Endothelin‐1 induces a histamine‐dependent flare in vivo, but does not activate human skin mast cells in vitro.

Abstract

The role of the mast cell in endothelin-1 induced flare has been investigated by in vivo and in vitro experiments. The intradermal injection of endothelin-1 (10 pmol) into human skin induced a pallor with surrounding axon-reflex flare which is similar to the flare response to histamine (1 nmol). At these doses, chosen to give identical flare areas, blood flow was increased in the area of the endothelin-induced flare over a longer period.A systemic Hl-receptor antagonist significantly inhibited the area of both flares, although blood flow in the remaining portion of the endothelin-induced flare remained raised.Endothelin-1 at concentrations up to 3 x 10-5 M failed to release histamine from human dispersed skin mast cells. We suggest from these results that a major component of endothelin-1 induced flare results from mast cell activation that is secondary to direct stimulation of sensory nerves by the peptide.

The Neurogenic Vasodilator Response to Endothelin‐1: A Study in Human Skin In Vivo

“…The relatively small amount of histamine released at the focus of the intradermal injection of ET_1 strongly suggests that histamine does not play a major role in modulating the neurogenic response to ET_1. These findings are consistent with those obtained by Brain et al (1992), which indicate that ET_1 does not release histamine from human cutaneous mast cells, in vitro. The lack of relationship between the extent of the flare and the amount of histamine released and the differences between ET-induced and codeine-induced histamine release indicate that these two agonists stimulate very different patterns of secondary mediator release which are capable of stimulating an axon-mediated flare.…”

Endothelin-1 induces itch and pain in the mouse cheek model

“…Besides evoking a sensation of burning pruritus (Ferreira et al, 1989), injection of ET-1 into the forearm of volunteers also induces a wheal and flare response which is reduced by treatment with histamine H 1 receptors antagonists, but fails to release histamine from human acutely dispersed skin mast cells (Brain et al, 1992). Other studies, however, have shown that ET-1 can induce degranulation of peritoneal mast cells (Yamamura et al, 1994;Maurer et al, 2004).…”

Endothelin‐1‐induced ETA receptor‐mediated nociception, hyperalgesia and oedema in the mouse hind‐paw: modulation by simultaneous ETB receptor activation

“…On the other hand, endothelin‐1 has recently been found to elicit pain‐related paw‐flinching behaviour in the rat, when applied (albeit at high concentrations) to the epineural surface of the sciatic nerve (Davar et al ., 1998), which could indicate that it may directly activate sensory neurones. This view is further substantiated by evidence that the peptide causes substance P‐mediated depolarization of ventral roots in the rat newborn spinal cord (Yoshizawa et al ., 1989), markedly augments substance P release from rat isolated sensory neurones (Dymshitz & Vasko, 1994), interacts with specific binding sites in rat dorsal root ganglia (Kar et al ., 1991) and causes a histamine‐dependent axon‐reflex (sensory neuron‐mediated) flare reaction in human skin, without directly causing human mast‐cell degranulation in vitro (Brain et al ., 1992; Wenzel et al ., 1998).…”