title: Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment-resistant hypertension.
abstract: In conditions with albuminuria, plasminogen is aberrantly filtered across the glomerular barrier and activated along the tubular system to plasmin. In the collecting duct, plasmin activates epithelial sodium channels (ENaC) proteolytically. Hyperactivity of ENaC could link microalbuminuria/proteinuria to resistant hypertension. Amiloride, an ENaC inhibitor, inhibits urokinase-type plasminogen activator. We hypothesized that amiloride (1) reduces blood pressure (BP); (2) attenuates plasminogen-to-plasmin activation; and (3) inhibits urine urokinase-type plasminogen activator in patients with resistant hypertension and type 2 diabetes mellitus (T2DM).In an open-label, non-randomized, 8-week intervention study, a cohort (n = 80) of patients with resistant hypertension and T2DM were included. Amiloride (5 mg/d) was added to previous triple antihypertensive treatment (including a diuretic and an inhibitor of the renin-angiotensin-aldosterone system) and increased to 10 mg if BP control was not achieved at 4 weeks. Complete dataset for urine analysis was available in 60 patients. Systolic and diastolic BP measured by ambulatory BP monitoring and office monitoring were significantly reduced. Average daytime BP was reduced by 6.3/3.0 mm Hg. Seven of 80 cases (9%) discontinued amiloride due to hyperkalemia >5.5 mol/L, the most frequent adverse event. Urinary plasmin(ogen) and albumin excretions were significantly reduced after amiloride treatment (P < .0001). Urokinase activity was detectable in macroalbuminuric urine, with a tendency toward reduction in activity after amiloride treatment. Amiloride lowers BP, urine plasminogen excretion and activation, and albumin/creatinine ratio, and is a relevant add-on medication for the treatment of resistant hypertension in patients with T2DM and microalbuminuria.
authors.affiliation: Research Unit for Cardiovascular and Metabolic Prevention, Department of Endocrinology, Odense University Hospital, Odense, Denmark. Electronic address: Christina.schmidt@rsyd.dk.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Oxlund
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Kristian B
authors.initials: KB
authors.lastname: Buhl
authors.affiliation: Research Unit for Cardiovascular and Metabolic Prevention, Department of Endocrinology, Odense University Hospital, Odense, Denmark.
authors.forename: Ib A
authors.initials: IA
authors.lastname: Jacobsen
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Mie R
authors.initials: MR
authors.lastname: Hansen
authors.affiliation: Department of Endocrinology, Sydvestjysk Sygehus, Esbjerg, Denmark.
authors.forename: Jeppe
authors.initials: J
authors.lastname: Gram
authors.affiliation: Research Unit for Cardiovascular and Metabolic Prevention, Department of Endocrinology, Odense University Hospital, Odense, Denmark.
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Henriksen
authors.affiliation: Department of Medicine, Sygehus Lillebælt, Fredericia, Denmark.
authors.forename: Karoline
authors.initials: K
authors.lastname: Schousboe
authors.affiliation: Steno Diabetes Center, Nordsjaellands Hospital, Århus University, Århus, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
mesh_terms: D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy; D000584:Amiloride / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D015153:Blotting, Western; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000652:urine*; D004232:Diuretics / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D062686:Epithelial Sodium Channel Blockers / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D010958:Plasminogen / Q000652:urine*; D013148:Spironolactone / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D004232:Diuretics; D062686:Epithelial Sodium Channel Blockers; D013148:Spironolactone; D000584:Amiloride; D010958:Plasminogen; D003404:Creatinine
keywords: Albuminuria; epithelial sodium channel; plasmin; type 2 diabetes mellitus; urinary plasminogen activator