Pharmacological heterogeneity of constrictions mediated by endothelin receptors in rat pulmonary arteries.
The endothelin (ET) receptors mediating rat pulmonary arterial constrictions were investigated. ET-1 and ET-3 constricted both isolated intrapulmonary artery (IPA) and extrapulmonary artery (EPA), with ET-1 having a potency approximately 10 times that of ET-3. The ET(B) selective agonist IRL-1620 produced constriction of only IPA. The ET(B) selective antagonist BQ-788 suppressed the ET-1-induced constriction of IPA only. The ET(A) selective antagonist BQ-123 more effectively antagonized the ET-1-induced constriction of EPA than that of IPA. The combination of BQ-123 and BQ-788 increased the antagonistic response to ET-1 in IPA but not in EPA. Then, large constriction remained in IPA and EPA. The receptor nonselective antagonist PD-145065 almost completely inhibited the ET-1-induced constriction of IPA and EPA. BQ-123 completely inhibited the ET-3-induced constriction of EPA; however, it partially suppressed that of IPA. The combination of BQ-123 and BQ-788 completely inhibited the ET-3-induced constriction of IPA. These results demonstrate that the ET-1-induced constrictions are mediated by both ET(A) and ET(B) in IPA and by ET(A) in EPA. Because of differences in sensitivity to ET receptor antagonists for ET-1- and ET-3-induced constrictions, pharmacological heterogeneity of ET(A) is suggested. Additionally, endothelial denudation affected the ET-3-induced constriction of EPA, but not of IPA, and it didn't affect the response to ET-1. This suggests that the vasodilatory effect of endothelium on ET-3-induced vasoconstrictions varies depending on pulmonary vascular regions.
Higashi
T
T
Third Department of Internal Medicine, Fukui Medical School, Japan.
Ishizaki
T
T
Shigemori
K
K
Nakai
T
T
Miyabo
S
S
Inui
T
T
Yamamura
T
T
D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D019334:Endothelin-3 / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D016232:Endothelins; D010446:Peptide Fragments; D017466:Receptors, Endothelin; C074308:sovateltide