FR139317, A SPECIFIC ET(A)-RECEPTOR ANTAGONIST, INHIBITS CEREBRAL ACTIVATION BY INTRAVENTRICULAR ENDOTHELIN-1 IN CONSCIOUS RATS

A comprehensive series of time-related behavioral, physiological and c erebral metabolic studies was conducted using conscious Sprague-Dawley rats to discern the anti-endothelin (ET) properties of the specific E T(A) receptor antagonist, FR139317. Endothelin-1 (9 pmol given by inje ction into one lateral ventricle, i.c.v.) produced convulsions, acute arterial hypertension, arterial hyperglycemia, and hyperventilation. B rain structures close to the i.c.v. site of injection, such as the cau date nucleus, lateral septal nucleus, corpus callosum and hippocampal CA3 medial lamellae, as well as 14 other individual structures, displa yed moderate-to-intense levels of metabolic activation after endotheli n. Data were assessed quantitatively by means of the autoradiographic [C-14]deoxyglucose technique combined with image analysis. Neural circ uits in the efferent projection paths of the stimulated forebrain stru ctures, such as the midbrain oculomotor complex, amygdaloid nuclei, su bstantia nigra pars reticulata and caudal subicular subregions of the hippocampal formation, were stimulated focally by endothelin. Specific medullary nuclei and cerebellar cortical subregions displayed high ra tes of glucose metabolism following endothelin injection at the time o f maximum behavioral and physiological stimulation. I.c.v. treatment w ith greater than or equal to 14 nmol FR139317 before endothelin signif icantly inhibited the effects produced by the peptide. At the highest dose of FR139317 (28 nmol), there was only mild behavioral stimulation following endothelin injection, and hypermetabolic responses in the b rain were abolished except in two specific areas of the cerebellar cor tex (approx 40% increases in metabolic activity in the copula pyramis and paramedian lobule). The results indicate that the cerebral stimula tory effects of i.c.v. endothelin are mediated by the A type of endoth elin receptor. By itself, i.c.v. FR1393I7 had no effects on the parame ters assessed. Further evaluation of FR139317 is warranted as a possib le therapeutic agent for neuropathologies suspected of deriving from c entral neural or vascular stimulation by endothelin, such as aneurysma l vasospasm, ischemia, excitotoxicity, and peptide-mediated epilepsies .