradrenaline and neuropeptide Y are 'mediating' the sustained vasodilator response directly or acting to 'prime' (or kick-start) it. What is the main finding and its importance? We have found that noradrenaline and neuropeptide Y are required at the initiation of vasodilatation in response to local skin warming, if a complete vasodilator response is to be achieved; however, they are not required once vasodilatation has begun. In a three-part study, we examined whether noradrenaline, neuropeptide Y (NPY) and endothelial nitric oxide synthase (eNOS) were involved in the sustained vasodilatation in response to local skin warming. Forearm skin sites were instrumented with intradermal microdialysis fibres, local skin heaters and laser-Doppler flow probes. Local skin temperature (T(loc)) was increased from 34 to 42°C at a rate of 0.5°C (10 s)(-1). Laser-Doppler flow was expressed as cutaneous vascular conductance (CVC; laser-Doppler flow/mean arterial pressure). In part 1, three skin sites were prepared; two were treated with the study vehicle (lactated Ringer solution), while the third site was treated with yohimbine and propranolol to antagonize α- and β-receptors, and 10 min of baseline data were record at a T(loc) of 34°C. Receptor antagonism was confirmed via infusion of clonidine. The T(loc) was increased to 42°C at all sites. Once CVC had stabilized, site 2 was treated with yohimbine and propranolol to examine the effect of adrenergic receptor blockade on sustained vasodilatation of the skin. Receptor antagonism was again confirmed via infusion of clonidine. All sites were treated with sodium nitroprusside, and T(loc) was increased to 43°C to elicit maximal vasodilatation. In parts 2 and 3, the general protocol was the same, except that BIBP-3226 was used to antagonize Y(1)-receptors, NPY to test the efficacy of the antagonism, N(G)-amino-l-arginine to inhibit eNOS and ACh to test the adequacy of inhibition. Compared with control conditions, antagonism of α- and β-receptors, Y(1)-receptors and eNOS before local skin warming reduced the initial and sustained vasodilatation in response to increased T(loc). However, treatment with yohimbine and propranolol or BIBP-3226 after local skin warming did not affect the sustained vasodilatation [CVC, 90 ± 3 versus 89 ± 3%max (control vs. yohimbine and propranolol) and 88 ± 5 versus 87 ± 4%max (control vs. BIBP-3226); P > 0.05]. N(G)-Amino-l-arginine perfusion caused a large reduction in CVC during this phase (89 ± 5 versus 35 ± 4%max; P < 0.05). These data indicate that if their actions are antagonized after local warming and cutaneous vasodilatation has occurred, noradrenaline and NPY play little, if any, role in the sustained vasodilatation in response to local skin warming. However, eNOS contributes markedly to the sustained vasodilatation regardless of when it is inhibited.
authors.affiliation: * Department of Kinesiology, 2007 Moore Hall, The University of Alabama, Tuscaloosa, AL 35487, USA. ghodges1@bamaed.ua.edu.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Hodges
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sparks
mesh_terms: D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D006801:Humans; D008297:Male; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D012867:Skin / Q000187:drug effects; D012881:Skin Temperature / Q000187:drug effects / Q000528:radiation effects*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: C092926:BIBP 3226; D009478:Neuropeptide Y; D009599:Nitroprusside; D015016:Yohimbine; C063904:N(G)-aminoarginine; D001120:Arginine; D011433:Propranolol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D003000:Clonidine; D009638:Norepinephrine