High-Dose Enalapril Treatment Reverses Myocardial Fibrosis in Experimental Uremic Cardiomyopathy

Abstract

Aims: Patients with renal failure develop cardiovascular alterations which contribute to the higher rate of cardiac death. Blockade of the renin angiotensin system ameliorates the development of such changes. It is unclear, however, to what extent ACE-inhibitors can also reverse existing cardiovascular alterations. Therefore, we investigated the effect of high dose enalapril treatment on these alterations.Methods: Male Sprague Dawley rats underwent subtotal nephrectomy (SNX, n = 34) or sham operation (sham, n = 39). Eight weeks after surgery, rats were sacrificed or allocated to treatment with either high-dose enalapril, combination of furosemide/dihydralazine or solvent for 4 weeks. Heart and aorta were evaluated using morphometry, stereological techniques and TaqMan PCR.Results: After 8 and 12 weeks systolic blood pressure, albumin excretion, and left ventricular weight were significantly higher in untreated SNX compared to sham. Twelve weeks after SNX a significantly higher volume density of cardiac interstitial tissue (2.5760.43% in SNX vs 1.5060.43% in sham, p,0.05) and a significantly lower capillary length density (45326355 mm/mm 3 in SNX vs 50236624 mm/mm 3 in sham, p,0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.6360.25%, p,0.05), but not capillary reduction (39086486 mm/ mm 3 ) or increased intercapillary distance. In contrast, alternative antihypertensive treatment showed no such effect. Significantly increased media thickness together with decreased vascular smooth muscles cell number and a disarray of elastic fibres were found in the aorta of SNX animals compared to sham. Both antihypertensive treatments failed to cause complete regression of these alterations. Conclusions:The study indicates that high dose ACE-I treatment causes partial, but not complete, reversal of cardiovascular changes in SNX.

Speckle Tracking Echocardiography Detects Uremic Cardiomyopathy Early and Predicts Cardiovascular Mortality in ESRD

“…[26][27][28][29][30][31] Activation of the renin-angiotensin system is thought to be an important contributor to myocardial remodeling because in patients with ESRD, the severity of left ventricular hypertrophy correlates with plasma aldosterone concentration and administration of angiotensin-converting enzyme inhibitors improved structural changes as interstitial fibrosis in experimental and clinical studies. [32][33][34] Anemia, increased afterload due to aortic stiffness and hypertension, increased oxidative stress, and insulin resistance are other important contributors to the development of UC. 25,35,36 Another factor is hyperphosphatemia; in rats with subtotal nephrectomy, a high-phosphorus diet increased the severity of interstitial fibrosis and microvascular disease.…”

Long-term effects of ACE inhibitor on vascular remodelling

“…However, the application of ACE inhibitor in hypertensive rats may be not as benefi cial in prevention of neointimal thickening as in normotensive ones [13]. Further, the effi cacy of such therapy may depend on age [14], way of application [15] and degree of atherosclerosis [16]. Unfortunately, some studies of primate or human tissues did not confi rm the benefi cial effects of this medication on the long-term changes of the vascular architecture [7,17].…”

Cardioprotective Effect of Quercetin in 5/6-Nephrectomized Rats: Focus on Myocardial fibrosis and Oxidative Stress

“…The pathophysiological characteristics produced by this method are similar to CKD in human such as glomerular hypertrophy, proteinuria, and glomerular injury (Chaykovska et al 2011; Griffin et al 1994). Stabile and moderate renal failure were achieved through hemodynamic changes and disturbances in renal autoregulation (Griffin et al 1994;Tyralla et al 2011).Numerous changes were observed in cardiac tissue in CKD. These includes decrease myocardial capillary density, decrease aortic lumen diameter, increase aortic media thickness, and upregulation of myocardial angiotensin II type I receptor, renin, profibrotic cytokines, and brain natriuretic peptide (BNP) (Chaykovska et al 2011;Tyralla et al 2011;Kennedy et al 2008).…”

“…Stabile and moderate renal failure were achieved through hemodynamic changes and disturbances in renal autoregulation (Griffin et al 1994;Tyralla et al 2011).…”

“…However, captopril significantly reduced proteinuria (p<0.05) but not quercetin (p>0.05). Meanwhile, there was no significant difference among all of the groups in average body weight, heart weight, and heart-to-body weight ratio (data not shown).Captopril was used as a standard therapy because of its ability to reduce proteinuria in CKD patients (Tyralla et al 2011;Viberti et al 1994). Captopril with dose of 10 mg was chosen because it reduces creatinine, blood pressure, and myocardial hypertrophy in animal model of hypertension (Khattab et al 2005).…”