Different localization of ETA and ETB receptors in the hyperplastic vascular wall.
We investigated which subtypes of endothelin-1 (ET-1) receptors are involved in the pathogenesis of angioplasty-induced lesion formation in the rabbit carotid artery. Four weeks after removing endothelial cells (EC), we noted a marked intimal hyperplasia. The Bmax values for [125I]ET-1 and [125I]IRL1620 (an agonist for the ETB receptors) bindings were greater in the hyperplastic artery, without changes in Kd values. [125I]ET-1 binding was completely inhibited by unlabeled ET-1 and Ro 46-2005, a mixed-type antagonist for the ETA and ETB receptors, but partially by BQ123, a selective antagonist for ETA receptors, and IRL1620. The [125I]ET-1 binding sites not inhibited with BQ123 were significantly increased in the hyperplastic artery. The binding study suggested the presence of non-ETA/non-ETB receptors. The rank order of the increasing ratio in the density of receptors was ETB > putative non-ETA/non-ETB > total ET-1 receptors > ETA. The histochemical experiments with biotinylated ET-1 at lysine-9 side chain alone or in combination with unlabeled ET-1, BQ123, Ro 46-2005, or IRL1620, showed the ETA receptors to be localized mainly in the media, whereas the ETB receptors localized mainly in the neointima. These results suggest that the increased ET-1 receptors, especially ETB and/or putative non-ETA/non-ETB, are closely related to the occurrence of the intimal hyperplasia after endothelial removal.
Azuma
H
H
Department of Medicinal Chemistry, Tokyo Medical and Dental University, Japan.
Hamasaki
H
H
Sato
J
J
Isotani
E
E
Obayashi
S
S
Matsubara
O
O
D000704:Analysis of Variance; D017130:Angioplasty / Q000009:adverse effects; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology; D006965:Hyperplasia; D008297:Male; D008855:Microscopy, Electron, Scanning; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000032:analysis* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; C074308:sovateltide; C083751:Ro 46-2005; D000096926:Benzenesulfonamides; C072247:cyclo(Trp-Asp-Pro-Val-Leu)