Expression of EndothelinA Receptors in Human Gliomas and Meningiomas, with High Affinity for the Selective Antagonist PD156707

Expression of EndothelinA Receptors in Human Gliomas and Meningiomas, with High Affinity for the... AbstractOBJECTIVE:Endothelin (ET) immunoreactivity, ET production, and specific ET receptors have been identified in the brain. Changes in ET concentration or receptor expression have been implicated in the pathophysiological changes in vasospasm after subarachnoid hemorrhage and in cerebral neoplasia. In this study, we have characterized the ETa and ETB receptor subtypes present in human normal cerebral cortex (NCC) and two common central nervous system tumors, i.e., meningioma (MNG) and glioblastoma multiforme (GBM). A knowledge of the ET receptor subtypes present may provide a novel therapeutic target for newly developed ET antagonists.METHODS:Saturation, competition, and autoradiographic studies were performed with the subtype-specific radioligands 125I-PD151242 and 125I-BQ3020, to characterize the ETA and ETB receptors present in NCC, MNG, andGBM.RESULTS:NCC expresses high-affinity ETA receptors on pial and intraparenchymal vessels and high-affinity ETB receptors on glia and neurons. MNGs express mainly (85%) high-affinity ETA receptors in a diffuse pattern, whereas GBMs express high-affinity ETA receptors on the neovasculature and ETB receptors on the nonvascular elements. The ET antagonist PD156707 (Kd = 0.059 nmol/L) showed a higher affinity for the ETA receptor subtype than did bosentan (Kd = 1.1 nmol/L).CONCLUSION:ETA receptors are expressed in high concentrations in MNGs and in the vasculature of NCC and GBMs. The ETA-selective antagonist PD156707 may be of potential therapeutic value in vascular and neoplastic diseases of the central nervous system. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Expression of EndothelinA Receptors in Human Gliomas and Meningiomas, with High Affinity for the Selective Antagonist PD156707

Expression of EndothelinA Receptors in Human Gliomas and Meningiomas, with High Affinity for the Selective Antagonist PD156707

EXPER IM EN TA L S T U D IE S Expression of EndothelinA Receptors in Human Gliomas and Meningiomas, with High Affinity for the Selective Antagonist P D 1 5 6 7 0 7 Spencer P. Harland, F.R.C.S.(S.N.), Rhoda E. Kuc, E>.Sc., John D. Pickard, M.Chir., F.R.C.S., Anthony P. Davenport, Ph.D. A cad em ic Department of Neurosurgery (SPH, )DP) and C lin ic a l Pharm acology Unit (REK, A PD ), University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom ’t )1 fc OBJECTIVE: Endothelin (ET) immunoreactivity, ET production, and specific ET receptors have been identified in the brain. Changes in ET concentration or receptor expression have been implicated in the pathophysiological changes in vasospasm after subarachnoid hemorrhage and in cerebral neoplasia. In this study, we have charac­ terized the ETa and ETB receptor subtypes present in human normal cerebral cortex (NCC) and two common central nervous system tumors, i.e., meningioma (MNG) and glioblastoma multiforme (GBM). A knowledge of the ET receptor subtypes present may provide a novel therapeutic target for newly developed ET antagonists. METHODS: Saturation, competition, and autoradiographic studies were performed with the subtype-specific radio­ ). ligands 12>I-PD151242 and 12>I-BQ3020, to characterize the ETA and ETB receptors present in NCC, MNG, and GBM. RESULTS: NCC expresses high-affinity ETA receptors on pial and intraparenchymal vessels and high-affinity ETB receptors on glia and neurons. MNGs express mainly (85%) high-affinity ETA receptors in a diffuse pattern, whereas GBMs express high-affinity ETA receptors on the neovasculature and ETB receptors on the nonvascular elements. The ET antagonist PD156707 (Kd = 0.059 nmol/L) showed a higher affinity for the ET A receptor subtype than did bosentan (Kd = 1.1 nmol/L). CO N CLU SIO N : ETA receptors are expressed in high concentrations in MNGs and in the vasculature of NCC and < t GBMs. The ETA-selective antagonist...
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Publisher
Oxford University Press
Copyright
© Published by Oxford University Press.
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1097/00006123-199810000-00097
Publisher site
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Abstract

AbstractOBJECTIVE:Endothelin (ET) immunoreactivity, ET production, and specific ET receptors have been identified in the brain. Changes in ET concentration or receptor expression have been implicated in the pathophysiological changes in vasospasm after subarachnoid hemorrhage and in cerebral neoplasia. In this study, we have characterized the ETa and ETB receptor subtypes present in human normal cerebral cortex (NCC) and two common central nervous system tumors, i.e., meningioma (MNG) and glioblastoma multiforme (GBM). A knowledge of the ET receptor subtypes present may provide a novel therapeutic target for newly developed ET antagonists.METHODS:Saturation, competition, and autoradiographic studies were performed with the subtype-specific radioligands 125I-PD151242 and 125I-BQ3020, to characterize the ETA and ETB receptors present in NCC, MNG, andGBM.RESULTS:NCC expresses high-affinity ETA receptors on pial and intraparenchymal vessels and high-affinity ETB receptors on glia and neurons. MNGs express mainly (85%) high-affinity ETA receptors in a diffuse pattern, whereas GBMs express high-affinity ETA receptors on the neovasculature and ETB receptors on the nonvascular elements. The ET antagonist PD156707 (Kd = 0.059 nmol/L) showed a higher affinity for the ETA receptor subtype than did bosentan (Kd = 1.1 nmol/L).CONCLUSION:ETA receptors are expressed in high concentrations in MNGs and in the vasculature of NCC and GBMs. The ETA-selective antagonist PD156707 may be of potential therapeutic value in vascular and neoplastic diseases of the central nervous system.

Journal

NeurosurgeryOxford University Press

Published: Oct 1, 1998

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