THERAPEUTIC POTENTIAL OF ENDOTHELIN RECEPTOR ANTAGONISTS IN CEREBROVASCULAR-DISEASE

The actions of the endothelins (endothelin-1, endothelin-2 and endothe lin-3) are mediated via endothelin-A (ET(A)) and endothelin-B (ET(B)) receptors, the former generally mediating vasoconstriction and the lat ter vasodilation. Peptide antagonists selective for either receptor su btype [e.g. BQ 123 (ET(A)) and BQ 788 (ET(B))] and combined ET(A)/ET(B ) receptor antagonists (e.g. PD 145065 and TAK 044) have been develope d. More recently, small molecule non-peptide antagonists have also bee n synthesised. ET(A) receptor-selective agents include PD 155080 and B MS 182874, while Ro 46-2005 and bosentan are combined ET(A)/ET(B) rece ptor antagonists. The role of the endothelin family of vasoconstrictor peptides in the pathophysiology of cerebrovascular disease has been s peculated upon. Increases in plasma and CSF levels of endothelin-1 in delayed vasospasm following subarachnoid haemorrhage and acute ischaem ic stroke have implicated the endothelins in these cerebrovascular dis eases. The development of non-peptide endothelin receptor antagonists has facilitated investigations into the role of the endothelins in cer ebrovascular disease. The endothelin receptor antagonists have been de monstrated to attenuate cerebral vasospasm following experimental suba rachnoid haemorrhage in a variety of species. Additionally, the endoth elin receptor antagonists ameliorate neuronal damage following experim ental focal and global cerebral ischaemia. These actions have highligh ted the therapeutic potential of endothelin receptor antagonists in ce rebrovascular disease.