title: Long-term administration of tolvaptan increases myocardial remodeling and mortality via exacerbation of congestion in mice heart failure model after myocardial infarction.
abstract: BACKGROUND
  In contrast to loop diuretics, tolvaptan does not cause neurohormonal activation in several animal heart failure models. However, it remains unknown whether chronic vasopressin type 2 receptor blockade exerts beneficial effects on mortality in murine heart failure after myocardial infarction (MI). In an experimental heart failure model, we tested the hypothesis that tolvaptan reduces myocardial remodeling and mortality.
  
  
  RESULTS
  MI was induced in 9-week-old male C57Bl6/J by the left coronary artery ligation. In study 1, animals were randomly assigned to treatment with placebo or tolvaptan starting 14days post-MI. In study 2, animals were randomized to tolvaptan or furosemide+tolvaptan starting 14days post-MI. Interestingly, results showed lower survival rate in tolvaptan group compared to placebo. Tolvaptan group had higher serum osmolality, heavier body weight, more severe myocardial remodeling, and lung congestion at day 28 of drug administration compared to placebo. In study 2, addition of furosemide significantly reduced mortality rate seen with tolvaptan, and presented with decreased osmolality, myocardial remodeling, and lung congestion compared to tolvaptan-treated mice. Increase in proximal tubular expression of aquaporin 1, Angiotensin II, and vasopressin seen with tolvaptan treatments were normalized to basal levels, similar to levels in placebo-treated mice.
  
  
  CONCLUSIONS
  Contrary to our hypothesis, tolvaptan was associated with increased mortality in murine heart failure after MI. This increase in lung congestion, myocardial remodeling, could be prevented by co-administration of furosemide, which resulted in normalized serum osmolality, neurohormonal activation, and renal aquaporin 1 expression, and hence decreased mortality post-MI.
authors.affiliation: Division of Cardiovascular Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Division of Cardiovascular Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Iwasaku
authors.affiliation: Division of Cardiovascular Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Okuhara
authors.affiliation: Division of Cardiovascular Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Division of Cardiovascular Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.affiliation: Division of Cardiovascular Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
authors.affiliation: Division of Cardiovascular Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. Electronic address: hirotani@hyo-med.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirotani
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D001552:Benzazepines / Q000008:administration & dosage* / Q000009:adverse effects; D004195:Disease Models, Animal; D006333:Heart Failure / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000401:mortality*; D008171:Lung Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000401:mortality; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009026:Mortality / Q000639:trends; D009203:Myocardial Infarction / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000401:mortality*; D011897:Random Allocation; D013997:Time Factors; D000077602:Tolvaptan; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan
keywords: Angiotensin II; Aquaporin 1; Heart failure; Serum osmolality; Vasopressin type 2 receptor antagonist