Spironolactone prevents cardiac collagen proliferation after myocardial infarction in rats

Abstract

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 microg/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 microg/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.

Infarto do miocárdio experimental em ratos: análise do modelo

“…For this reason, this model is ideal for the study of therapeutic interventions to minimize the morphological and functional alterations that can occur after the infarction. Thus, many of the interventions used in infarction patients were initially analyzed in the rat model, such as: angiotensinconverting enzyme inhibitors 14,41 , angiotensin-II receptor antagonists 72 , aldosterone antagonists 73 and betablockers 74 .…”

Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

“…Aldosterone antagonists demonstrate indirect effects on MMP activity and collagen deposition post-MI. Spironolactone prevents cardiac collagen deposition post-MI in rodents [120]. Spironolactone and hydrochlorothiazide both demonstrated an ability to reduce vascular MMP-2 activity and expression in a model of renovascular hypertension [121].…”

Remodeling in the ischemic heart: the stepwise progression for heart

“…Expression of CTGF, another profibrotic factor that is also involved in collagen deposition in infarcted hearts, increases in non-infarcted myocardium during injury healing (15). Due to activation of this cytokine cascade, considerable collagen deposition can be observed in infarcted and non-infarcted areas as early as 3 days after MI, which increases during the following 28 days (16,17). Regarding the importance of extracellular matrix remodeling in cardiac dysfunction, Baicu et al (18) showed that isolated papillary muscles exhibit impaired systolic performance if fibrillar collagen is degraded in a timely manner (18).…”

“…Mill et al (17) showed that aldosterone also contributes to increased collagen deposition in non-infarcted viable tissue. Another effect of aldosterone observed in infarcted rats showed that immediate treatment with eplerenone, a selective aldosterone antagonist, improved left ventricular function and reduced deleterious effects of cardiac remodeling by modulation of inflammatory response in acute phase of the healing process (36).…”