Abstract
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.
Footnotes
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Send reprint requests to: Dr. D. J. Campbell, St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
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↵1 This study was funded by a grant from the National Health and Medical Research Council of Australia.
- Abbreviations:
- ACE
- angiotensin-converting enzyme
- Ang I
- angiotensin I
- Ang II
- angiotensin II
- ANP
- atrial natriuretic peptide
- BK-(1–7)
- bradykinin-(1–7)
- BK-(1–8)
- bradykinin-(1–8)
- BK-(1–9)
- bradykinin-(1–9)
- GMP
- guanosine monophosphate
- HPLC
- high-performance liquid chromatography
- NEP
- neutral endopeptidase
- RB104
- 2-[(3-iodo-4-hydroxy)phenylmethyl]-4-N-[3-(hydroxyamino-3-oxo-1-phenylmethyl)propyl]amino-4-oxobutanoic acid
- RIA
- radioimmunoassay
- S 21402–1
- (2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido] propionic acid
- Received June 2, 1997.
- Accepted November 10, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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