Vasoconstrictor effect of endothelin-1 in human skin: role of ET_Aand ET_Breceptors

Abstract

The aim of this project was to investigate the role of ETA and ETB receptors in the mediation of endothelin (ET)-1-induced vasoconstriction in human skin. This information should provide important insights into the design of pharmacological intervention against skin vasospasm induced by ET-1 in peripheral vascular disease or surgical trauma. Vasoconstriction in response to intra-arterial drug infusion in isolated perfused human skin flaps (8 × 18 cm) derived from dermolipectomy specimens was assessed by studying changes in skin perfusion and perfusion pressure under constant flow rate in each drug treatment ( n = 4). It was observed that ET-1 (10−10 to 10−8 M) and norepinephrine (NE, 10−8 to 10−5 M) caused skin vasoconstriction in a concentration-dependent manner, with the vasoconstrictor potency of ET-1 ∼200-fold higher than NE. The ETA-receptor antagonist BQ-123 but not the ETB-receptor antagonist BQ-788 blocked the vasoconstrictor effect of ET-1. This observation was confirmed by studying skin perfusion using the dermofluorometry technique. In addition, ETB-receptor agonists BQ-3020 and sarafotoxin S6c (10−9 to 10−6 M) did not evoke skin vasoconstriction. BQ-3020 also did not elicit skin vasoconstriction even in the presence of 10−5M of N ω-nitro-l-arginine methyl ester and indomethacin. Furthermore, results from saturable and competitive ET-1 radioligand membrane receptor binding assays revealed that high-affinity and capacity binding sites are predominantly the ETA receptor subtype in endothelium-denuded skin arteries and veins of 0.5–1.5 mm diameter, with an ETA-to-ETBreceptor ratio of 83:17 in arteries ( n= 5) and 78:22 in veins ( n = 7). Results from the present functional and radioligand receptor binding studies clearly indicate that ET-1 is a very potent vasoconstrictor in human skin and its vasoconstrictor effect is primarily mediated by ETAreceptors, with no significant participation from ETB receptors.

Pharmacological characterization of vasomotor activity of human musculocutaneous perforator artery and vein

“…The dose-response effect of L-type Ca 2ϩ channel blockers on skin hemodynamics and viability in flap surgery has yet to be investigated. It has been demonstrated that the vasoconstrictor effect of ET-1 is mediated by ET A receptors, with little participation from ET B receptors (30). Therefore, selective ET A -receptor antagonists may also be used as a combined treatment for skin flap vasospasm.…”

Endothelins - clinical perspectives

“…Mo re re cen tly, ET R Bs ha ve al so been iden ti fi ed in vas cu lar smoo th mus cle cel ls, and these two re cep to rs me dia te va so con stric tion (43). The pre sen ce of ETRB wi th the va ria tion of ETRA/ ETRB ra tio was de tec ted on en dot he lial cel ls and it is hig her in ar te ries than in vei ns.…”

The isolated perfused human skin flap model: A missing link in skin penetration studies?

“…This tissue is normally discarded in abdominal dermolipectomy (Kreidstein et al, 1991). Several techniques have confirmed the perfusion of the flap (Black et al, 2001;Kreidstein et al, 1995;Lipa et al, 1999;Miland et al, 2008). Miland and colleagues (2008) confirmed the suitability of the dynamic infrared thermography (DIRT) to monitor skin flap perfusion and to differentiate between well and less perfused areas.…”