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Spironolactone reduces aortic stiffness via blood pressure-dependent effects of canrenoate

Abstract

Spironolactone is thought to improve aortic stiffness via blood pressure (BP) independent (antifibrotic) effects, but the exact mechanism is unknown. We used metabolomics and hemodynamic measures to reveal the underlying actions of spironolactone in people with a hypertensive response to exercise (HRE). Baseline and follow-up serum samples from 115 participants randomized to 3 months spironolactone (25 mg/day) or placebo were analysed using liquid chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy. Hemodynamic measures recorded at baseline and follow-up included aortic pulse wave velocity (stiffness) and 24 h ambulatory BP. Aortic stiffness was significantly reduced by spironolactone compared with placebo (−0.18 ± 0.17 vs 0.30 ± 0.16 m/s; p < 0.05), but this was no longer significant after adjustment for the change in daytime systolic BP (p = 0.132). Further, the change in aortic stiffness was correlated with the change in daytime and 24 h systolic BP (p < 0.05). Metabolomics detected 42 features that were candidate downstream metabolites of spironolactone (no endogenous metabolites), although none were correlated with changes in aortic stiffness (p > 0.05 for all). However, the spironolactone metabolite canrenoate was associated with the change in daytime systolic BP (r = −0.355, p = 0.017) and 24 h pulse pressure (r = −0.332, p = 0.026). This remained highly significant on multiple regression and was independent of age, body mass index and sex. Canrenoate appears to be an active metabolite with BP-dependent effects on the attenuation of aortic stiffness in people with HRE. This finding, together with the lack of change in endogenous metabolites, suggests that the antifibrotic effects of spironolactone could be BP-dependent.

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Acknowledgments

The study was supported by a Grant-In-Aid from the National Heart Foundation of Australia (reference G05B 2041). Dr Sharman was supported by a NHMRC Career Development Award (reference 569519).

Conflict of interest

None of the authors have a conflict of interest relevant to this work.

Ethical Standard

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

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Correspondence to James E. Sharman.

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Lindsay M. Edwards and James E. Sharman are joint last authors.

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Nikolic, S.B., Wilson, R., Hare, J.L. et al. Spironolactone reduces aortic stiffness via blood pressure-dependent effects of canrenoate. Metabolomics 10, 105–113 (2014). https://doi.org/10.1007/s11306-013-0557-2

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  • DOI: https://doi.org/10.1007/s11306-013-0557-2

Keywords

  • Metabolomics
  • Canrenone
  • Canrenoate
  • Hypertension
  • Exercise