Evidence for ETA and ETB receptors in rat skin and an investigation of their function in the cutaneous microvasculature.

1. The relative contribution of ETA and ETB receptors in the response of rat skin to endothelins was investigated by use of the selective ETB agonist IRL-1620 and the selective ETA antagonist BQ-123. 2. Binding data suggest the presence of ETA and ETB receptors as preincubation with [Ala3,11,18Nle7]-endothelin-1 reduced ET-1 binding by approximately 40%. 3. Intradermal injection of endothelin-1 (ET-1, 1-10 pmol/site) and ET-3 (3-100 pmol/site) induced a dose-dependent decrease in local blood flow assessed by 133Xe clearance at test sites in rat skin. 4. The endothelin analogue [Ala3,11,18Nle7]-ET-1 (30-1000 pmol/site) induced significant vasoconstriction (P < 0.05) at the highest doses used and the selective ETB receptor agonist, IRL-1620 [Suc[Glu9,Ala11,15] endothelin (8-21)], (0.01-100 pmol/site) acted in a potent manner to induce a significant (P < 0.01) dose-dependent decrease in 133Xe clearance. 5. Co-injection with the selective ETA receptor antagonist, BQ-123 (1 nmol/site), completely abolished the vasoconstriction to ET-1 and partially to ET-3, but had no effect on IRL-1620-induced vasoconstriction. In addition, IRL-1620 responses were not altered at sites treated with submaximal doses of a nitric oxide synthase inhibitor or a prostaglandin synthase inhibitor. 6. ET-1 and IRL-1620 (100 fmol-1 pmol/site) did not induce oedema formation as measured by [125I]-albumin accumulation in the presence or absence of the vasodilator, calcitonin gene-related peptide (CGRP). ET-1 (1-3 pmol/site) inhibited substance P-induced oedema formation and this effect,suggested to be secondary to a vasoconstrictor effect, was significantly reversed by BQ-123 (1 nmol/site).7. The findings in this study indicate that there are ETA and ETB receptors in rat skin and agents which activate either receptor act to mediate a decrease in cutaneous blood flow, but have no effect on increased microvascular permeability.