Synthesis and renin inhibitory properties of a new soluble pepstatin derivative.
A new pepstatin derivative, pepstatinyl arginine methyl ester hydrochloride (pepstatinyl-Arg-O-Me), was synthesized with the aim of increasing water solubility without altering capacity to inhibit the renin-angiotensinogen reaction. Pepstatinyl-Arg-O-Me was shown to inhibit in vitro the reaction between either rat or purified hog renin and the natural rat renin substrate. In a fluorimetric assay, this derivative competitively inhibited the reaction between purified hog renin and a synthetic N-acetyl-tetradecapeptide renin substrate with a Ki of the same order of magnitude as that of pepstatin. In urethaneanesthetized ganglion-blocked rats, binephrectomized 24 hr before the experiments, both the plasma reinin concentration and the rise in blood pressure following intravenous injection of hog renin were inhibited by pepstatinyl-Arg-O-Me disappeared within 60 min. Pepstatinyl-Arg-O-Me inhibited the 1.4 mumoles/kg. The in vivo inhibitory effect of 1.4 mumoles/kg of pepstatinyl-Arg-O-Me disappeared within 60 min. Pepstatinyl-Arg-Op-Me inhibited the reaction of endogenous and exogenous renin with plasma substrate both in vitro and in vivo.
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D008297:Male; D009392:Nephrectomy; D009842:Oligopeptides / Q000494:pharmacology*; D010436:Pepstatins / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D012083:Renin / Q000097:blood; D013552:Swine; D000092502:Renin Inhibitors
D000804:Angiotensin II; D009842:Oligopeptides; D010436:Pepstatins; D012083:Renin; D000092502:Renin Inhibitors