Phosphoramidon-sensitive endothelin-converting enzymes modulate cerebral blood flow and neural damage of hypoxic rats.

The enzymatic activity of endothelin-converting enzymes (ECE) was altered to determine the potential effect of endothelins (ET) on cerebral blood flow measured by laser Doppler flowmetry (CBF(LDF)) and the resultant neural damage of rats, made hypoxic via breathing 12% O(2) for 35 min. Intrastriatal administration of phosphoramidon (PRN, 5 microM), a dual inhibitor of ECE and neutral endopeptidase (NEP), significantly increased infarct volume to hypoxia with a significant attenuation of CBF(LDF). However, intrastriatal thiorphan (TRN, 5 microM), an inhibitor of NEP, had no effect on the CBF(LDF) responses or infarct volume induced by the hypoxic challenge. These findings showed that inhibition of ECE by PRN interfered with the vasodilator activity of ET to the hypoxic response that increased neural damage, thus suggesting that PRN-sensitive ECE is functionally active in the modulation of cerebral blood flow in rats undergoing hypoxia.