Angiotensin analogues that selectively augment the force of contraction of the isolated heart

Angiotensin II (Ang II) produces a positive inotropic effect on the heart; however, its usefulness as an inotropic agent is limited because of its inherent vasoconstrictor action. We therefore designed Ang II analogues that are potent, positive inotropic agents with minimal myotropic properties. Replacement of the proline residue in position 7 with alanine reduced the pressor and vascular contractile response to less than 1% of Ang II. In spite of negligible vascular actions, however, [7-alanine]Ang II produced 50% of the inotropic activity of Ang II in the cat papillary muscle. The results of pharmacological evaluation of various position 7-substituted analogues were as follows: 1) Replacement of proline in position 7 of angiotensin I (Ang I) and Ang II with primary amino acids produced cardiac-specific, positive inotropic properties. 2) The selectivity of positive cardiac inotropic activity of position 7-substituted analogues of Ang II was dependent upon the nature of the amino acid in position 1. Replacement of aspartic acid in position 1 with sarcosine increased vasoconstrictor activity, thereby diminishing cardiac selectivity. However, this change did not affect cardiac selectivity in Ang I analogues. 3) Introduction of any type of steric hindrance in position 7 (e.g., replacement of alanine with N-methyl- or alpha-methylalanine) led to a considerable loss in inotropic activity. In conclusion, contrary to rigid, structural requirements (solution conformation) for the pressor action of Ang II, a less organized structure or a random conformation at the carboxyl terminus appears to favor cardiac-selective contractile response (or positive inotropic response).