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Cardiac aldosterone production and ventricular remodeling

2000; Elsevier BV; Volume: 57; Issue: 4 Linguagem: Inglês

10.1046/j.1523-1755.2000.00973.x

1523-1755

Claude Delcayre, Jean‐Sébastien Silvestre, Anne Garnier, Abdeslam Oubénaı̈ssa, Stéphane Cailmail, Estelle Tatara, Bernard Swynghedauw, Valérie Robert,

Hormonal and reproductive studies

Cardiac aldosterone production and ventricular remodeling. An intracardiac production of aldosterone has been recently reported in rat. This production is increased both acutely and chronically by angiotensin II, observations suggesting that the heart contains a steroidogenic system that is regulated similarly to the adrenal one. Cardiac production of aldosterone is small compared with that of the adrenal, raising the question of its function in normal conditions. Moreover, the regulation of this synthesis in pathophysiologic states remains unknown. In an analysis of the effects of a one-month myocardial infarction (MI) on the cardiac steroidogenic system, it was observed that aldosterone-synthase mRNA and the aldosterone concentration were increased by 2- and 3.5-fold, respectively, in the noninfarcted part of the rat left ventricle. MI also induced a 1.9-fold increase in the cardiac angiotensin II level. Losartan prevented these changes, and the MI-induced collagen deposition in noninfarcted area of the left ventricle was reduced by 1.6- and 2.5-fold by both spironolactone and losartan treatments, respectively. Thus, these observations indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac angiotensin II via the angiotensin II type 1 (AT1) receptor, and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling. Cardiac aldosterone production and ventricular remodeling. An intracardiac production of aldosterone has been recently reported in rat. This production is increased both acutely and chronically by angiotensin II, observations suggesting that the heart contains a steroidogenic system that is regulated similarly to the adrenal one. Cardiac production of aldosterone is small compared with that of the adrenal, raising the question of its function in normal conditions. Moreover, the regulation of this synthesis in pathophysiologic states remains unknown. In an analysis of the effects of a one-month myocardial infarction (MI) on the cardiac steroidogenic system, it was observed that aldosterone-synthase mRNA and the aldosterone concentration were increased by 2- and 3.5-fold, respectively, in the noninfarcted part of the rat left ventricle. MI also induced a 1.9-fold increase in the cardiac angiotensin II level. Losartan prevented these changes, and the MI-induced collagen deposition in noninfarcted area of the left ventricle was reduced by 1.6- and 2.5-fold by both spironolactone and losartan treatments, respectively. Thus, these observations indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac angiotensin II via the angiotensin II type 1 (AT1) receptor, and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling. Aldosterone (Aldo) plays a crucial role in sodium and potassium homeostasis of vertebrates by acting on epithelial tissues, namely kidney and colon. However, several clinical and experimental arguments indicate that Aldo may also modulate cardiovascular function. For example, an increase of plasma Aldo affects the left ventricle geometry in primary aldosteronism1Rossi G.P. Sacchetto A. Pavan E. Palatini P. Graniero G.R. Canali C. Pessina A.C. Remodeling of the left ventricle in primary aldosteronism due to Conn's adenoma.Circulation. 1997; 95: 1471-1478Crossref PubMed Scopus (217) Google Scholar. Previously, the multicenter CONSENSUS study demonstrated a relationship between the plasma Aldo concentration and mortality in patients with congestive heart failure2Swedberg K. Eneroth P. Kjekshus J. Wilhelmesen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality: CONSENSUS trial study group.Circulation. 1990; 82: 1730-1736Crossref PubMed Scopus (1082) Google Scholar. Using classic methods of physiology and pharmacology, several studies have shown that cardiovascular tone may be modified (generally increased) by mineralocorticoids and glucocorticoids [reviewed in3Ullian M. The role of corticosteroids in the regulation of vascular tone.Cardiovasc Res. 1999; 41: 55-64Crossref PubMed Scopus (172) Google Scholar. The mechanisms of their action remained, however, to be determined. Besides brain and blood vessels, the expression of specific mineralocorticoid receptors (MRs) also has been described in the heart of several species, including humans, rabbit, and rat4Funder J.W. Duval D. Meyer P. Cardiac glucocorticoid receptors: The binding of triated dexamethasone in rat and dog heart.Endocrinology. 