Renin inhibitors based on the octapeptide sequence His-Pro-Phe-His-Leu-Leu-Val-Tyr found between positions six and thirteen of the natural substrate have been developed in this laboratory. Under physiologic conditions these competitive inhibitors suppress angiotensin i formation in human plasma. The first objective of the proposed research is to synthesize peptide inhibitors which bind renin one order of magnitude more tightly than those presently available. The relationship between inhibitory constant (Ki) to lipophilicity has been defined which predicts that replacement of specific amino acids with more hydrophobic analogs will yield the desired inhibitors. In vivo prevention of blood pressure increases in test animals may then be effected with moderate doses of inhibitor. Affinity labels containing the C-terminal four residues of the basic octapeptide will be synthesized and tested as irreversible renin inhibitors. Reaction of these with purified renal renin may permit key residues in the catalytic site of the enzyme to be identified. Development of inhibitors several orders of magnitude more effective than those now available will be explored through the synthesis of transition state analogs of the octapeptide. Application of the renin inhibitors to the diagnoses and treatment of renovascular hypertension is the ultimate goal of this research.