H-77: a potent new renin inhibitor. In vitro and in vivo studies.
Chemical modification of the backbone at the cleavage site in the (6-13)-octapeptide of equine angiotensinogen resulted in greatly increased binding affinity and resistance to cleavage by renin. The D-His6-Tyr13 octapeptide analog containing the reduced bond -CH2-NH-instead of a peptide bond -CO-NH- at the Leu10-Leu11 linkage (H-77) was a powerful in vitro inhibitor of canine renin (IC50 = 24nM). It gave an IC50 of 1 microM against human renin and 0.6 microM against rat renin. In sodium-depleted conscious dogs, infusion of H-77 caused dose-related falls of plasma angiotensin I plasma angiotensin II concentration and mean arterial pressure; the minimum effective dose was 0.1 mg . kg-1 hr-1. Similar infusions of H-77 in chronically catheterized rats have no effect on blood pressure or plasma angiotensin II concentration. Thus, the in vitro effect of H-77 as an inhibitor of renin in dog, human, and rat plasma was paralleled by its action in the whole animal.
D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D014882:Water-Electrolyte Balance / Q000187:drug effects; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000804:Angiotensin II; D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors; C034503:H 77