Metabolism of angiotensins II and III by membrane-bound peptidases from rat brain.

This study examines the metabolism of 125I-angiotensin II (125I-ANG II) and 125I-angiotensin III (applied 125I-ANG III or 125I-ANG IIIapp) by membrane peptidases. The first step in the metabolism of 125I-ANG II was the formation of 125I-ANG III (generated 125I-ANG III or 125I-ANG IIIgen). The ability of both ANG II and ANG III to reduce 125I-ANG IIIgen production without ANG(1-5), ANG(2-5), amastatin or bestatin being similarly effective suggests that this step may be highly substrate-specific. Subsequent metabolism of 125I-ANG IIIgen was similar to that of 125I-ANG IIIapp in that 125I-ANG(2-7) and 125I-ANG(2-4) fragments were produced. The formation of 125I-ANG(2-7) appeared to be a very substrate-specific process because it was only inhibited by ANG II and ANG III. In contrast, the production of 125I-ANG(2-4) was unaffected at the concentration of inhibitors used and is considered to be a relatively nonspecific process. However, despite these similarities sequential N-terminal cleavage leading to the formation of 125I-ANG(3-8), 125I-ANG(4-8) and 125I-Tyrosine appears to be the preferred pathway in the metabolism of 125I-ANG IIIapp. The absence of this pathway in the metabolism of 125I-ANG IIIgen suggests that applied and generated 125I-ANG III may be metabolized in separate degradative compartments. These data demonstrate that 125I-ANG II and 125I-ANG III are metabolized by membrane-bound peptidases in an orderly and sequential manner.(ABSTRACT TRUNCATED AT 250 WORDS)