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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Benetos, A., Lacolley, P., & Safar, M. E. (1997). Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arteriosclerosis, Thrombosis, and Vascular Biology, 17(6), 1152–1156.
Brown, M., Wedge, D. C., Goodacre, R., et al. (2011). Automated workflows for accurate mass-based putative metabolite identification in LC/MS-derived metabolomic datasets. Bioinformatics, 27(8), 1108–1112. doi:10.1093/bioinformatics/btr079.
Chobanian, A. V., Bakris, G. L., Black, H. R., et al. (2003). The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA, 289(19), 2560–2572. doi:10.1001/jama.289.19.2560.
De Meyer, T., Sinnaeve, D., Van Gasse, B., et al. (2008). NMR-based characterization of metabolic alterations in hypertension using an adaptive, intelligent binning algorithm. Analytical Chemistry, 80(10), 3783–3790. doi:10.1021/ac7025964.
Dieterle, F., Ross, A., Schlotterbeck, G., & Senn, H. (2006). Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. Analytical Chemistry, 78(13), 4281–4290. doi:10.1021/ac051632c.
Dunn, W. B., Broadhurst, D. I., Atherton, H. J., Goodacre, R., Griffin, J. L., et al. (2011a). Systems level studies of mammalian metabolomes: The roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chemical Society Reviews, 40(1), 387–426. doi:10.1039/b906712b.
Dunn, W. B., Broadhurst, D., Begley, P., et al. (2011b). Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nature Protocols, 6(7), 1060–1083. doi:10.1038/nprot.2011.335.
Edwards, L. M., Lawler, N. G., Nikolic, S. B., Peters, J. M., Horne, J., Wilson, R., et al. (2012). Metabolomics reveals increased isoleukotoxin diol (12,13-DHOME) in human plasma after acute Intralipid infusion. Journal of Lipid Research, 53(9), 1979–1986. doi:10.1194/jlr.P027706.
Edwards, N. C., Steeds, R. P., Stewart, P. M., Ferro, C. J., & Townend, J. N. (2009). Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: A randomized controlled trial. Journal of the American College of Cardiology, 54(6), 505–512. doi:10.1016/j.jacc.2009.03.066.
Funder, J. W., Pearce, P. T., Smith, R., & Campbell, J. (1989). Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology, 125(4), 2224–2226.
Hare, J. L., Sharman, J. E., Leano, R., Jenkins, C., Wright, L., & Marwick, T. H. (2013). Impact of spironolactone on vascular, myocardial, and functional parameters in untreated patients with a hypertensive response to exercise. American Journal of Hypertension,. doi:10.1093/ajh/hpt008.
Hatakeyama, H., Miyamori, I., Fujita, T., Takeda, Y., Takeda, R., & Yamamoto, H. (1994). Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. Journal of Biological Chemistry, 269(39), 24316–24320.
Head, G. A., McGrath, B. P., Mihailidou, A. S., et al. (2012). Ambulatory blood pressure monitoring in Australia: 2011 consensus position statement. Journal of Hypertension, 30(2), 253–266. doi:10.1097/HJH.0b013e32834de621.
Holland, D. J., Sacre, J. W., McFarlane, S. J., Coombes, J. S., & Sharman, J. E. (2008). Pulse wave analysis is a reproducible technique for measuring central blood pressure during hemodynamic perturbations induced by exercise. American Journal of Hypertension, 21(10), 1100–1106. doi:10.1038/ajh.2008.253.
Lacolley, P., Safar, M. E., Lucet, B., Ledudal, K., Labat, C., & Benetos, A. (2001). Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats. Journal of the American College of Cardiology, 37(2), 662–667.
Laurent, S., Cockcroft, J., Van Bortel, L., et al. (2006). Expert consensus document on arterial stiffness: Methodological issues and clinical applications. European Heart Journal, 27(21), 2588–2605. doi:10.1093/eurheartj/ehl254.
Lombes, M., Oblin, M. E., Gasc, J. M., Baulieu, E. E., Farman, N., & Bonvalet, J. P. (1992). Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circulation Research, 71(3), 503–510.
Mahmud, A., & Feely, J. (2005). Aldosterone-to-renin ratio, arterial stiffness, and the response to aldosterone antagonism in essential hypertension. American Journal of Hypertension, 18(1), 50–55. doi:10.1016/j.amjhyper.2004.08.026.
Mottram, P. M., Haluska, B., Leano, R., Cowley, D., Stowasser, M., & Marwick, T. H. (2004). Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation, 110(5), 558–565. doi:10.1161/01.cir.0000138680.89536.a9.
Mundal, R., Kjeldsen, S. E., Sandvik, L., Erikssen, G., Thaulow, E., & Erikssen, J. (1994). Exercise blood pressure predicts cardiovascular mortality in middle-aged men. Hypertension, 24(1), 56–62.
Overdiek, H. W., & Merkus, F. W. (1987). The metabolism and biopharmaceutics of spironolactone in man. Rev Drug Metab Drug Interact, 5(4), 273–302.
Palatini, P., Frigo, G., Bertolo, O., Roman, E., Da Corta, R., & Winnicki, M. (1998). Validation of the A&D TM-2430 device for ambulatory blood pressure monitoring and evaluation of performance according to subjects’ characteristics. Blood Press Monit, 3(4), 255–260.
Pickering, T. G., Hall, J. E., Appel, L. J., et al. (2005). Recommendations for blood pressure measurement in humans and experimental animals: Part 1: Blood pressure measurement in humans: A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation, 111(5), 697–716. doi:10.1161/01.CIR.0000154900.76284.F6.
Pitt, B., Zannad, F., Remme, W. J., et al. (1999). The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine, 341(10), 709–717. doi:10.1056/nejm199909023411001.
Sharman, J. E., Lim, R., Qasem, A. M., et al. (2006). Validation of a generalized transfer function to noninvasively derive central blood pressure during exercise. Hypertension, 47(6), 1203–1208.
Wehling, M. (2005). Effects of aldosterone and mineralocorticoid receptor blockade on intracellular electrolytes. Heart Failure Reviews, 10(1), 39–46. doi:10.1007/s10741-005-2347-z.
Wishart, D. S. (2008). Applications of metabolomics in drug discovery and development. Drugs R D, 9(5), 307–322.
Zannad, F., Alla, F., Dousset, B., Perez, A., & Pitt, B. (2000). Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: Insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation, 102(22), 2700–2706.
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Lindsay M. Edwards and James E. Sharman are joint last authors.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11306-013-0557-2