Expression of EndothelinA Receptors in Human Gliomas and Meningiomas, with High Affinity for the Selective Antagonist PD 156707

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Abstract

OBJECTIVE:

Endothelin (ET) immunoreactivity, ET production, and specific ET receptors has 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 autoradiographics studies were performed with the subtype-specific radioligands 125I-PD151242 and 125I-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 in the nonvascular elements. The ET antagonist PD 156707 (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 concentration 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.

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