ENDOTHELIN-I INDUCES VASODILATION IN HUMAN SKIN BY NOCICEPTOR FIBERS AND RELEASE OF NITRIC-OXIDE

Aims Endothelin is a peptide produced by endothelial cells with many b iological properties. In the human skin microcirculation endothelin in duces neurogenic vasodilation associated with burning pruritus. We inv estigated the mechanisms involved in this response. Methods The effect s of prolonged pretreatment with capsaicin, a specific inhibitor of po limodal nociceptor fibres, and of the nitric oxide synthase inhibitor L-NMMA on endothelin-1-induced vasodilation were studied in 15 human s ubjects. Furthermore, we investigated the effects of the ETA-selective antagonist PD147953 on bradykinin-induced vasodilation. Results After local injection, endothelin-1 caused vasoconstriction at the injectio n site and a profound vasodilation in the surrounding area (flare reac tion, P<0.01). This response was specific and not induced by saline, a lbumin, acetylcholine or an ET-antagonist. Prolonged capsaicin pretrea tment inhibited endothelin-1 induced vasodilation in the area surround ing the injection site, but not the central vasoconstriction at the in jection site. Bradykinin also induced a marked vasodilation in the are a surrounding the injection-Site; this was not inhibited by an ETA-sel ective antagonist, while the flare reaction was. L-NMMA applied at the site of the flare reaction prevented endothelin-1-induced vasodilatio n. Conclusions Endothelin-1 in the human skin microcirculation stimula tes polimodal nociceptor fibres leading to the release of nitric oxide . This response may play a pathophysiological role in inflammatory pro cesses in the human skin.