Noradrenaline and neuropeptide Y contribute to initial, but not sustained, vasodilatation in response to local skin warming in humans.

NEW FINDINGS: 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 ß-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 ß-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.

Contributions of endothelial nitric oxide synthase, noradrenaline, and neuropeptide Y to local warming-induced cutaneous vasodilatation in men.

We performed a two-part study to determine the roles of endothelial nitric oxide synthase (eNOS) and the vasoconstrictor nerves neurotransmitters noradrenaline (NA) and neuropeptide Y (NPY) in the cutaneous vasodilator response to local skin warming. Forearm skin sites were instrumented with intradermal microdialysis fibres, local heaters, and laser-Doppler flow (LDF) probes. Sites were locally heated from 34 to 42°C. LDF was expressed as cutaneous vascular conductance (CVC; LDF/mean arterial pressure). In Part I, we tested whether sympathetic noradrenergic nerves acted via eNOS. In 8 male participants, treatments were as follows: 1) untreated; 2) bretylium tosylate (BT), preventing sympathetic neurotransmitter release; 3) l-NAA to inhibit eNOS; and 4) combined BT+l-NAA. At treated sites, the initial peak response was markedly reduced, and the plateau phase response to 35min of local warming was also reduced (P<0.05), which was not different among those sites (P>0.05). In Part II, we tested whether NA and NPY were involved in the vasodilator response to local warming. In Part IIa, treatments were: 1) untreated; 2) propranolol and yohimbine to antagonize α- and ß-receptors; 3) l-NAA; and 4) combined propranolol, yohimbine, and l-NAA. In Part IIb, conditions were: 1) untreated; 2) BIBP to antagonize Y1-receptors; 3) l-NAA; and 4) combined BIBP and l-NAA. All treatments caused a reduction in the initial peak and plateau responses to local skin warming (P<0.05). The results of Part II indicate that both NA and NPY play roles in the cutaneous vasodilator response and their actions are achieved via eNOS. These data indicate that NA and NPY are involved in the initial, rapid rise in skin blood flow at the onset of local skin warming. However, their vasodilator actions in response to local skin warming appears to be manifested through eNOS.