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. (ABSTRACT TRUNCATED AT 250 WORDS)
Takase
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H
Department of Cardiology, Cardiovascular Research, University Hospital/Inselspital, Bern, Switzerland.
Moreau
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P
Lüscher
T F
TF
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology*; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D017466:Receptors, Endothelin / Q000145:classification / Q000378:metabolism*; D013152:Splanchnic Circulation / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C079574:FR 139317; D000077300:Bosentan