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Significant natriuretic and antihypertensive action of the epithelial sodium channel blocker amiloride in diabetic patients with and without nephropathy

Andersen, Henrik; Hansen, Pernille B.L.; Bistrup, Claus; Nielsen, Flemming; Henriksen, Jan Erik; Jensen, Boye L.

doi: 10.1097/HJH.0000000000000967
ORIGINAL PAPERS: Therapeutic aspects

Objective: Diabetic nephropathy is associated with aberrant glomerular filtration of serine proteases. The study was designed to test the hypothesis that the epithelial sodium channel is activated proteolytically by urine plasmin in diabetic nephropathy and mediates renal sodium retention.

Methods: In an open-label intervention study on type 1 diabetes patients on standardized NaCl intake (200 mmol/day) with (n = 15) and without diabetic nephropathy (control, n = 12), urinary Na+ excretion in response to oral amiloride (20 or 40 mg/day for 2 days) was compared.

Results: A total of 27 patients completed the study and nine diabetic nephropathy and eight control study participants were compliant (24-h urine Na+ excretion of 200 mmol ± 30%). Amiloride increased significantly total and fractional Na+ excretion in both groups. Total natriuresis and weight loss were significantly larger in the control group compared with diabetic nephropathy at day 1 of amiloride, whereas fractional Na+ excretion did not differ. Amiloride intervention increased plasma renin concentration only in diabetic nephropathy group; it reduced SBP in both groups, whereas DBP was reduced in diabetic nephropathy group only. Albuminuria was reduced significantly by amiloride in diabetic nephropathy group. Urine total amiloride concentration was not different between groups (12 ± 1 and 16 ± 1 μmol/l, respectively). Urine total plasminogen and active plasmin were reduced after amiloride in diabetic nephropathy.

Conclusion: Amiloride increased renal Na+ excretion, reduced blood pressure, albuminuria, and total and active plasmin in urine. It is concluded that epithelial sodium channel is an attractive target to attain blood pressure control in long-term type I diabetes with no enhanced activity associated with nephropathy.

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aDepartment of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark

bDepartment of Nephrology, Odense University Hospital

cClinical Pharmacology, Institute of Public Health, University of Southern Denmark

dDepartment of Endocrinology, Odense University Hospital, Odense, Denmark

Correspondence to Henrik Andersen, MD, PhD, University of Southern Denmark, Odense, Denmark. E-mail:

Abbreviations: AQP2, aquaporin 2; BP, blood pressure; CI, confidence interval; eGFR, estimated glomerular filtration rate; ENaC, epithelial sodium channel; GFR, glomerular filtration rate; IC50 , half maximal inhibitory concentration; PRC, plasma renin concentration; RAAS, renin–angiotensin–aldosterone system; uPA, urokinase-type plasminogen activator; γENaC; γ subunit ectodomain of ENaC

Received 23 December, 2015

Revised 3 April, 2016

Accepted 18 April, 2016

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