(Hypertension. 1995;25:739-743.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin Receptor Subtypes in Small Arteries
Studies With FR139317 and Bosentan
From the Department of Cardiology, Cardiovascular Research, University Hospital/Inselspital, Bern, Switzerland.
Correspondence to Thomas F. Lüscher, Cardiology, Cardiovascular Research, University Hospital/Inselspital, CH-3010 Bern, Switzerland.
Abstract 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 3x10-8 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 (3x10-8 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.
Key Words: endothelins • receptors, endothelin • vascular resistance
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