1973; 93: 1300-1308Crossref PubMed Scopus (62) Google Scholar,5Lombès M. Oblin M.E. Gasc J.M. Baulieu E.E. Farman N. Bonvalet J.P. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor.Circ Res. 1992; 71: 503-510Crossref PubMed Scopus (267) Google Scholar, thus suggesting that cardiac tissue may be a target for Aldo. This may explain deleterious effects such as cardiac fibrosis that have been evidenced by several laboratories in experimental hyperaldosteronism6Brilla C.G. Pick R. Tan L.B. Janicki J.S. Weber K.T. Remodeling of the rat right and left ventricles in experimental hypertension.Circ Res. 1990; 67: 1355-1364Crossref PubMed Scopus (666) Google Scholar, 7Robert V. Nguyen V.T. Cheav S.L. Mouas C. Swynghedauw B. Delcayre C. Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension.Hypertension. 1994; 24: 30-36Crossref PubMed Scopus (187) Google Scholar, 8Young M. Fullerton M. Dilley R. Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis.J Clin Invest. 1994; 93: 2578-2583Crossref PubMed Scopus (415) Google Scholar. The discovery of the production of Aldo in rat heart brings a new step to the evolution of our ideas concerning the physiology of this hormone9Silvestre J.S. Robert V. Heymes C. Aupetit-Faisant B. Mouas C. Moalic J.M. Swynghedauw B. Delcayre C. Myocardial production of aldosterone and corticosterone in the rat: Physiological regulation.J Biol Chem. 1998; 273: 4883-4891Crossref PubMed Scopus (425) Google Scholar. This demonstrates the existence of an Aldo tissular system—that is, the presence in a cell or a group of cells of all the biochemical elements necessary to hormone synthesis and of its specific receptors—making a local autocrine or paracrine action possible. Intervention of this Aldo from cardiac origin in remodeling of the left ventricle in postinfarction has been evidenced very recently in the rat10Silvestre J.S. Heymes C. Oubenaissa A. Robert V. Aupetit-Faisant B. Carayon A. Swynghedauw B. Delcayre C. Activation of cardiac aldosterone production in rat myocardial infarction: Effect of angiotensin II receptor blockade and role in cardiac fibrosis.Circulation. 1999; 99: 2694-2701Crossref PubMed Scopus (362) Google Scholar. All of these observations reinforce the idea that mineralocorticoids have functions, in physiologic as well as in pathologic conditions, in cardiovascular tissue. Glucocorticoids and mineralocorticoids (mainly Aldo) are synthesized from cholesterol in adrenal cortex. The two forms of the cytochrome P-450 enzyme that catalyze the final step of these synthetic pathways are encoded by two closely related genes, CYP11B1 and CYP11B2, respectively, that display differences in their enzymatic activity, regulation, and tissular distribution11Fardella C.E. Miller W.L. Molecular biology of mineralocorticoid metabolism.Ann Rev Nutr. 1996; 16: 443-470Crossref PubMed Scopus (59) Google Scholar. P-450 11β-hydroxylase (11β-OHase) synthesizes corticosterone from deoxycorticosterone (DOC) in the zona fasciculata-reticularis and is mainly regulated by adrenocorticotropic hormone (ACTH). P-450 aldosterone-synthase (Aldo-synthase) catalyzes synthesis of Aldo from DOC in the zona glomerulosa. Its activity is principally controlled by angiotensin II and potassium and more weakly by ACTH and sodium Figure 1. Noticeably, Aldo-synthase and 11β-OHase are mitochondrial enzymes and thus are highly sensitive to the tissue oxygen concentration. Our laboratory has shown that the main enzymes for Aldo biosynthesis are present in rat heart11Fardella C.E. Miller W.L. Molecular biology of mineralocorticoid metabolism.Ann Rev Nutr. 1996; 16: 443-470Crossref PubMed Scopus (59) Google Scholar. