ENDOTHELIN RECEPTOR SUBTYPES IN SMALL ARTERIES - STUDIES WITH FR139317 AND BOSENTAN

We studied the effects of the selective endothelin A receptor antagonist FR139317 and the combined endothelin A/endothelin B receptor antagonist bosentan in rat mesenteric arteries by using a video dimension analyzer. In endothelium-denuded arteries, increasing concentrations of endothelin-1 evoked a biphasic vasoconstriction. The first phase was observed at low concentrations (10(-16) to 10(-11) mol/L) of endothelin-1 and was relatively weak. However, the contractions characterizing the second phase, which occurred at higher concentrations (10(-10) to 3 X 10(-8) mol/L) of endothelin-1, were much stronger. FR139317 concentration-dependently shifted the second phase of the endothelin-1-induced contraction curve to the right without affecting the first phase. In contrast, bosentan inhibited both the first and the second phase. Even after the blockade of endothelin A receptor, increasing concentrations of the endothelin B receptor agonists endothelin-3 and sarafotoxin S6c still induced small contractions. Maximal contractions induced by single-bolus extraluminal application of endothelin-3 (10(-9) mol/L) or sarafotoxin S6c (3 X 10(-8) mol/L) were markedly more pronounced than responses induced by cumulative concentrations, suggesting endothelin B receptor downregulation upon repeated and sustained activation. The response induced by a single bolus of endothelin-3 (10(-9) mol/L) was antagonized by bosentan but not by FR139317, confirming that endothelin B receptors were involved. In endothelium-intact arteries half-maximally precontracted with norepinephrine, bosentan but not FR139317 inhibited the relaxations induced by intraluminally applied endothelin-3. Thus, selective endothelin A receptor antagonist preserves relaxations to endothelins, and combined endothelin A/endothelin B receptor antagonist is more efficacious in inhibiting contractions in resistance arteries.