Rat model for evaluating inhibitors of human renin.
A rat model that provides a rapid method for the in vivo evaluation of potential inhibitors of human renin has been developed and validated. Recombinant human renin was infused intravenously into anesthetized, nephrectomized, ganglion-blocked rats. The resulting blood pressure had an approximate 60 mm Hg human renin-dependent component. The angiotensin I to angiotensin II converting enzyme inhibitor, captopril, and the renin inhibitor, ditekiren (U-71038), were capable of abolishing this component after oral administration. Oral administration of ditekiren to rats receiving human renin infusions evoked dose-dependent hypotensive responses that were greater in magnitude and longer in duration than those elicited in rats receiving hog renin infusions. Observations made in the renin-infused rats reflected the results of in vitro kinetic studies that had indicated a greater binding affinity of ditekiren for human renin than for hog renin.
Pals
D T
DT
Upjohn Company, Cardiovascular Diseases Research, Kalamazoo, MI 49001.
Lawson
J A
JA
Couch
S J
SJ
D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D009392:Nephrectomy; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D013552:Swine; D000092502:Renin Inhibitors
D002216:Captopril; D009842:Oligopeptides; D011994:Recombinant Proteins; D000092502:Renin Inhibitors; C050898:ditekiren