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis evidences not only Aldo-synthase, but also the 11β-OHase gene expression in atria and ventricles of the young normal rat. Cardiac levels of 11β-OHase mRNA are sevenfold higher than those of Aldo-synthase mRNA. Interestingly, the 11β-OHase mRNA/Aldo-synthase mRNA ratio is identical in adrenals and in heart. The total amount of both mRNA molecules in whole heart is only 100-fold lower than in adrenal glands. To ascertain whether the steroid synthesis pathway is functional, Aldo and corticosterone production have been measured in the isolated rat heart (to avoid contamination by plasma steroids) using celite column chromatography coupled to radioimmunoassay. Aldo is detected in heart homogenate under baseline conditions, and its level is markedly increased after three hours of perfusion by angiotensin II or ACTH. Interestingly, the Aldo concentration in myocardium is about 17-fold higher than in plasma. Corticosterone is also present and increased by angiotensin II or ACTH, whereas the common precursor DOC is decreased in parallel. Additional experiments aimed to study the chronic regulation of this cardiac steroidogenic system have shown that it behaves in a very similar way to that of the adrenal gland. The Aldo synthesis pathway is sensitive to a low-sodium/high-potassium diet and to angiotensin II, whereas the corticosterone synthesis pathway responds positively to angiotensin II and ACTH. Thus, it is likely that Aldo synthesis in the heart is controlled by pathways similar to those described in adreno-cortical cells, as depicted in Figure 1. Extra-adrenal sites of steroid hormone production have also been identified in peripheric vessels. Indeed, Aldo and corticosterone production and 11β-OHase and Aldo-synthase gene expression have been demonstrated in mesenteric rat artery and in endothelial and smooth muscle cells isolated from human pulmonary artery12Hatakeyama H. Miyamori I. Fujita T. Takeda Y. Takeda R. Yamamoto H. Vascular aldosterone: Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells.J Biol Chem. 1994; 269: 24316-24320Abstract Full Text PDF PubMed Google Scholar, 13Takeda Y. Miyamori I. Yoneda T. Iki K. Hatakeyama H. Blair I.A. Hsieh F.Y. Takeda R. Production of aldosterone in isolated rat blood vessels.Hypertension. 1995; 25: 170-173Crossref PubMed Google Scholar, 14Takeda Y. Miyamori I. Yoneda T. Iki K. Hatakeyama H. Blair I.A. Hsieh F.Y. Takeda R. Synthesis of corticosterone in the vascular wall.Endocrinology. 1996; 135: 2283-2286Crossref Scopus (63) Google Scholar. Moreover, these authors have shown that this vascular Aldo potentiates angiotensin II-induced hypertrophy of cultured vascular smooth muscle cells, suggesting a physiologic role for this locally generated steroid12Hatakeyama H. Miyamori I. Fujita T. Takeda Y. Takeda R. Yamamoto H. Vascular aldosterone: Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells.J Biol Chem. 1994; 269: 24316-24320Abstract Full Text PDF PubMed Google Scholar. Whatever its origin, plasmatic or tissular, Aldo has effects in heart because of the presence of its MR in cardiomyocytes and in the endothelial wall of main coronary arteries5Lombès M. Oblin M.E. Gasc J.M. Baulieu E.E. Farman N. Bonvalet J.P. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor.Circ Res. 1992; 71: 503-510Crossref PubMed Scopus (267) Google Scholar. The intracellular MR is a transcription factor and forms a subfamily with glucocorticoid receptors (GRs), progesterone, and androgen receptors. In addition to epithelial tissues (as kidney, parotid gland, and colon), both the mRNA and protein MR have also been found in rodent and human hearts5Lombès M. Oblin M.E. Gasc J.M. Baulieu E.E. Farman N. Bonvalet J.P. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor.Circ Res. 1992; 71: 503-510Crossref PubMed Scopus (267) Google Scholar, 15Lombès M. Alfaidy N. Eugene E. Lessana A. Farman N. Bonvalet J.P. Prerequisite for cardiac aldosterone action: Mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase in the human heart.Circulation. 1995; 92: 175-182Crossref PubMed Scopus (282) Google Scholar, 16Pearce P. Funder J.W. High affinity aldosterone binding sites (type I receptors in rat heart).Clin Exp Pharmacol Physiol. 1987; 14: 859-866Crossref PubMed Scopus (105) Google Scholar. In the heart, in situ hybridization indicates that MR is expressed in cardiomyocytes, endothelial cells, and fibroblasts15Lombès M. Alfaidy N. Eugene E. Lessana A. Farman N. Bonvalet J.P. Prerequisite for cardiac aldosterone action: Mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase in the human heart.Circulation. 