title: Potent in vivo inhibitors of rat renin: analogues of human and rat angiotensinogen sequences containing different classes of pseudodipeptides at the scissile site.
abstract: Using solid-phase methodology we have synthesised peptides based on the 8-14 or 6-14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P1-P1' cleavage site: Leu-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 Piv-His-Pro-Phe-His-Leu-psi[CH(OH)CH2]Leu-Tyr-Tyr-Ser-NH2(XXI) is the most potent inhibitor of rat plasma renin reported having an IC50 of 0.21 nM; it is a much weaker inhibitor of human 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 renal 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 potent in vivo inhibitors of rat renin could be useful not only in examining the role of circulating renin but also in elucidating the equally important involvement of extracirculatory renin pools.
authors.affiliation: Ferring Research Institute, Chilworth Research Centre, Southampton, United Kingdom. jdiaz@ferringr.com
authors.forename: J
authors.initials: J
authors.lastname: Sueiras-Diaz
authors.forename: D M
authors.initials: DM
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Szelke
authors.forename: B J
authors.initials: BJ
authors.lastname: Leckie
authors.forename: S R
authors.initials: SR
authors.lastname: Beattie
authors.forename: C
authors.initials: C
authors.lastname: Beattie
authors.forename: J J
authors.initials: JJ
authors.lastname: Morton
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood; D000808:Angiotensinogen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry; D006801:Humans; D007668:Kidney / Q000187:drug effects; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D000092502:Renin Inhibitors
chemical_list: D000596:Amino Acids; D000804:Angiotensin II; D000808:Angiotensinogen; D004151:Dipeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D000092502:Renin Inhibitors; C013165:statine