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Biomedical subjects

K Amann

Publications and source records attributed to K Amann.

At least 55 records · Page 3Linked to original sources
PubMed2000

Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure.

BACKGROUND: An excessive rate of cardiac death is a well-known feature of renal failure. Coronary heart disease is frequent and the possibility has been raised that the natural history of the coronary plaque is different in uraemic patients. We assessed the morphology of coronary arteries in patients with end-stage renal failure and compared them with coronary arteries of matched non-uraemic control patients. METHODS: Fifty-four cases were identified at autopsy who met the inclusion criteria: cases, end-stage renal disease (n=27); controls, non-renal patients with coronary artery disease (n=27). At autopsy all three coronary arteries were prepared at corresponding sites for investigations: (i) qualitative analysis (after Stary), (ii) quantitative measurements of intima and media thickness (by planimetry), (iii) immunohistochemical analysis of the coronary plaques and (iv) X-ray diffraction of selected calcified plaques. RESULTS: Qualitative analysis of the coronary arteries showed significantly more calcified plaques of coronary arteries in patients with end-stage renal failure. Plaques of non-uraemic patients were mostly fibroatheromatous. Media thickness of coronary arteries was significantly higher in uraemic patients (187+/-53 microm vs 135+/-29 microm in controls) and intima thickness tended to be higher (158+/-38 microm vs 142+/-31 microm) but this difference was not statistically significant. Plaque area (4.09+/-1. 50 mm(2) vs 4.39+/-0.88 mm(2)) was comparable in both groups. Lumen area, however, was significantly lower in end-stage renal patients. Immunohistochemical analysis of the cellular infiltrate in coronary arteries showed no major differences in these advanced plaques of uraemic and non-uraemic subjects. CONCLUSION: Coronary plaques in patients with end-stage renal failure are characterized by increased media thickness and marked calcification. In contrast to the previous opinion the most marked difference compared to non-uraemic controls does not concern the size, but the composition of the plaque. Deposition of calcium within the plaques may contribute to the high complication rate in uraemic patients.

Aged↗
PubMed2000

Capillary/myocyte mismatch in the heart in renal failure--a role for erythropoietin?

BACKGROUND: Chronic renal failure is characterized by remodeling of the heart with left ventricular hypertrophy (increasing oxygen demand) and capillary deficit leading to capillary/myocyte mismatch (decreasing oxygen supply). Erythropoietin (Epo) has known angiogenic properties causing endothelial cell activation, migration and sprouting, mediated at least in part via the JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway. In uraemic cardiac hypertrophy the presence of diminished capillary supply implies that capillary growth does not keep pace with development of hypertrophy. To investigate whether this was due to a deficit of the angiogenic hormone Epo we examined whether Epo levels are altered and whether an increase in haematocrit by administration of rhEpo influences capillary supply, i.e. capillary/myocyte mismatch in experimental renal failure. METHOD: Male Spraque-Dawley rats were either subjected to partial renal ablation or sham operation. Only modest amounts of renal tissue were removed so that the rats were not anemic. Subgroups of rats received either human (rh)Epo alone or in combination with unspecific antihypertensive treatment (dihydralazine plus furosemide) in order to control the Epo induced rise in blood pressure. Capillary supply was measured stereologically as capillary length per volume myocardium using the orientator method. RESULTS: Capillary length density was reduced by approximately 25% after partial renal ablation (3237+/-601 vs 4293+/-501 mm/mm(3) in controls). It was not statistically different in animals with partial renal ablation+rhEpo+antihypertensive treatment (3620+/-828 mm/mm(3)) compared to partial ablation alone. CONCLUSION: The study shows that lack of Epo does not cause, or contribute to, the deficit of capillary growth in the hypertrophied left ventricle of rats with renal failure. In addition, a rise in haematocrit is not accompanied by beneficial effects on alterations of cardiovascular structure in experimental renal failure.

Animals↗
PubMed2000

Adult human mesangial cells (HMCs) express endothelin-B-receptors which mediate endothelin-1-induced cell growth.

