POTENT IN-VIVO INHIBITORS OF RAT RENIN - ANALOGS OF HUMAN AND RAT ANGIOTENSINOGEN SEQUENCES CONTAINING DIFFERENT CLASSES OF PSEUDODIPEPTIDES AT THE SCISSILE SITE

Using solid-phase methodology we have synthesised peptides based on th e 8-14 or 6-14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P-1-P-1' cleavage site: Le u-Psi[CH2NH]Leu; Leu-Psi[CH(OH)CH2]Val; Leu-Psi[CH(OH)CH2]Leu and Leu- Psi[CH(NH2)CH2]Val. In vitro, peptide Pro-Phe-His-Leu-Psi[CH(OH)CH2]Le u-Tyr-Ser-NH2(XXI) is the most potent inhibitor of rat plasma renin re ported having an IC50 of 0.21 nM; it is a much weaker inhibitor of hum an renin (IC50 45 nM). Peptide Boc-His-Pro-Phe-His-Leu-Psi[CH(OH)CH2] Leu-Val-Ile-His-NH2 (XX) was a highly effective inhibitor of rat renin in vivo. When infused (1 mg/kg/h) into two-kidney, one-clip chronic r enal hypertensive rats, it lowered blood pressure and suppressed both plasma renin and angiotensin II. When given as a bolus (1 mg/kg) there was a divergence between the rapid rebound of renin levels and blood pressure, which remained suppressed. These results indicate that poten t in vivo inhibitors of rat renin could be useful not only in examinin g the role of circulating renin but also in elucidating the equally im portant involvement of extracirculatory renin pools. (C) Munksgaard 19 97.