INVITRO TISSUE POTENCIES OF CONVERTING ENZYME-INHIBITORS - PRODRUG ACTIVATION BY KIDNEY ESTERASE

The inhibition of angiotensin converting enzyme by ramipril, ramiprilat, enalapril, enalaprilat, and captopril was studied in the plasma and various tissues (lung, heart, renal cortex, renal medulla) of normotensive rats and spontaneously hypertensive rats. Displacement curves for [H-3]ramiprilat were established on each tissue with the converting enzyme inhibitors, and their potencies were expressed as the concentration that inhibited 50% of the specific [H-3]ramiprilat binding. In the plasma, lung, and heart, the order of activities was: ramiprilat > enalaprilat > captopril > ramipril > enalapril. This order was different in the kidney (cortex and medulla): ramiprilat > enalaprilat > ramipril > captopril > enalapril. For ramiprilat, enalaprilat, and captopril, there were no differences in their respective potencies between tissues or between rat strains. However, the two prodrugs ramipril and enalapril were 10-30 times more active in the kidney than in the other tissues in both groups of rats. This was due to the deesterification of the prodrugs: in the presence of an esterase inhibitor (diethyl nitrophenyl phosphate, 10-mu-M), the potencies of ramipril in the kidney were not different from that obtained in the lung, which was not affected by the presence of the esterase inhibitor. These results suggest that the variations in the tissue activities of an angiotensin converting enzyme inhibitor are probably not due to differences in tissue affinities of the angiotensin converting enzyme inhibitor but depend on the concentration of this angiotensin converting enzyme inhibitor in each tissue.