1995; 92: 175-182Crossref PubMed Scopus (282) Google Scholar. The high amino acid sequence identity in the ligand-binding domains of MR and GR leads to substantial binding of glucocorticoids to MR. As circulating concentrations of glucocorticoids are commonly three orders of magnitude higher than those of Aldo, it is important to determine how Aldo may exert a specific action. This is achieved by two means: (1) The NAD-dependent enzyme 11β-hydroxysteroid dehydrogenase II (11β-HSD II) converts cortisol and corticosterone into cortisone and 11-dehydrocorticosterone, respectively, which have negligible affinity for MR. (2) MR may also discriminate Aldo from glucocorticoids independently of 11β-HSD II. Indeed, the off-rate of Aldo from MR is five times lower than that of glucocorticoids, despite similar-affinity constants17Lombès M. Kenouch S. Souque A. Farman N. Rafestin-Oblin M.E. The mineralocorticoid receptor discriminates aldosterone from glucocorticoids independently of the 11β-hydroxysteroid dehydrogenase.Endocrinology. 1994; 135: 834-840Crossref PubMed Google Scholar. These have been described in kidney and also seem to be operative in heart, since the 11β-HSD II is coexpressed with MR in human and rat hearts, with, however, a low activity17Lombès M. Kenouch S. Souque A. Farman N. Rafestin-Oblin M.E. The mineralocorticoid receptor discriminates aldosterone from glucocorticoids independently of the 11β-hydroxysteroid dehydrogenase.Endocrinology. 1994; 135: 834-840Crossref PubMed Google Scholar, 18Slight S.H. Ganjam V.K. Gomez-Sanchez C.E. Zhou M.Y. Weber K.T. High affinity NAD+-dependent 11β-hydroxysteroid dehydrogenase in the human heart.J Mol Cell Cardiol. 1996; 28: 781-787Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 19Walker B.R. Yau J.L. Brett L.P. Seckl J.R. Monder C. Williams B.C. Edwards C.R.W. 11β-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: Implications for cardiovascular responses to glucocorticoids.Endocrinology. 1991; 129: 3305-3310Crossref PubMed Scopus (142) Google Scholar. Binding of Aldo induces dissociation of chaperone proteins (which maintain the receptors inactive) and exposition of nuclear localization signals in MR. In the absence of hormone, MR is present in both cytoplasm and nucleus, whereas in the presence of Aldo, activated MR rapidly accumulates in dynamic clusters in the cell nucleus20Fejes-Toth G. Pearce D. Naray-Fejes-Toth A. Subcellular localization of mineralocorticoid receptors in living cells: Effects of receptor agonists and antagonists.Proc Natl Acad Sci USA. 1998; 95: 2973-2978Crossref PubMed Scopus (205) Google Scholar. In agreement with the high degree of homology of their DNA binding site, MR and GR bind to common nuclear glucocorticoid response elements (GREs). The regulation of transcription is also dependent on an interaction with the transcription initiation complex and on diverse intracellular signaling pathways21Lim-Tio S.S. Fuller P.J. Intracellular signaling pathways confer specificity of transactivation by mineralocorticoid and glucocorticoid receptors.Endocrinology. 1998; 139: 1653-1661Crossref PubMed Scopus (36) Google Scholar. In addition, increasing evidence indicates the existence of coactivators and corepressors acting as a bridging factor between activated receptor and transcription initiation complex22Halachmi S. Marden E. Martin G. MacKay H. Abbondanza C. Brown M. Estrogen receptor associated proteins: Possible mediators of hormone-induced transcription.Science. 1994; 264: 1455-1458Crossref PubMed Scopus (558) Google Scholar,23Kurukowa R. Soderstrom M. Horlein A. Halachmi S. Brown M. Rosenfeld M.G. Glass C.K. Polarity-specific activities of retinoic acid receptors determined by a nuclear co-repressor.Nature. 1995; 377: 451-454Crossref Scopus (478) Google Scholar. MR is thus able to bind specific DNA sequences and to regulate the expression of Aldo-responsive genes, like Na+,K+-ATPase in kidney24Verrey F. Kraehenbuhl J.P. Rossier B.C. Aldosterone induces a rapid increase in the rate of Na,K-ATPase gene transcription in cultured kidney cells.Mol Endocrinol. 1989; 3: 1369-1376Crossref PubMed Scopus (76) Google Scholar. In heart, however, Aldo target genes are not fully elucidated. It should also be pointed out that rapid (2 to 10 min) effects of Aldo have been described. These effects, not inhibited by spironolactone, are presumably mediated by a yet unknown membrane receptor and do not involve protein synthesis. They may have physiopathologic consequences, since a study from Wehling's laboratory performed in patients during cardiac catheterization describes rapid changes of systemic vascular resistance and cardiac output 10 minutes after Aldo infusion25Wehling M. Spes C.H. Win N. Janson C.P. Schmidt B.M. Theisen K. Christ M. Rapid cardiovascular action of aldosterone in man.J Clin Endocrinol Metab. 