Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists

Olga V. Fedorova, Igor V. Emelianov, Konstantin A. Bagrov, Yulia N. Grigorova, Wen Wei, Ondrej Juhasz, Elena V. Frolova, Courtney A. Marshall, Edward G. Lakatta, Alexandra O. Konradi, Alexei Y. Bagrov

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Endogenous cardiotonic steroids, including marinobufagenin (MBG), stimulate vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of cardiotonic steroids on the Na/K-ATPase, we hypothesized that spironolactone would reverse the profibrotic effects of MBG. Methods: Experiment 1: Explants of thoracic aortae and aortic vascular smooth muscle cells from Wistar rats were cultured for 24h in the presence of vehicle or MBG (100nmol/l) with or without canrenone (10μmol/l), an active metabolite of spironolactone. Experiment 2: In 16 patients (56±2 years) with resistant hypertension on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy, we determined arterial pressure, pulse wave velocity, plasma MBG, and erythrocyte Na/K-ATPase before and 6 months after addition of placebo (n=8) or spironolactone (50mg/day; n=8) to the therapy. Results: In rat aortic explants and in vascular smooth muscle cells, pretreatment with MBG resulted in a two-fold rise in collagen-1, and a marked reduction in the sensitivity of the aortic rings to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC 50 =480±67 vs. 23±3nmol/l in vehicle-treated rings; P<0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC 50 =17±1nmol/l). Resistant hypertension patients exhibited elevated plasma MBG (0.42±0.07 vs. 0.24±0.03nmol/l; P=0.01) and reduced Na/K-ATPase activity (1.9±0.15 vs. 2.8±0.2μmol Pi/ml per h, P<0.01) vs. seven healthy individuals. Six-month administration of spironolactone, unlike placebo treatment, was associated with a decrease in pulse wave velocity and arterial pressure, and with restoration of Na/K-ATPase activity in the presence of unchanged MBG levels. Conclusion: MBG-induced vascular fibrosis is a likely target for spironolactone.

Original languageEnglish (US)
Pages (from-to)1602-1610
Number of pages9
JournalJournal of hypertension
Volume33
Issue number8
DOIs
StatePublished - Aug 11 2015
Externally publishedYes

Keywords

  • Friend leukemia virus integration 1
  • Na/K-ATPase
  • arterial fibrosis
  • cardiotonic steroids
  • collagen
  • marinobufagenin
  • mineralocorticoid receptor antagonists
  • pulse wave velocity
  • resistant hypertension
  • spironolactone

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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