EFFECT OF BQ-123 AND RO-47-0203 (BOSENTAN) ON ENDOTHELIN-INDUCED VASOCONSTRICTION IN THE RAT SKIN

The effectiveness of intradermal (i.d.) BQ-123 (cyclo[D-Asp-Pro-D-Val- Leu-D-Trp]) and i.d. Ro 47-0203 (bosentan, 4-tert-butyl-N-[6-(2-hydrox y-ethoxy)-5 enoxy)-2,2'-bipyrimidin-4-yl]-benzene-sulfonamide) has bee n evaluated on local microvascular responses to endothelin-1 and endot helin-3, measured by a multiple site Xe-133 clearance technique in rat skin in vivo. Intradermal injection of endothelin-1 (0.3 pmol/site) a nd endothelin-3 (10 pmol/site) induced a similar (approximately 50-60% ) decrease in basal blood flow in rat skin. BQ-123 (3-1000 pmol/site), a selective endothelin ET(A) receptor antagonist, caused a significan t dose-dependent decrease in the vasoconstriction induced by endotheli n-1 (P < 0.05) but was less effective on vasoconstriction induced by e ndothelin-3. Bosentan (3-1000 pmol/site), a new non-peptide mixed anta gonist of endothelin ET(A) and endothelin ET(B) receptors, significant ly reduced the vasoconstriction induced by endothelin-1 but was less e ffective than BQ-123. BQ-123 and bosentan were similarly effective as antagonists of endothelin-3. BQ-123 and bosentan had no effect on basa l blood flow and no inhibitory activity on vasoconstriction induced by vasopressin (0.03 pmol/site) or phenylephrine (300 pmol/site). These findings indicate that BQ-123 and bosentan are effective and selective inhibitors of the vasoconstriction induced by endothelins in the rat skin microvasculature.