Activation of Cardiac Aldosterone Production in Rat Myocardial Infarction : Effect of Angiotensin II Receptor Blockade and Role in Cardiac Fibrosis (original) (raw)
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Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion
Background. Serum levels of aldosterone in heart failure are increased up to 20 times compared to normal subjects. After an acute myocardial infarction, aldosterone increases progressively as well as interstitial fibrosis and collagen synthesis from cardiac fibroblasts, forming a patchy heterogeneous interstitial collagen matrix that affects ventricular function. Even if angiotensine converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists (ARA) can reduce aldosterone levels early during treatment, they increase again after a 12 week treatment. The aim of this study was to evaluate the changes in structure and function of the left ventricle in symptomatic (NYHA I-III) diastolic heart failure patients receiving an aldosterone receptor antagonist.
Induction of Cardiac Fibrosis by Aldosterone
Journal of Molecular and Cellular Cardiology, 2000
P. L V. P. Induction of Cardiac Fibrosis by Aldosterone. Journal of Molecular and Cellular Cardiology (2000) 32, 865-879. An intracardiac aldosterone system which responds to short-and long-term physiological stimuli has been described. This cardiac generated aldosterone has possibly autocrine or paracrine actions.
British Journal of Pharmacology, 2005
1 Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart. 2 Hearts of male Wistar rats were perfused according to Langendorff. Ang II and aldosterone increased left ventricular pressure (LVP) by maximally 1174 and 972%, and decreased coronary flow (CF) by maximally 3677 and 2074%, respectively. Spironolactone did not significantly affect LVP or CF. 3 In hearts that were exposed to a 45-min coronary artery occlusion and 3 h of reperfusion, a 15-min exposure to spironolactone prior to occlusion reduced infarct size (% of risk area) from 6872 to 4573%, similar to the reduction (3472%) observed following 'preconditioning' (15 min occlusion followed by 10 min reperfusion) prior to the 45-min occlusion. Aldosterone exposure did not affect infarct size (7175%). 4 In cardiomyocytes, aldosterone decreased [ 3 H]thymidine incorporation maximally by 7373%, whereas in cardiac fibroblasts it decreased [ 3 H]proline incorporation by 3377%. Spironolactone inhibited both effects. Ang II increased DNA and collagen synthesis, and these effects were reversed by aldosterone. 5 In conclusion, aldosterone induces positive inotropic and vasoconstrictor effects in a nongenomic manner, and these effects are comparable to those of Ang II. Aldosterone reduces DNA and collagen synthesis via MR activation, and counteracts the Ang II-induced increases in these parameters. MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure.
Cardiovascular …, 2009
Time for primary review: 24 days Aims Blockade of mineralocorticoid receptors in the central nervous system (CNS) prevents sympathetic hyperactivity and improves left ventricle (LV) function in rats post-myocardial infarction (MI). We examined whether aldosterone produced locally in the brain may contribute to the activation of mineralocorticoid receptors in the CNS. Methods and results Two days after coronary artery ligation, Wistar rats received an intra-cerebroventricular (icv) infusion via osmotic mini-pumps of the aldosterone synthase inhibitor FAD286 at 100 mg/kg/ day or vehicle for 4 weeks. LV function was assessed by echocardiography at 2 and 4 weeks, and by Millar catheter at 4 weeks. At 4 weeks post-MI, aldosterone in the hippocampus was increased by 70% and tended to increase in the hypothalamus by 20%. These increases were prevented by FAD286. Across groups, aldosterone in the hippocampus and hypothalamus showed a high correlation. There were no differences in brain corticosterone levels. Compared to sham rats, at both 2 and 4 weeks post-MI rats treated with vehicle showed increased LV dimensions and decreased LV ejection fraction. Icv infusion of FAD286 attenuated these changes in LV dimensions and ejection fraction by 30%. At 4 weeks post-MI, LV peak systolic pressure (LVPSP) and dP/dt max/min were decreased and LV end-diastolic pressure (LVEDP) was increased. In rats treated with icv FAD286, LVPSP and dP/dt min remained normal and LVEDP and dP/dt max were markedly improved. Post-MI increases in cardiac fibrosis and cardiomyocyte diameter were substantially attenuated by icv FAD286. Conclusion These data suggest that aldosterone produced locally in the brain acts as the main agonist of mineralocorticoid receptors in the CNS and contributes substantially to the progressive heart failure post MI.
