Rat model for evaluating inhibitors of human renin

Abstract

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.