THERAPEUTIC EFFECTS OF ENDOTHELIN RECEPTOR ANTAGONISTS IN STROKE

The presence of the endothelin isopeptides and endothelin receptors on neurons, glial cells and brain capillary endothelium suggests that en dothelins may play a significant role in neuromodulation, astrocytic f unction and in regulation of cerebral blood flow. Furthermore, endothe lins may play a significant role in the central regulation of neuroend ocrine and autonomic nervous system functions (i.e., plasma volume, ca rdiovascular and respiratory control). Endothelin has potent cerebrova scular and proliferative effects suggesting a pathogenic role in cereb rovascular diseases. Endothelin receptors may represent important ther apeutic targets for the treatment of both hemorrhagic and ischemic str oke. A review of the available data on endothelin levels and the effec ts of endothelin antagonists in cerebrovascular diseases is provided i n the present report. Most notably is evidence in support of increased brain endothelin levels in hemorrhagic and ischemic stroke both in an imal models and in humans. Also, endothelin receptor antagonists exert significant efficacy in animal models of cerebrovascular disease. For example, SE 209670, a rationally designed, potent, nonpeptide endothe lin receptor antagonist, exerts therapeutic efficacy in reducing vasos pasm following subarachnoid hemorrhage and neuroprotection following i schemic stroke. Certainly the available data warrants further evaluati on of novel, selective endothelin receptor antagonists or endothelin c onverting enzyme inhibitors in cerebrovascular diseases.