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1.
PLoS One ; 6(1): e15287, 2011 Jan 27.
Article in English | MEDLINE | ID: mdl-21298056

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 (2.57±0.43% in SNX vs 1.50±0.43% in sham, p<0.05) and a significantly lower capillary length density (4532±355 mm/mm(3) in SNX vs 5023±624 mm/mm(3) in sham, p<0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.63±0.25%, p<0.05), but not capillary reduction (3908±486 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.


Subject(s)
Cardiomyopathies/drug therapy , Enalapril/administration & dosage , Endomyocardial Fibrosis/drug therapy , Uremia/complications , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Cardiomyopathies/etiology , Cardiomyopathies/pathology , Endomyocardial Fibrosis/pathology , Male , Nephrectomy , Rats , Rats, Sprague-Dawley , Treatment Outcome
2.
J Am Soc Nephrol ; 14(11): 2833-42, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14569093

ABSTRACT

Interventions to block the renin-angiotensin system (RAS) halt the progression of renal lesions in renal damage models. It has recently also been reported that established glomerulosclerosis can be reversed by pharmacologic blockade of the RAS. It was the aim of this study to confirm that high doses of angiotensin-converting enzyme (ACE) inhibitors reverse established glomerulosclerosis and to extend the findings by providing quantitative information on glomerular geometry, podocytes and other glomerular cells, renal vessels and tubulointerstitial tissue. Male Sprague Dawley rats were subjected to subtotal surgical renal ablation (SNX) (n = 27) or sham operation (n = 31) and fed using a pair-feeding protocol. Eight weeks after surgery, rats were either sacrificed or allocated to two arms: enalapril treatment (48 mg/kg body wt per day administered in the drinking fluid for 4 wk) or no treatment. Renal morphology was evaluated after 8 or 12 wk, respectively, by stereology in tissue fixed by pressure-controlled perfusion. Both systolic BP and albumin excretion rate were significantly higher in SNX compared with sham-operated controls. They were significantly reduced in SNX after delayed enalapril treatment. The glomerulosclerosis (GSI), tubulointerstitial (TII), and vascular (VI) damage indices were significantly higher in all SNX groups than in sham-operated controls. At the end of the experiment (12 wk after SNX) GSI, TII, and VI were significantly lower in SNX with delayed enalapril treatment (0.77 +/- 0.18, 0.63 +/- 0.19 and 0.43 +/- 0.16, respectively) compared with untreated SNX (1.64 +/- 0.14, 1.16 +/- 0.34 and 0.67 +/- 0.29, respectively). GSI, TII, and VI were also significantly lower in SNX with delayed enalapril treatment compared with SNX sacrificed without treatment 8 wk after SNX. The same was true for glomerular volume. The number of podocytes was not affected by SNX, but podocyte volume was increased. Both indices remained unaffected by treatment. The numbers of cells within the mesangium and endothelial cells per glomerulus were significantly lower in SNX after delayed enalapril treatment compared with untreated SNX. These results strongly suggest regression of preexisting lesions, i.e., glomerular, tubular, and vascular remodeling as well as reversal of glomerular hypertrophy by ACE inhibitor treatment. The study confirms that high-dose ACE inhibitor treatment causes partial reversal of glomerular as well as interstitial lesions in subtotally nephrectomized rats.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Enalapril/administration & dosage , Glomerulosclerosis, Focal Segmental/drug therapy , Glomerulosclerosis, Focal Segmental/etiology , Kidney Glomerulus/drug effects , Animals , Dose-Response Relationship, Drug , Drug Administration Schedule , Glomerulosclerosis, Focal Segmental/pathology , Kidney Glomerulus/pathology , Male , Nephrectomy , Rats , Rats, Sprague-Dawley , Remission Induction , Time Factors
3.
Kidney Int Suppl ; (84): S80-3, 2003 May.
Article in English | MEDLINE | ID: mdl-12694316