American Heart Journal, 2001
chiometric amount during type III collagen synthesis. The reparative process after myocardial infarction (MI) is associated with an expansion of the collagen extracellular matrix, as demonstrated in experimental models 4 and in humans. 5 Angiotensin converting enzyme (ACE) inhibitors are able to limit heart tissue collagen deposition after MI 4,6,7 in relation with the well-established role of angiotensin II (Ang II) in collagen synthesis. 8,9 Studies by Weber and Brilla 10 have demonstrated that cardiac fibrosis is mediated by aldosterone (Ald) more than by Ang II in patients with left ventricular hypertrophy. This mechanism is not clearly demonstrated, to the best of our knowledge, in patients who had an MI.
Canadian Journal of Physiology and Pharmacology, 2005
Activation of the renin–angiotensin–aldosterone system is associated with increased extracellular matrix and inflammatory markers in the cardiovascular system. We evaluated the effects of aldosterone antagonism on cardiovascular structure, collagen deposition, and expression of inflammatory markers in 2-week angiotensin (Ang) II-infused rats (120 ng·kg–1·min–1, s.c.) ± spironolactone or hydralazine (25 mg·kg–1·d–1). Aortic and cardiac collagen density was evaluated with Sirius red staining. NFκB and AP-1 were measured by a electrophoretic mobility shift assay, and ED-1 (macrophage marker) and vascular cell adhesion molecule-1 (VCAM-1) were measured by immunohistochemistry. Ang II increased blood pressure (176 ± 2 mmHg vs. 115 ± 1 mmHg in controls, p < 0.01), which was attenuated by spironolactone (147 ± 4 mmHg, p < 0.01) and prevented by hydralazine (124 ± 2 mmHg, p < 0.01). Ang II enhanced left ventricular interstitial collagen type I/III deposition (4.1% ± 0.1% vs. 3.1% ±...
Spironolactone prevents cardiac collagen proliferation after myocardial infarction in rats
Clinical and Experimental Pharmacology and Physiology, 2003
1. Aldosterone has been considered a key hormone in the regulation of water, sodium and potassium metabolism, thus influencing blood pressure regulation. More recently, several studies have demonstrated that aldosterone is also produced in extra-adrenal tissues (e.g. the heart), suggesting a paracrine effect for aldosterone, such as to increase collagen synthesis in the heart. 2. Because aldosterone production in the heart increases after myocardial infarction (MI), we investigated the effect of chronic administration of spironolactone, an aldosterone receptor antagonist, in rats after MI compared with the effects produced by losartan and hydralazine. 3. Myocardial infarction was produced in male Wistar rats by surgical ligature of the left coronary artery. Sham-operated animals were used as controls. 4. Spironolactone (20 mg/kg per day), losartan (15 mg/kg per day) or hydralazine (20 g/kg per day) were administered after MI and used for 1 month. 5. At the end of the treatment period, animals underwent haemodynamic recording (arterial and intraventricular pressures). The collagen content of the heart was evaluated by measuring the hydroxyproline (OH-Pro) concentration in right (RV) and left ventricle (LV) muscle fragments. 6. Infarct size was unaffected by drug treatments. The increased LV end-diastolic pressure observed in MI rats was prevented by losartan and remained unchanged following administration of spironolactone or hydralazine. 7. Losartan prevented RV and LV hypertrophy, as well as collagen proliferation in both ventricles, after MI. The postinfarction hypertrophy observed in RV and LV after MI remained unchanged in infarcted groups treated with spironolactone or hydralazine. 8. The OH-Pro concentration was significantly reduced in LV muscle in the MI group treated with spironolactone (682 ± 40 vs 557 ± 21 g/g for MI vs MI + spironolactone, respectively; P < 0.05), an effect not observed in the hydralazine-treated group. 9. These data suggest that spironolactone prevents collagen proliferation in the surviving myocardium by mechanisms independent of the loading conditions of the heart chambers. Control of postinfarction hypertrophy and collagen accumulation produced by losartan seems to depend on the reduction in loading conditions of the heart chambers.
Aldosterone Receptor Antagonist and Heart Failure Following Acute Myocardial Infarction
Acta Cardiologica …, 2010
The presence of heart failure or LV systolic dysfunction in the setting of acute myocardial infarction is associated with poor prognosis. Aldosterone is an important downstream mediator of the renin-angiotensin-aldosterone system which, in the post-acute myocardial infarction setting, promotes myocardial collagen deposition, myocardial fibrosis, apoptosis, endothelial dysfunction, ventricular remodeling, and heart failure, with attendant increased morbidity and mortality. Extending the findings from the Randomized Aldactone Evaluation Study (RALES) in chronic heart failure patients, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone offered a significant survival benefit, attenuated the progression of heart failure, and prevented sudden cardiac death when used in addition to optimal medical therapy. The current evidence-based guidelines suggest that aldosterone blockade should be an integral component of heart failure therapy to improve outcomes in this high-risk population.