Neuropeptide Y antagonism reduces reflex cutaneous vasoconstriction in humans

Abstract

Previous studies have provided evidence of a non-noradrenergic contributor to reflex cutaneous vasoconstriction in humans but did not identify the transmitter responsible. To test whether neuropeptide Y (NPY) has a role, in two series of experiments we slowly reduced whole body skin temperature (TSK) from 34.5 to 31.7 degrees C. In protocol 1, Ringer solution and the NPY receptor antagonist BIBP-3226 alone were delivered intradermally via microdialysis. In protocol 2, yohimbine plus propranolol (Yoh + Pro), Yoh + Pro in combination with BIBP-3226, and Ringer solution were delivered to antagonize locally the vasomotor effects of NPY and norepinephrine. Blood flow was measured by laser Doppler flowmetry (LDF). Mean arterial blood pressure (MAP) was monitored at the finger (Finapres). In protocol 1, cutaneous vascular conductance (CVC) fell by 45%, to 55.1 +/- 5.6% of baseline at control sites (P < 0.05). At BIBP-3226-treated sites, CVC fell by 34.1% to 65.9 +/- 5.0% (P < 0.05; P < 0.05 between sites). In protocol 2, during body cooling, CVC at control sites fell by 32.6%, to 67.4 +/- 4.3% of baseline; at sites treated with Yoh + Pro, CVC fell by 18.7%, to 81.3 +/- 4.4% of baseline (P < 0.05 vs. baseline; P < 0.05 vs. control) and did not fall significantly at sites treated with BIBP-3226 + Yoh + Pro (P > 0.05; P < 0.05 vs. other sites). After cooling, exogenous norepinephrine induced vasoconstriction at control sites (P < 0.05) but not at sites treated with Yoh + Pro + BIBP-3226 (P > 0.05). These results indicate that NPY participates in sympathetically mediated cutaneous vasoconstriction in humans during whole body cooling.

The effect of microdialysis needle trauma on cutaneous vascular responses in humans

“…The finding that the combination of ice or LA with fiber placement reverses the increased threshold is not in keeping with this speculation about damage to nerve fibers by fiber placement. The finding that fiber placement increases the threshold for activation of the active vasodilator system to a higher temperature might also be due to fiber placement disrupting local transmitters, such as substance P (34) or others (4,17,20,25,32,33). It could also be that the elevated levels of histamine observed in the first 30 min following fiber placement (7) lead to its depletion.…”

Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling

“…We have previously found that this combination and level of adrenergic antagonists was effective in inhibiting the cutaneous vascular responses to exogenous norepinephrine (36 -37, 39). Subjects had two microdialysis probes placed intradermally (3,7,20,39). These probes, described previously (3,7,20), consisted of 1 cm of microdialysis tubing (inner diameter 200 m, 18 kDa nominal molecular weight cutoff) attached at each end to polyimide tubing.…”

“…1). Finally, norepinephrine (10 mM) was perfused through the microdialysis tubing to the sites to test for the adequacy of blockade (39). A reduction in CVC at a yohimbinepropranolol-treated site of Ͼ10% was taken to indicate inadequate blockade, and data from any such site were excluded from further analysis.…”

“…Procedures were the same as for part 1. The exception was that a 10 M solution of the NPY Y1 antagonist BIBP-3226 (8,13,34,39), in Ringer solution, was perfused at 4 l/min through one of two microdialysis membranes. Sterile Ringer solution was perfused through the other.…”

“…We also examined whether blockade of receptors for neuropeptide Y (NPY) might indicate a role for that known sympathetic cotransmitter (39). Finally, we sought to discover whether there was a role for sensory elements in the skin by applying local anesthetic to the areas of cooling and blood flow measurement.…”