ABSTRACT

In patients with renal failure, cardiovascular complications are a major clinical problem; cardiac death is the main cause of death in these patients. Cardiac risk is increased by a factor of 20 in uremic patients, compared with matched segments of the general population. It has been known for a long time that atherosclerosis, particularly plaque in the epicardiac coronary conduit arteries, are more frequent in patients with chronic renal failure. Recently, however, clinical studies showed that myocardial infarction is responsible for only 30% to 50% of all cardiac deaths. In contrast, 30% to 40% of patients with renal failure and ischemic heart disease show patent coronary arteries on coronary angiogram. Thus, it is very likely that in uremic patients myocardial ischemia tolerance is markedly reduced even in the absence of classical atherosclerosis (i.e., relevant stenosis of coronary arteries). This finding in uremic patients can be at least partially explained by structural and metabolic abnormalities of the myocardium, and in part by alterations of the extracardiac vasculature. The present paper focuses on structural changes of the heart and the vasculature, in particular on atherosclerosis of cardiac and extracardiac arteries, and its potential repercussions for cardiovascular function. In 1827 Richard Bright already pointed to the common presence of left ventricular hypertrophy (LVH) and thickening of the aorta in patients with end-stage renal failure (ESRF). At present, cardiovascular complications account for 45% of all deaths in uremic patients [1]. The recent report of Herzog, Ma, and Colins [2] documented a 59.3% 1-year mortality rate in dialyzed patients who survived myocardial infarction (i.e., mortality was significantly higher than in the general population). It is widely acknowledged that several specific structural and nonstructural alterations of the heart and the extracardiac vasculature are present in patients with renal failure, which presumably contribute to the markedly increased cardiovascular risk in these patients [3].


Subject(s)
Arteries/pathology , Arteriosclerosis/mortality , Kidney Failure, Chronic/mortality , Myocardial Infarction/mortality , Myocardium/pathology , Arteriosclerosis/pathology , Humans , Myocardial Infarction/pathology , Risk Factors , Uremia/mortality
4.
Kidney Int ; 63(5): 1708-13, 2003 May.
Article in English | MEDLINE | ID: mdl-12675846

ABSTRACT

BACKGROUND: The development of left ventricular hypertrophy (LVH) and of structural abnormalities of the heart is a key abnormality in renal failure that potentially contributes to the high rate of cardiac death. In renal failure, the behavior of cardiomyocyte volume and number in the development of LVH has so far not been investigated. A potential role of the (local) renin-angiotensin system (RAS) in the genesis of LVH has been suspected. It was the aim of the present study in short-term experimental renal failure (1) to characterize cardiomyocyte volume and number and (2) to study whether they are affected by the angiotensin-converting enzyme (ACE) inhibitor ramipril. METHODS: Sprague-Dawley rats (N = 8 to 10 per group) had a subtotal nephrectomy (SNX) or sham operation and followed for 8 weeks. One SNX group received the ACE inhibitor ramipril (0.5 mg/kg body weight) in the drinking fluid. After perfusion fixation, the morphology of the heart was investigated using stereologic techniques. RESULTS: Systolic blood pressure was slightly, but not significantly, higher in untreated SNX, but the left ventricular (LV) weight and LV weight/body weight ratio (2.32 +/- 0.20 mg/g) were significantly higher in SNX than in sham-operated animals (1.90 +/- 0.16 mg/g). Sarcomeric length was not significantly different between SNX and sham-operated animals. There was an increase in the number of terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL)-positive myocytes in SNX compared to sham-operated animals and a significant increase in cardiomyocyte volume (15,713 +/- 4557 microm3 vs. 10,067 +/- 2242 microm3, P < 0.01) as well as a decrease of cardiomyocyte numbers per unit myocardial volume (61.2 +/- 16.2 vs. 92.2 +/- 20.9 x 103/mm3) and per left ventricle (70.9 +/- 16.5 x 106 vs. 94.8 +/- 18.1 x 106, P < 0.05). Both abnormalities were abrogated by treatment with ramipril (6347 +/- 972.4 microm3 and 106 +/- 18.9 103/mm3 or 118 +/- 39.5 x 106, respectively), which also completely prevented the increase in LV weight/body weight ratio (1.83 +/- 0.14 mg/g). CONCLUSION: LVH in renal failure is characterized by cardiomyocyte hypertrophy, but also cardiomyocyte drop out. A role of the RAS is suggested by the beneficial effect of ramipril treatment that is not accounted for by differences in blood pressure.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/prevention & control , Ramipril/pharmacology , Renal Insufficiency/complications , Animals , Disease Models, Animal , Hypertrophy, Left Ventricular/etiology , Immunohistochemistry , In Situ Nick-End Labeling , Male , Myocytes, Cardiac/pathology , Rats , Rats, Sprague-Dawley , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Sarcomeres/pathology
5.
Kidney Int ; 63(4): 1296-301, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12631346

