New inhibitors of human renin tested in vitro and in vivo in the anaesthetized baboon.
A new inhibitor of human renin (H. 189) is described. It is a decapeptide analogue of human renin substrate with the amino acid, statine, substituted for leucine in the scissile bond. Its inhibitory potency as shown by IC50 is 1.0 X 10(-8) M with human plasma renin and 1.5 X 10(-8) M with baboon plasma renin. It is less effective with dog and rat renin, but its inhibitory potency with human renin is similar to that of another inhibitor of ours (H. 142) having a reduced isostere in the scissile bond. H. 189 has some inhibitory effect on cathepsin D (IC50 6.5 X 10(-5) M) but H. 142 has no discernible effect. Pepstatin, on the other hand, was highly effective against cathepsin D (IC50 1.2 X 10(-8) M). H. 142 and H. 189 were infused intravenously at 10 mg/kg/h in four anaesthetized salt-deplete baboons (Papio hamadryas). The activity of renin in plasma decreased markedly as did the circulating concentration of its products, angiotensin I and angiotensin II.
D000768:Anesthesia, General; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000808:Angiotensinogen / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D006801:Humans; D007263:Infusions, Parenteral; D010215:Papio; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D012083:Renin / Q000097:blood; D012964:Sodium / Q000172:deficiency; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000804:Angiotensin II; D000808:Angiotensinogen; D002402:Cathepsin D; D010455:Peptides; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C039583:H 142; C045142:H 189