Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes

Ilkka Tikkanen, Tuula Tikkanen, Zemin Cao, Terri J. Allen, Belinda J. Davis, Markus Lassila, David Casley, Colin I. Johnston, Louise M. Burrell, Mark E. Cooper

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Objective: The effects of combined inhibition of neutral endopeptidase (NEP) with either angiotensin-converting enzyme (ACE), or endothelin-converting enzyme (ECE) on blood pressure, urinary albumin excretion and heart weight were explored in experimental diabetes. Design: Streptozotocin-induced diabetic Sprague-Dawley rats were treated with vehicle, the NEP/ACE inhibitor S 21402, the NEP/ECE inhibitor CGS 26303, the NEP inhibitor SCH 42495, the ACE inhibitor captopril or the endothelin receptor antagonist bosentan for 4 weeks. Methods: Blood pressure was measured by tail-cuff method and radiotelemetry. Albuminuria, plasma renin activity and plasma atrial natriuretic peptide (ANP) were determined by radioimmunoassay. NEP binding was assessed by in vitro quantitative autoradiography. Metabolic and biochemistry parameters including food intake, 24-h urine volume, plasma glucose, glycated hemoglobin, glomerular filtration rate (GFR) and urinary sodium excretion were also determined. Results: Mean blood pressure over the 4-week study period after commencement of treatment was reduced to a similar extent by a range of treatments including the ACE inhibitor, NEP/ACE inhibitor, endothelin receptor antagonist, NEP/ECE inhibitor, but not the NEP inhibitor, compared with vehicle-treated diabetic rats. Heart to body weight ratio in diabetic rats was only reduced by the NEP/ACE and the NEP/ECE inhibitor. Increased albuminuria in diabetic rats (1.1 ×/÷ 1.2 mg/day) was reduced by the NEP/ACE (0.6 ×/÷ 1.2 mg/day) and the NEP/ECE inhibitors (0.4 ×/÷ 1.2 mg/day). Renal NEP was reduced by the NEP/ACE inhibitor (35 ± 4%) or NEP/ECE inhibitor (38 ± 4%) as well as bythe pure NEP inhibitor (27 ± 4%) compared with the untreated diabetic group. Other abnormal metabolic and biochemical parameters in diabetic rats were not influenced by any drug treatment. Conclusions: Combined inhibition of NEP/ACE or NEP/ECE confers beneficial effects on blood pressure, albuminuria and heart to body weight ratio in experimental diabetes.

Original languageEnglish
Pages (from-to)707-714
Number of pages8
JournalJournal of Hypertension
Issue number4
Publication statusPublished - 1 Apr 2002
Externally publishedYes


  • Angiotensin converting enzyme
  • Diabetes
  • Endothelin converting enzyme
  • Neutral endopeptidase

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