Endothelin (ET) receptor antagonists are nephroprotective in renal damage models of the rat. It is unknown whether ET receptor antagonists are also beneficial in human renal diseases. Major differences exist between the ET systems in rats and humans, therefore this study was designed to characterize the ET receptors expressed on human adult mesangial cells (HMCs). HMCs cultures are a surrogate model for the development of glomerulosclerosis. Binding experiments with [125I]ET-1 in the presence or the absence of the test compounds [endothelin-1, -3 (ET-1, ET-3), sarafotoxin 6c (S6c), or BQ123] revealed an affinity (IC50 values) of 10.5 nm for ET-1 and 87.6 nm for ET-3. The affinities of the ET(B) agonist S6c and the ET(A) antagonist BQ123 were 85.9 nm and > 10 microm, respectively. Thus, the ET receptor on HMCs shows an ET(B)-like pharmacology, but in contrast to the classical ET(B)-receptor the affinities are low. No affinity for BQ123 up to > 10 microm excludes the presence of ET(A)-receptors. Functional studies using microfluorimetry (fura-2 method) showed comparable biphasic calcium signals induced by 10 nm ET-1, ET-3 and S6c. This effect could not be inhibited by BQ123, but by the ET(B) antagonist BQ788. Reverse transcriptase polymerase chain reaction (RT-PCR) studies under different culture conditions showed that both ET(A)- and ET(B)-receptor mRNAs are expressed in HMCs. The amount of ET(A)-receptor mRNA increased 2.7-fold and that of the ET(B)-receptor mRNA 7.1-fold after stimulation with 10% fetal calf serum (FCS). ET-1, ET-3 and S6c stimulated HMCs growth (ET-1 > S6c > ET-3), but the magnitude of the effect of ET-1 is lower than reported in rat mesangial cells (rat MCs). The effect on HMCs growth could be inhibited by BQ788, but not by BQ123. Our data provide evidence for the expression of ET(B)-receptors on HMCs that are functionally active. This finding differs from the ET receptor expression in rat MCs as reported by others.

Adult↗
PubMed2000

Endothelin-receptor antagonists in uremic cardiomyopathy.

Increased endothelin-1 (ET-1) levels were found in patients with chronic renal failure. These correlate with the severity of renal failure. Patients with elevated ET-1 concentrations show an increased cardiovascular mortality. The prevalence of severe left ventricular hypertrophy (LVH) is a very important factor for survival and morbidity in uremic patients The aim of this study was to assess the protective effect of ET-receptor antagonists in chronic uremia. Sprague Dawley rats were subtotally nephrectomized (SNX) and treated either with the endothelin-A- (ET(A)) receptor antagonist LU302146 or with the unselective ET(A)/ET(B)-receptor antagonist LU302872 (30 mg/kgbw/day both). After subtotal nephrectomy protein excretion SNX (130.0 +/- 22.5 mg/24 h) was increased in comparison to the ET(A)-group (446 +/- 103 mg/24 h) and the ET(AB)-group (23.2 +/- 37 mg/24 h) vs sham: 115 +/- 19 mg/24 h). Heart weight was decreased by the ET(A)/ET(B)-receptor antagonist LU302146. Left ventricular contractility was impaired in SNX by about 40%. Treatment with the ET-receptor antagonists prevented the impairment in left ventricular function. Our study results provide a possible therapeutic approach using ET receptor antagonists to reduce cardiac hypertrophy and renal proteinuria. Further human studies are needed to show whether this protection of the heart and kidney might influence the survival and life-expectancy of patients suffering from chronic renal failure.

Animals↗
PubMed1999

Endothelin receptor antagonists influence cardiovascular morphology in uremic rats.

BACKGROUND: In is generally held that renal failure results in blood pressure (BP)-independent structural changes of the myocardium and the vasculature. The contribution, if any, of endothelin (ET) to these changes has been unknown. METHODS: We morphometrically studied random samples of the left ventricle myocardium and small intramyocardial arteries in subtotally (5/6) nephrectomized (SNx) male Sprague-Dawley rats treated with either the selective ETA receptor antagonist BMS182874 (30 mg/kg/day) or the nonselective ETA/ETB receptor antagonist Ro46-2005 (30 mg/kg/day) in comparison with either sham-operated rats, untreated SNx, or SNx rats treated with the angiotensin-converting enzyme inhibitor trandolapril (0.1 mg/kg/day). RESULTS: Eight weeks later, systolic BP was lower in trandolapril-treated SNx compared with untreated SNx animals. No decrease in BP was seen following either ET receptor antagonist at the dose used. A significantly increased volume density of the myocardial interstitium was found in untreated SNx rats as compared with sham-operated controls. Such interstitial expansion was prevented by trandolapril and either ET receptor antagonist. SNx caused a substantial increase in the wall thickness of small intramyocardial arteries. The increase was prevented by trandolapril or BMS182874 treatment. The arteriolar wall:lumen ratio was significantly lower in all treated groups when compared with untreated SNx. In contrast, only trandolapril, but not the ET receptor antagonists, attenuated thickening of the aortic media in SNx animals. CONCLUSIONS: The ETA-selective and ETA/ETB-nonselective receptor antagonists appear to prevent development of myocardial fibrosis and structural changes of small intramyocardial arteries in experimental chronic renal failure. This effect is independent of systemic BP.

