In the brain angiotensin converting enzyme is highly localized to a striatonigral pathway, which contains no endogenous angiotensin. Substance P, also localized to a striatonigral pathway, is degraded by ACE via two different pathways. The lung and striatal isozymes of angiotensin converting enzyme exhibit differential cleavage of substance P, with lung preferring an initial tripeptide cleavage, and striatum an initial dipeptide cleavage. Substance K is degraded by the striatal isozyme but is not cleaved by the lung isozyme. Substance P 5-11 is not cleaved by either form of angiotensin converting enzyme.