Abstract

The objectives of this study were to identify angiotensin I (ANGI) analogs that antagonize angiotensin II (ANGII) receptors and/or block angiotensin converting enzyme (ACE) in vivo, to determine whether any receptor antagonist activity was direct (i.e., mediated by the intact peptide) vs. indirect (i.e., mediated by conversion of the intact peptide to corresponding smaller peptide fragments via ACE) and to determine whether the potency of a given ANGI analog was influenced by circulation through a tissue (lungs) rich in ACE. The effects of six ANGI analogs on mesenteric vascular responses to intramesenteric artery (IMA) infusions of ANGI and ANGII were examined in nephrectomized rats in the absence and presence of captopril. ANGI analogs were infused either intravenously (i.v.) or IMA. It is concluded that: 1) the ANGI analogs did not inhibit ACE sufficiently to attenuate responses to ANGI; 2) Thr8-ANGI does not block ANGII receptors, either directly or indirectly; 3) infused IMA Ile8-ANGI is a weak direct antagonist; however, given i.v., its potency is increased 30-fold due to conversion by pulmonary ACE; 4) Phe4-Tyr8-ANGI is a moderately potent indirect antagonist infused either IMA or i.v.; 5) infused IMA Cys8-ANGI is a moderately potent direct antagonist, and given i.v., its potency is increased 20-fold due to conversion by pulmonary ACE; 6) Val8-ANGI is a highly potent antagonist infused either IMA or i.v. due to both direct and indirect actions; and 7) Leu8-ANGI is a highly potent antagonist infused either IMA or i.v., and its antagonist properties do not require ACE. Possible applications of these findings are discussed.