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Title: Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes.
Austin Authors: Tikkanen, Ilkka;Tikkanen, Tuula;Cao, Zemin;Allen, Terri J;Davis, Belinda J;Lassila, Markus;Casley, David J;Johnston, Colin I;Burrell, Louise M ;Cooper, Mark E
Affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia
Issue Date: 1-Apr-2002
Publication information: Journal of Hypertension; 20(4): 707-14
Abstract: 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.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.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.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 times/divided by 1.2 mg/day) was reduced by the NEP/ACE (0.6 times/divided by 1.2 mg/day) and the NEP/ECE inhibitors (0.4 times/divided by 1.2 mg/day). Renal NEP was reduced by the NEP/ACE inhibitor (35 +/- 4%) or NEP/ECE inhibitor (38 +/- 4%) as well as by the 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.Combined inhibition of NEP/ACE or NEP/ECE confers beneficial effects on blood pressure, albuminuria and heart to body weight ratio in experimental diabetes.
Gov't Doc #: 11910307
Journal: Journal of Hypertension
Type: Journal Article
Subjects: Albuminuria.drug therapy
Angiotensin-Converting Enzyme Inhibitors.administration & dosage.pharmacology
Aspartic Acid Endopeptidases.antagonists & inhibitors
Atrial Natriuretic Factor.blood
Blood Pressure.drug effects
Diabetes Mellitus, Experimental.drug therapy.enzymology.pathology.physiopathology
Drug Interactions
Endothelin Receptor Antagonists
Heart.drug effects
Kidney.drug effects.physiopathology
Neprilysin.antagonists & inhibitors
Organ Size.drug effects
Organophosphonates.administration & dosage.blood.pharmacology
Protease Inhibitors.administration & dosage.blood.pharmacology
Rats, Sprague-Dawley
Sulfonamides.administration & dosage.pharmacology
Tetrazoles.administration & dosage.blood.pharmacology
Appears in Collections:Journal articles

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