Cardiac and vascular actions of decapeptide angiotensin analogs

We have reported previously the characterization of the angiotensin (A) II myocardial receptor and provided biological evidence that the inotropic activities of the octapeptide AII are receptor mediated. In addition to the inotropic activities that this compound demonstrates, it also has potent vascular contractile activities. The decapeptide AI exhibits both cardiac (+)-inotropic and vascular contractile activities. The responses to AI are in large part secondary to conversion to smaller peptides, principally the octapeptide AII. To attempt to separate the inotropic and vascular response to these peptides, several decapeptide A analogs with amino acid substitutions in either the 1, 5 or 7 positions were studied. The compounds were as follows: [Sar1Ile5Ala7]AI; [Sar1Ile5 alpha-MeAla7]AI; [Sar1Val5N-MeAla7]AI and [Sar1Val5Sar7]AI. These analogs were studied in rabbit point-stimulated left atria, isometrically contracting aortic rings and competition for [125I]AII binding to myocardial ventricular membranes. All the peptides exhibited partial AII agonist activities in cardiac and vascular tissues with potencies equivalent to or less than AI. The inotropic and vascular contractile response to the decapeptides was decreased in the presence of the A converting enzyme inhibitor enalaprilat. The inotropic and vascular activities of these compounds in the presence of A converting enzyme inhibitor suggest that A converting enzyme may be responsible for the conversion to smaller peptides. Biologically active compounds were obtained with amino acid substitutions in the no. 1, 5 and 7 positions. Sarcosine substitution in position 1 did not enhance vascular potency as was observed with AII analogs.