effect of aldosterone on sodium transport has also been
described in vascular smooth muscle cells (27–30), involving
in particular the Na
antiport and the Na
ATPase pump (31).
Numerous studies have shown that myocardial ﬁbrosis in
response to chronic mineralocorticoid excess and salt load-
ing is independent of the degree of hypokalemia, hyperten-
sion, and cardiac hypertrophy (8,18,19). Furthermore, low-
dose spironolactone administration has been shown to offset
the effects of aldosterone on cardiac ﬁbrosis with minimal
changes in blood pressure and cardiac mass (5,8). In the
present study, spironolactone caused little change in blood
pressure and cardiac hypertrophy but a striking reduction in
cardiac collagen accumulation was observed. This reduction
was much more pronounced than that observed on the
carotid artery. One possibility is that collagen content (but
not density) is simply higher in the heart than in the arteries,
resulting in a more substantial lowering under spironolac-
tone, according to the low of initial value. Another possi-
bility is that the number and/or sensitivity of mineralocor-
ticoid receptors differ markedly in the heart and in the
vessels. An indirect argument in favor of this possibility is
that these receptors are in higher number in larger than in
smaller arteries (22), resulting in a signiﬁcant increase in
distensibility under spironolactone without signiﬁcant
change in mean arterial pressure and hence arteriolar resis-
In conclusion, the goal of the present study was not to
perform an age-dependent/dose-dependent set of exper-
iments with respect to arterial stiffness and spironolac-
tone treatment. It was only to assess that even in old
normotensive rats, spironolactone is able to prevent an
age-induced increase in extracellular matrix accumulation
together with an improvement of arterial elasticity and
that this ﬁnding was independent of blood pressure
changes. Because in old normotensive rats, a similar effect
has not been observed under chronic converting enzyme
inhibition, the action of spironolactone might be consid-
ered as speciﬁc. Thus, spironolactone treatment may be
proposed in situations involving a development of extra-
cellular matrix as during aging and hypertension. In the
latter situation, particularly in essential hypertension in
which a positive statistical association has been observed
between increased arterial stiffness and increased aldoste-
rone (32), the clinical relevance of this ﬁnding should be
We thank Maryse Deboute´ for her excellent assistance.
Reprint requests and correspondence: Dr. Michel Safar, Me´-
decine Interne 1, Hoˆpital Broussais, 96 rue Didot, 75674 Paris
Cedex 14, France. E-mail: firstname.lastname@example.org.
1. Yin F. The aging vasculature and its effects on the heart. In: Weisfeldt
M, editor. The Aging Heart. New York: Raven Press, 1990:137–213.
2. Corman B, Duriez M, Poitevin P, et al. Aminoguanidine prevents
age-related arterial stiffening and cardiac hypertrophy. Proc Natl Acad
3. Albaladejo P, Bouaziz H, Duriez M, et al. Angiotensin converting
enzyme inhibition prevents the increase in aortic collagen in rats.
4. Michel JB, Heudes D, Michel O, et al. Effect of chronic ANG
I-converting enzyme inhibition on aging processes. II. Large arteries.
Am J Physiol 1994;267:R124–35.
5. Benetos A, Lacolley P, Safar ME. Prevention of aortic ﬁbrosis by
spironolactone in spontaneously hypertensive rats. Arterioscler
Thromb Vasc Biol 1997;17:1152–6.
6. Weber KT, Brilla CG. Pathological hypertrophy and cardiac intersti-
tium: ﬁbrosis and renin-angiotensin-aldosterone system. Circulation
7. Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive
heart disease and the role of hormones. Hypertension 1994;23(part
8. Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in
cultured adult rat cardiac ﬁbroblasts: response to angiotensin II and
aldosterone. J Mol Cell Cardiol 1994;26:809–20.
9. Lacolley P, Ghodsi N, Glazer E, et al. Inﬂuence of graded changes in
vasomotor tone on the carotid arterial mechanics in live spontaneously
hypertensive rats. Br J Pharmacol 1995;115:1235–44.
10. Tardy Y, Meister JJ, Perret F, Waeber B, Brunner HR. Assessment of
the elastic behaviour of peripheral arteries from non-invasive measure-
ment of their diameter-pressure curves. Clin Phys Physiol Meas
11. Kratky RG, Lo DK, Roach MR. Quantitative measurement of ﬁxation
rate and dimension changes in the aldehyde/pressure ﬁxed canine
carotid artery. Blood Vess 1991;28:386–95.
12. Lee RMKW. Preservation of in vivo morphology of blood vessels for
morphometric studies. Scanning Microsc 1987;1:1298–93.
13. Valmsley JG, Gore RW, Dacey RG Jr, Damon DN, Duling BR.
Quantitative morphology of arterioles from the hamster cheek pouch
related to mechanical analysis. Microvasc Res 1982;24:249–71.
14. Richer C, Mulder P, Fornes P, Domergue V, Heudes D, Giudicelli
J-F. Long-term treatment with trandolapril opposes cardiac remodel-
ing and prolongs survival after myocardial infraction in rats. J Cardio-
vasc Pharmacol 1992;20:147–56.
15. Owens GK. Inﬂuence of blood pressure on the development of aortic
medial smooth muscle hypertrophy in spontaneously hypertensive rats.
16. Levy BI, Michel JB, Salzman JL, et al. Effects of chronic inhibition of
converting enzyme on mechanical and structural properties of arteries
in rat renovascular hypertension. Circ Res 1988;63:227–39.
17. Kofﬁ I, Safar ME, Labat C, Lacolley P, Benetos A, Mourad JJ.
Arterial structural changes with verapamil in spontaneously hyperten-
sive rats. Am J Hypertens 1999;12:732–8.
18. Robert V, Van Thiem N, Cheav SL, Mouas C, Swynghedauw B,
Delcayre C. Increased cardiac types I and III collagen mRNAs in
aldosterone-salt hypertension. Hypertension 1994;24:30–6.
19. Young M, Fullerton M, Dilley R, Funder J. Mineralcorticoids,
hypertension and cardiac ﬁbrosis. J Clin Invest 1994;93:2578–83.
20. Marquat FX, Bellon G, Gillery P, Wegrowski Y, Borel JP. Stimulation
of collagen synthesis in ﬁbroblast cultures by a triterpene extracted
from Centella asiatica. Connect Tissue Res 1990;24:107–20.
21. Ooshima A, Fuller GC, Cardinale GJ, Spector S, Udenfried S.
Increased collagen synthesis in blood vessels of hypertensive rats and
its reversal by antihypertensive agents. Proc Natl Acad SciUSA
22. Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, Bonvalet
JP. Immunohistochemical and biochemical evidence of a cardiovascu-
lar mineralocorticoid receptor. Circ Res 1992;71:503–10.
23. Lockett MF. Hormonal actions of the heart and the lungs on the
isolated kidney. J Physiol 1967;193:661–9.
24. Kornel L, Kanamariapudi N, Travers T, et al. Studies on high afﬁnity
binding of mineralo- and glucocorticoids in rabbit aorta cytosol. J
Steroid Biochem 1982;16:245–64.
JACC Vol. 37, No. 2, 2001
Aortic Fibrosis Prevention by Spironolactone in Old Normotensive Rats