ABSTRACT

BACKGROUND: Hyperphosphatemia is a known predictor of cardiovascular death and specifically of cardiac death in hemodialysis patients. The pathomechanisms involved have not been completely clarified. While a number of observations suggest an important role of hyperphosphatemia and positive calcium balance on atherosclerosis and calcification of the coronary conduit arteries, independent effects on postcoronary microvessels and on cardiac fibrosis have not been excluded. METHODS: Male Sprague-Dawley rats were sham operated (N = 14) or subtotally nephrectomized (SNX, N = 17) and subsequently placed on low phosphorus (0.08% w/w) and high phosphorus (1.2% w/w) diet under pair-feeding conditions. After 8 weeks, serum chemistry and inhibitory parathyroid hormone (iPTH) were measured, and the hearts were harvested using perfusion fixation. Arteriolar thickness and volume density of the interstitium (excluding vessels) were quantitated using stereologic techniques. RESULTS: In SNX animals with moderate renal failure serum phosphorus concentrations were higher than in sham-operated controls on low phosphorus diet (1.7 +/- 0.37 mmol/L) and were significantly higher in SNX + high phosphorus diet (2.33 +/- 0.23 mmol/L) compared to SNX + low phosphorus diet (1.95 +/- 0.32 mmol/L; P < 0.05). In sham-operated controls, dietary phosphorus content had no effect on cardiac morphologic indices. In contrast, in SNX + high phosphorus diet the index of interstitial cardiac fibrosis was significantly higher (3.22 +/- 0.44%) than in SNX + low phosphorus (2.75 +/- 0.46%) or in sham-operated controls (2.5 +/- 0.05% on high phosphorus and 2.4 +/- 0.89 on low phosphorus, respectively). In SNX + high phosphorus (14.0 +/- 9.0 microm), but not in SNX + low phosphorus (9.2 +/- 4.5 microm), arterial wall thickness was significantly higher compared to sham-operated controls (10.2 +/- 5.1 on high phosphorus and 9.8 +/- 5.0 micro;m on low phosphorus, respectively). The data were confirmed in an independent repeat experiment. CONCLUSION: High dietary phosphorus and hyperphosphatemia have significant effects on cardiac fibrosis and arterial wall thickening. Such abnormalities of cardiac architecture may be relevant for the increased cardiac risk in hyperphosphatemic uremic patients.


Subject(s)
Cardiomyopathies/physiopathology , Phosphorus Metabolism Disorders/physiopathology , Uremia/physiopathology , Animals , Cardiomyopathies/complications , Cardiomyopathies/pathology , Coronary Vessels/pathology , Fibrosis , Male , Microcirculation , Nephrectomy , Phosphorus Metabolism Disorders/complications , Phosphorus Metabolism Disorders/pathology , Phosphorus, Dietary/pharmacology , Rats , Rats, Sprague-Dawley , Renal Insufficiency/complications , Renal Insufficiency/physiopathology , Uremia/complications
6.
Blood Purif ; 20(5): 462-5, 2002.
Article in English | MEDLINE | ID: mdl-12207093

ABSTRACT

In patients with renal failure cardiovascular complications are an important clinical problem and cardiac death is the main cause of death in these patients. It is well documented that cardiac risk is increased by a factor of 20 in uremic patients compared with age- and sex-matched segments of the general population. This finding in patients with renal failure can be at least partially explained by the well-described structural and metabolic abnormalities of the myocardium. The present article focuses on the structural changes in the heart and the vasculature and their potential repercussions for cardiovascular function, in particular their contribution to the high cardiovascular morbidity and mortality in patients with renal failure.


Subject(s)
Cardiovascular Diseases/pathology , Renal Insufficiency/complications , Cardiovascular Diseases/etiology , Coronary Circulation , Endomyocardial Fibrosis/etiology , Endomyocardial Fibrosis/pathology , Humans , Hypertrophy, Left Ventricular/etiology , Hypertrophy, Left Ventricular/pathology , Microcirculation/pathology
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