1998; 83: 3517-3522Crossref PubMed Scopus (130) Google Scholar. One of the best documented effects of Aldo on the heart is the induction of an important fibrosis, with detrimental consequence for the cardiac pump. Karl Weber's group has found that fibrosis appears in rat heart only if Aldo and sodium intake are chronically increased6Brilla C.G. Pick R. Tan L.B. Janicki J.S. Weber K.T. Remodeling of the rat right and left ventricles in experimental hypertension.Circ Res. 1990; 67: 1355-1364Crossref PubMed Scopus (666) Google Scholar. The role of sodium in the pathogenesis of fibrosis is crucial but still unresolved26Funder J.W. Aldosterone, salt and cardiac fibrosis.Clin Exp Hypertens. 1997; 19: 885-899Crossref PubMed Scopus (48) Google Scholar. To confirm the specific effect of the hormone, it has been shown that inhibition of Aldo binding to MR by a low dose of spironolactone prevents only fibrosis, but not the associated hypertension and left ventricle hypertrophy, whereas a high dose prevents all secondary effects of the treatment27Brilla C. Matsubara L.S. Weber K.T. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism.J Mol Cell Cardiol. 1993; 25: 563-575Abstract Full Text PDF PubMed Scopus (398) Google Scholar. Whereas the increase in hypertrophy and atrial natriuretic peptide mRNA are restricted to the left ventricle, fibrosis appears in both ventricles6Brilla C.G. Pick R. Tan L.B. Janicki J.S. Weber K.T. Remodeling of the rat right and left ventricles in experimental hypertension.Circ Res. 1990; 67: 1355-1364Crossref PubMed Scopus (666) Google Scholar, 7Robert V. Nguyen V.T. Cheav S.L. Mouas C. Swynghedauw B. Delcayre C. Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension.Hypertension. 1994; 24: 30-36Crossref PubMed Scopus (187) Google Scholar, 8Young M. Fullerton M. Dilley R. Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis.J Clin Invest. 1994; 93: 2578-2583Crossref PubMed Scopus (415) Google Scholar, supporting the contention that this Aldo-induced cardiac response is independent of hemodynamic factors. One characteristic feature of this experimental model of hypertension is the long interval of time observed between the increase of plasma Aldo (obtained by osmotic minipumps) and the modifications of cardiac structure28Robert V. Silvestre J.S. Charlemagne D. Sabri A. Trouve P. Wassef M. Swynghedauw B. Delcayre C. Biological determinants of aldosterone-induced cardiac fibrosis in rats.Hypertension. 1995; 26: 971-978Crossref PubMed Scopus (177) Google Scholar. Indeed, types I and III procollagen increase in both ventricles at two weeks only, whereas progressive cardiac fibrosis is found at one month. At two months, total MatrixMetalloProtease-2 activity is increased and localized by in situ zymography within the media of coronary arteries, suggesting a role in vascular remodeling29Robert V. Besse S. Sabri A. Silvestre J.S. Assayag P. Nguyen V.T. Swynghedauw B. Delcayre C. Differential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart.Lab Invest. 1997; 76: 729-738PubMed Google Scholar. Thus, cardiac alterations are late, precluding a direct modulation of cardiac collagen synthesis by Aldo in vivo. The early mechanisms by which Aldo induces fibrosis are far from being understood. Recent results from our laboratory show that cardiac angiotensin II receptor may be a target for Aldo, suggesting a potentiation of fibrogenic properties of angiotensin II. Indeed, ventricular density of AT1 receptors is 1.5-fold increased in rats treated one month with Aldo-salt, this increase being prevented by both spironolactone and losartan30Robert V. Heymes C. Silvestre J.S. Sabri A. Swynghedauw B. Delcayre C. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: Role in aldosterone-salt induced fibrosis.Hypertension. 