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Lacolley, P. et al. Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats. J. Am. Coll. Cardiol. 37, 662-667

Department of Internal Medicine and INSERM U337, Broussais Hospital, Paris, France.
Journal of the American College of Cardiology (Impact Factor: 16.5). 03/2001; 37(2):662-7. DOI: 10.1016/S0735-1097(00)01129-3
Source: PubMed

ABSTRACT

Because the synthesis of aldosterone is mainly modulated by angiotensin II through type I receptor stimulation and because converting enzyme inhibition (CEI) does not modify aortic extracellular matrix in old normotensive rats, the aim of the present study was to determine whether inhibition of aldosterone formation was able to prevent aortic fibrosis in old Sprague-Dawley normotensive rats.
We have previously shown that long-term aldosterone antagonism prevents the age-related increase in aortic collagen accumulation in young spontaneously hypertensive rats, independent of blood pressure changes. In contrast, we reported that the positive effects of CEI in the prevention of aortic collagen accumulation were related to the inhibition of angiotensin II actions on angiotensin II type I receptors.
For this purpose, we studied the histomorphometric and stiffness (echo-tracking technique) changes of an eight-week treatment with the aldosterone antagonist spironolactone by comparison with placebo.
At the end of treatment, spironolactone in conscious animals did not change intra-arterial blood pressure, aortic and carotid wall thickness, and cardiac weight. Cardiac collagen density and, to a lesser extent, carotid collagen and elastin densities and contents were significantly decreased in association with an increase of carotid distensibility.
These results show that in old normotensive rats, spironolactone can markedly prevent cardiac and, to a lesser extent, arterial fibrosis and improve arterial stiffness, despite a lack of hypotensive effect.

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    • "It has been suggested that, irrespective of BP control, blocking vascular mineralocorticoid receptors may prevent or attenuate negative effects of aldosterone on the structure and function of the vascular wall (Lacolley et al. 2001; Mahmud and Feely 2005; Benetos et al. 1997). Thus, spironolactone treatment has been purported to improve vascular function via BPindependent , antifibrotic mechanisms (Lacolley et al. 2001; Benetos et al. 1997). "
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    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.
    Full-text · Article · Feb 2014 · Metabolomics
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    • "It has been suggested that, irrespective of BP control, blocking vascular mineralocorticoid receptors may prevent or attenuate negative effects of aldosterone on the structure and function of the vascular wall (Lacolley et al. 2001; Mahmud and Feely 2005; Benetos et al. 1997). Thus, spironolactone treatment has been purported to improve vascular function via BPindependent , antifibrotic mechanisms (Lacolley et al. 2001; Benetos et al. 1997). "
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    ABSTRACT: Background: Spironolactone is an aldosterone antagonist that is thought to have antifibrotic effects (e.g. reduces aortic stiffness), but little is known about the underlying mechanisms. This could occur through direct effects on the endogenous aldosterone pathway or via active metabolites derived from spironolactone. In this study we aimed to determine the physiological actions of downstream metabolites of spironolactone. Methods: Baseline and follow-up serum samples from 115 participants (54 +/- 9years) randomized to three months spironolactone (25 mg/d) or placebo were analysed by liquid chromatography/mass spectrometry (LC/MS) using a high resolution LTQ-Orbitrap. Physiological variables recorded at baseline and follow-up included aortic stiffness (pulse wave velocity; PWV) and 24 hour ambulatory BP. Actions of spironolactone metabolites were assessed by correlation with the change in physiological variables after three months spironolactone therapy. Results: Spironolactone significantly reduced aortic PWV and 24 hour systolic BP (P < 0.05 for both). LC/MS detected 43 individual features that were candidate downstream metabolites of spironolactone, although none were correlated with changes in aortic PWV (P > 0.05 for all). However, the spironolactone metabolite canrenoate was associated with the change in daytime systolic BP (r = -0.415, P = 0.007). This remained highly significant on multiple regression ([beta]=-0.408, P = 0.009) and was independent of age, body mass index and sex (adjusted R2 = 0.268, P < 0.021). Conclusions: Downstream drug metabolites of spironolactone do not appear to have significant antifibrotic effects, as measured by attenuation of aortic stiffness. However, canrenoate appears to be an active metabolite of spironolactone with regard to ambulatory BP lowering effects.
    Full-text · Article · Sep 2012 · Journal of Hypertension
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    • "Reduced flexibility of the blood vessel wall has predominantly been believed to be associated with changes in the vascular extracellular matrix (ECM). In this regard, increased collagen content and decreased elastin have been identified as the most significantly altered ECM components (Lacolley et al., 2001; Lakatta, 2002; Qiu et al., 2007). In addition to the ECM, vascular smooth muscle cells (VSMCs) represent the main cellular constituents of the arterial wall, and their active contractile properties provide for the active stress present within the wall. "
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    ABSTRACT: A spectral analysis approach was developed for detailed study of time-resolved, dynamic changes in vascular smooth muscle cell (VSMC) elasticity and adhesion to identify differences in VSMC from young and aged monkeys. Atomic force microscopy (AFM) was used to measure Young's modulus of elasticity and adhesion as assessed by fibronectin (FN) or anti-beta 1 integrin interaction with the VSMC surface. Measurements demonstrated that VSMC cells from old vs. young monkeys had increased elasticity (21.6 kPa vs. 3.5 kPa or a 612% increase in elastic modulus) and adhesion (86 pN vs. 43 pN or a 200% increase in unbinding force). Spectral analysis identified three major frequency components in the temporal oscillation patterns for elasticity (ranging from 1.7 × 10(-3) to 1.9 × 10(-2)  Hz in old and 8.4 × 10(-4) to 1.5 × 10(-2) Hz in young) and showed that the amplitude of oscillation was larger (P < 0.05) in old than in young at all frequencies. It was also observed that patterns of oscillation in the adhesion data were similar to the elasticity waveforms. Cell stiffness was reduced and the oscillations were inhibited by treatment with cytochalasin D, ML7 or blebbistatin indicating the involvement of actin-myosin-driven processes. In conclusion, these data demonstrate the efficacy of time-resolved analysis of AFM cell elasticity and adhesion measurements and that it provides a uniquely sensitive method to detect real-time functional differences in biomechanical and adhesive properties of cells. The oscillatory behavior suggests that mechanisms governing elasticity and adhesion are coupled and affected differentially during aging, which may link these events to changes in vascular stiffness.
    Full-text · Article · May 2012 · Aging cell
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