%0 Journal Article %A Frank Anastasopoulos %A Randal Leung %A Athena Kladis %A Gail M. James %A Todd A. Briscoe %A Thaddeus P. Gorski %A Duncan J. Campbell %T Marked Difference between Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Vivo by a Dual Inhibitor of Both Enzymes %D 1998 %J Journal of Pharmacology and Experimental Therapeutics %P 799-805 %V 284 %N 3 %X Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) offers the potential for improved therapy of hypertension and cardiac failure. S 21402–1 {(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido] propionic acid} is a sulfhydryl-containing potent inhibitor of both NEP (Ki = 1.7 nM) and ACE (Ki = 4.5 nM). S 21402–1 and the sulfhydryl-containing ACE inhibitor captopril were administered to rats by intraperitoneal injection (0, 0.3, 3, 30, 300 mg/kg). Urine was collected for 4 h; then plasma and kidneys were collected. The difference in NEP and ACE inhibition by S 21402–1 in vivo was greater than 1000-fold. All doses of S 21402–1 inhibited NEP, as indicated by plasma NEP activity, radioinhibitor binding to kidney sections, urinary sodium excretion and bradykinin-(1–7)/bradykinin-(1–9) ratio. However, only 300 mg/kg S 21402–1 inhibited ACE, as indicated by plasma angiotensin II/angiotensin I ratio, renin and angiotensinogen levels. Although S 21402–1 (30 and 300 mg/kg) inhibited renal NEP, as indicated by the bradykinin-(1–7)/bradykinin-(1–9) ratio in kidney, S 21402–1 had no effect on renal ACE, as indicated by the angiotensin II/angiotensin I ratio in kidney. Moreover, captopril was greater than 10-fold more potent than S 21402–1 as an ACE inhibitor in vivo. In separate experiments, the pressor response of anesthetized rats to angiotensin I showed more rapid decay in ACE inhibition by S 21402–1 than by captopril. These studies indicated that in vivomodification of S 21402–1 caused a much greater decrease in potency of ACE inhibition than NEP inhibition. Consequently, effective ACE inhibition by S 21402–1 required doses much higher than those required for NEP inhibition. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/284/3/799.full.pdf