1999; 33: 981-986Crossref PubMed Scopus (215) Google Scholar. Additionally, a series of observations based on selective inhibition of different effectors has been made in Aldo-salt or deoxycorticosterone-salt excess, suggesting the involvement of other agents like calcium, bradykinin, endothelin, and possibly nitric oxide [reviewed in31Delcayre C. Silvestre J.S. Aldosterone and the heart: Towards a physiological function?.Cardiovasc Res. 1999; 43: 7-12Crossref PubMed Scopus (57) Google Scholar. Previous observations suggest that an elevation of the level of angiotensin II in heart may induce an elevation of the level of Aldo9Silvestre J.S. Robert V. Heymes C. Aupetit-Faisant B. Mouas C. Moalic J.M. Swynghedauw B. Delcayre C. Myocardial production of aldosterone and corticosterone in the rat: Physiological regulation.J Biol Chem. 1998; 273: 4883-4891Crossref PubMed Scopus (425) Google Scholar. This could happen in pathological situations in which such an increase of tissular angiotensin II has been evidenced, such as the myocardial infarction (MI). To verify this hypothesis and to evaluate its consequences, concentrations of angiotensin II and of Aldo were measured in the left ventricle one month after an experimental MI in rats10Silvestre J.S. Heymes C. Oubenaissa A. Robert V. Aupetit-Faisant B. Carayon A. Swynghedauw B. Delcayre C. Activation of cardiac aldosterone production in rat myocardial infarction: Effect of angiotensin II receptor blockade and role in cardiac fibrosis.Circulation. 1999; 99: 2694-2701Crossref PubMed Scopus (362) Google Scholar. Seven days after surgery, rats were randomized in three groups: MI, MI + spironolactone (20 mg/kg/day), and MI + losartan (8 mg/kg/day). Cardiac function was not altered one month after MI, and left ventricular hypertrophy was prevented only by losartan treatment. At this time point, Aldo-synthase mRNA is increased by 100%, Aldo concentration by 267%, and angiotensin II concentration by 90% in the noninfarcted part of left ventricle Figure 2. These variations are prevented by losartan, not by spironolactone. Plasma concentrations of aldo are unchanged whatever the treatment. The MI-induced increase in left ventricular collagen is decreased 1.6- and 2.5-fold by spironolactone and losartan, respectively. Whereas the left ventricular norepinephrine concentration is not modified by MI, both spironolactone and losartan decrease this value by 50%. Postinfarction thus involves a selective activation of the Aldo cardiac synthesis pathway Figure 3. This activation is at the expense of cardiac corticosterone production. These cardiac regulations are prevented by an AT1 antagonist. However, the plasmatic renin-angiotensin system is not activated one month after MI. In contrast, the cardiac angiotensin II level is increased. Thus, the stimulus that increases the cardiac production of Aldo would be the tissular increase of angiotensin II that is evidenced in MI. This experimental model allows a selective approach to dissociate the action of cardiac Aldo from that of plasmatic Aldo. Indeed, in contrast to the cardiac system, the adrenal steroidogenic system is not activated one month after MI. Spironolactone does not prevent the myocyte hypertrophy, but decreases fibrosis in the noninfarcted zone of left ventricle. Since the plasma Aldo concentration is unchanged and the cardiac Aldo production is increased, it can be concluded that the effect of spironolactone on the cardiac collagen content is only due to the blockade of cardiac Aldo. Thus, the selective activation of cardiac Aldo synthesis is involved in the ventricular remodeling secondary to MI. The results mentioned earlier in this article indicate that the heart is equipped with a functional system of Aldo synthesis and that its activation in pathological conditions may influence the cardiac structure and/or function. These observations raise the question of the potential role of such a system (which also produces glucocorticoids) in normal conditions. This question is related to the general problem of the local hormonal systems now identified in cardiac or vascular tissue, such as the renin-angiotensin and adrenergic systems. The possibility of autocrine or paracrine effects in myocardium has been a matter of controversy, and this controversy has lasted for about 10 years in the case of the intracardiac renin-angiotensin system. As it is the case for the cardiac steroidogenic system9Silvestre J.S. Robert V. Heymes C. Aupetit-Faisant B. Mouas C. Moalic J.M. Swynghedauw B. Delcayre C. Myocardial production of aldosterone and corticosterone in the rat: Physiological regulation.J Biol Chem. 1998; 273: 4883-4891Crossref PubMed Scopus (425) Google Scholar, the cardiac renin-angiotensin system generates tissular concentrations of angiotensin II that are far higher (10- to 20-fold) than those measured in plasma10Silvestre J.S. Heymes C. Oubenaissa A. Robert V. Aupetit-Faisant B. Carayon A. Swynghedauw B. Delcayre C. Activation of cardiac aldosterone production in rat myocardial infarction: Effect of angiotensin II receptor blockade and role in cardiac fibrosis.Circulation. 