We have investigated the mediators and mechanisms underlying the vasodilato
r effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its iso
mers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to
quantify the release of mediators within the dermal response and scanning
laser Doppler imaging to measure changes in blood flux. The effects of loca
l anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET r
eceptor blockade on the ET-induced vascular response were also investigated
. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by
a long-lasting flare which was accompanied by a short-lived burning pruritu
s. The concentration of nitric oxide (NO) in dialysate collected within the
pallor response to 5 muM ET-1 (1.43 +/- 0.64 muM, n = 5) was not significa
ntly different from baseline levels collected prior to injection (0.86 +/-
0.38 muM) whilst that in the flare increased to reach a peak value of 2.28
+/- 0.61 muM at between 4 and 10 min after intradermal injection (P < 0.004
). Pretreatment with local anaesthetic slowed the development of the flare
and significantly reduced its size by up to 52% at 20 min after injection (
P < 0.05) but had no significant effect on the central pallor. L-NAME, deli
vered by dialysis also caused a significant reduction in the ET-1-induced f
lare (P < 0.005). Bosentan, the non-selective ETA/ETB antagonist, when give
n by dialysis at the site of injection, reduced the area of both the ET-1-i
nduced palter and surrounding flare by 41 and 26%, respectively. No signifi
cant increase in tissue histamine was measured within either the pallor or
flare response to ET-1, -2 or -3. Together these data confirm that the vaso
dilator response to endothelin-1 in human skin is neurogenic in origin and
that it is in part mediated by the local release of nitric oxide. There app
ears to be little evidence for the involvement of mast cell-derived histami
ne in the initiation or modulation of ET-induced vasodilatation, in vivo.