title: Oral warfarin and the thrombin inhibitor dabigatran increase blood pressure in rats: hidden danger of anticoagulants?
abstract: BACKGROUND
  Hypertension is a common comorbidity in patients with chronic kidney disease (CKD). We reported earlier that oral anticoagulants, including warfarin and dabigatran, may induce acute kidney injury. No effects of oral anticoagulants on blood pressure (BP) have been previously reported. The aim of this study was to examine in detail the relationship of anticoagulant therapy and BP in rats.
  
  
  METHODS
  Sham-operated and 5/6 nephrectomy rats were treated with different doses of oral anticoagulants (warfarin and dabigatran), superoxide scavenger N-acetylcysteine (NAC), vitamin K, and protease activated receptor 1 (PAR-1) inhibitor SCH79797. BP was measured by a tail cuff daily.
  
  
  RESULTS
  Warfarin and dabigatran both increased systolic BP in sham-operated and 5/6 nephrectomy rats in a dose-dependent manner. SCH79797 also increased systolic BP in a dose-dependent manner. Vitamin K prevented warfarin-induced increase in BP but did not affect BP when administered alone. NAC delayed the warfarin-associated increase in BP. Warfarin effects on BP were similar in 5/6 nephrectomy rats with different CKD stages.
  
  
  CONCLUSIONS
  Both warfarin and dabigatran increase systolic BP in rats. The mechanism of this effect is not clear, but our data suggest that it is related to decreased thrombin activity associated with anticoagulant treatment. The superoxide scavenger NAC delayed, but did not prevent, warfarin-induced hypertension.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio;
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Ware
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Vance
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio;
authors.forename: Navin
authors.initials: N
authors.lastname: Muni
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Hebert
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio;
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Satoskar
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio;
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Nadasdy
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio;
authors.forename: Iouri
authors.initials: I
authors.lastname: Ivanov
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio;
authors.forename: Tibor
authors.initials: T
authors.lastname: Nadasdy
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio; sergey.brodsky@osumc.edu.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Brodsky
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D000069604:Dabigatran; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D009392:Nephrectomy; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D051436:Renal Insufficiency, Chronic; D014812:Vitamin K / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
chemical_list: D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D000991:Antithrombins; D001562:Benzimidazoles; D016166:Free Radical Scavengers; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D015091:beta-Alanine; D014812:Vitamin K; D014859:Warfarin; D000069604:Dabigatran; D000111:Acetylcysteine; D010975:Platelet Aggregation Inhibitors
keywords: 5/6 nephrectomy.; blood pressure; chronic kidney injury; dabigatran; hypertension; warfarin