1999; 99: 2694-2701Crossref PubMed Scopus (362) Google Scholar,32Dell'italia L.J. Meng Q.C. Balcells E. Wei C.C. Palmer R. Hageman G.R. Durand J. Hankes G.H. Oparil S. Compartmentalization of angiotensin II generation in the dog heart: Evidence for independent mechanisms in intravascular and interstitial spaces.J Clin Invest. 1997; 100: 253-258Crossref PubMed Scopus (184) Google Scholar. The high Aldo concentration in heart (relative to that of plasma) supports a putative physiological role. Such a role is yet not known. As suggested by several studies, cardiac Aldo may be involved in the control of ionic movements33Ikeda U. Hyman R. Smith T.W. Medford R.M. Aldosterone-mediated regulation of Na,K-ATPase gene expression in adult and neonatal rat cardiocytes.J Biol Chem. 1991; 266: 12058-12066Abstract Full Text PDF PubMed Google Scholar,34Korichneva I. Puceat M. Millanvoye-Van Brussel E. Geraud G. Vassort G. Aldosterone modulates both the Na/H antiport and Cl/HCO3 exchanger in cultured neonatal rat cardiac cells.J Mol Cell Cardiol. 1995; 27: 2521-2528Abstract Full Text PDF PubMed Scopus (39) Google Scholar. Angiotensin II and Aldo may have interactions in myocardium, as already mentioned since Ang II enhances cardiac Aldo synthesis. On the other hand, Aldo increases AT-1 receptor mRNA and density28Robert V. Silvestre J.S. Charlemagne D. Sabri A. Trouve P. Wassef M. Swynghedauw B. Delcayre C. Biological determinants of aldosterone-induced cardiac fibrosis in rats.Hypertension. 1995; 26: 971-978Crossref PubMed Scopus (177) Google Scholar,35Ullian M.E. Schelling J.R. Linas S.L. Aldo enhances angiotensin II receptor binding and inositol phosphate responses.Hypertension. 1992; 20: 67-73Crossref PubMed Scopus (132) Google Scholar and potentiates angiotensin II-stimulated hypertrophy12Hatakeyama H. Miyamori I. Fujita T. Takeda Y. Takeda R. Yamamoto H. Vascular aldosterone: Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells.J Biol Chem. 1994; 269: 24316-24320Abstract Full Text PDF PubMed Google Scholar. These actions may thus sensitize cardiac responses to circulating or locally produced angiotensin II. Finally, as detailed in this article, cardiac Aldo is involved in cardiac remodeling and in the generation of ventricular arrhythmia through the control of norepinephrine uptake36Barr C.S. Lang C.C. Hanson J. Arnott M. Kennedy N. Struthers A.D. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease.Am J Cardiol. 1995; 76: 1259-1265Abstract Full Text PDF PubMed Scopus (299) Google Scholar. Identification of the site of synthesis could also give useful information. Indeed, if the site of synthesis of these cardiac hormones is close to the site of action (and a comparative study of the localization of biosynthesis enzymes and of receptors would allow this question to be answered), the response of such a local system is necessarily very short. One may thus think that a hormonal system with rapid adaptation is able to modulate on the short term the properties of a group of cells, thus ensuring a fine tuning relative to the influence of circulating hormones. Discovery of tissular hormonal systems has suggested that they have local regulatory roles that are more or less independent from circulating hormones. The observations discussed here raise the possibility of interactions between local systems, since local variations of angiotensin II may modify the cardiac concentration of Aldo. The consequences of such changes are likely to be important in diverse pathologic situations, as shown in the MI study. The intracellular localization, the role(s) and the regulations in physiopathologic models of this new cardiac steroidogenic system are major research directions to expand our understanding of local hormonal systems. Transgenic technology is one of the possible ways to gain further insight into this matter. Additionally, it is important to note that the observations described earlier in this article have been made in rodents. The physiologic significance of this system would be strengthened if its existence could be demonstrated in humans.