MARKED DIFFERENCE BETWEEN ANGIOTENSIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE INHIBITION IN-VIVO BY A DUAL INHIBITOR OF BOTH ENZYMES

Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-c onverting enzyme (ACE) offers the potential for improved therapy of hy pertension and cardiac failure. S 21402-1 {(2S)-2-[(2S,3R)-2-thiomethy l-3-phenylbutanamido] propionic acid) is a sulfhydryl-containing poten t inhibitor of both NEP (K-i = 1.7 nM) and ACE (K-i = 4.5 nM). S 21402 -1 and the sulfhydryl-containing ACE inhibitor captopril were administ ered 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. T he difference in NEP and ACE inhibition by S 21402-1 in vivo was great er than 1000-fold. All doses of S 21402-1 inhibited NEP, as indicated by plasma NEP activity, radioinhibitor binding to kidney sections, uri nary sodium excretion and bradykinin-(1-7)/bradykinin-(1-9) ratio. How ever, only 300 mg/kg S 21402-1 inhibited ACE, as indicated by plasma a ngiotensin II/angiotensin I ratio, renin and angiotensinogen levels. A lthough 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 h ad no effect on renal ACE, as indicated by the angiotensin II/angioten sin I ratio in kidney. Moreover, captopril was greater than 10-fold mo re potent than S 21402-1 as an ACE inhibitor in vivo. In separate expe riments, the presser response of anesthetized rats to angiotensin I sh owed more rapid decay in ACE inhibition by S 21402-1 than by captopril . These studies indicated that in vivo modification of S 21402-1 cause d a much greater decrease in potency of ACE inhibition than NEP inhibi tion. Consequently, effective ACE inhibition by S 21402-1 required dos es much higher than those required for NEP inhibition.