Animals↗
PubMed1999

Protective effects of endothelin antagonists in chronic renal failure.

The present study suggests that ET-1 is involved in the pathogenesis of uraemic cardiac hypertrophy and in the progression of renal failure in rats with subtotal nephrectomy examined after an intermediate period of 12 weeks of renal failure. Furthermore, proteinuria is reduced by the selective ETA receptor antagonist more than by the unselective ETAB receptor antagonist, without reducing the blood pressure. ET receptor blockade might preserve renal function by reduction of protein excretion. In addition, ET receptor antagonists influence the aldosterone system. In our animal studies, the medication was well tolerated. Our study results provide a possible therapeutic approach using ET receptor antagonists for cardiac hypertrophy and renal protein excretion by blockade of endogenous ET-1. Further human studies are needed to show whether this protection of the heart and kidney might influence the survival and life expectancy of patients suffering from chronic renal failure, of patients on dialysis or after kidney transplantation.

Animals↗
PubMed1999

Treatment of cardiovascular changes in renal failure--ACE inhibition, endothelin receptor blockade or a combination of both strategies?

ACE-I and specific ETA receptor blockade comparably prevented the development of structural cardiovascular alterations such as LVH, myocardial interstitial expansion and wall thickening of intramyocardial and extracardiac arteries in experimental renal failure. However, the decrease in myocardial capillary supply and the concomitant increase in intercapillary distance could only be prevented by ETA receptor antagonism. These capillary changes which have been shown to occur in experimental renal failure as well as in uraemic patients play an important role in the pathogenesis of reduced cardiac ischaemia tolerance in renal failure. The data argue for a potential role of the local renin-angiotensin system as well as of the ET system in the pathogenesis of cardiovascular changes in renal failure and for ET receptor blockade as a new therapeutic option in the treatment of these alterations. In particular, myocardial capillary supply, which is particularly important for ischaemia tolerance in renal failure, seems to be modulated and regulated predominantly by ET-1. In contrast to what was found with respect to structural and functional changes of the kidney in various experimental models of renal damage, a combination therapy--at least in the doses used--does not seem to provide additional benefit in the prevention of cardiovascular changes compared with the respective monotherapies.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Hypertrophy of intramyocardial arteriolar smooth muscle cells in experimental renal failure.

Wall thickening of intramyocardial arteries in patients with chronic renal failure may contribute to the increased susceptibility of the uremic heart to ischemic injury. In this context, the following questions arise: (1) Is intramyocardial wall thickening in experimental renal failure due to hypertrophy, hyperplasia or both? (2) Which stimuli trigger wall thickening? Using novel stereologic techniques (Nucleator, Selector), intramyocardial arteries were examined in sham-operated and subtotally nephrectomized (SNX) Sprague Dawley rats with moderate renal failure of 8 wk duration. Systolic BP during the experiment was not significantly different in both groups. Absolute and relative left ventricular weight, wall thickness (5.69 +/- 1.11 microm versus 4.42 +/- 0.99 microm), and wall-to-lumen ratio of intramyocardial arteries (0.117 +/- 0.03 microm/microm versus 0.089 +/- 0.01 microm/microm) were significantly greater in SNX than in sham-operated rats. The mean cell and nuclear volume of intramyocardial arteriolar smooth muscle cells was significantly increased in SNX rats (650 +/- 230 microm3 versus 430 +/- 90 microm3 and 26 +/- 4.5 versus 19.9 +/- 2.2 microm3, respectively). In parallel, the total arteriolar wall volume was significantly greater in the left ventricle of SNX (+58%) compared with sham rats. In contrast, the total length of all left ventricular arteries was comparable in both groups. The increase in mean cell volume without significant change in cell number indicates that arteriolar wall thickening in the heart of SNX rats is explained by hypertrophy rather than hyperplasia of arterial smooth muscle cells. This finding in a nonhypertensive experimental model of chronic renal failure contrasts with findings in spontaneously hypertensive rats. Independent of BP and left ventricular hypertrophy, specific growth signals must act on cardiac arteriolar smooth muscle cells.

Animals↗
PubMed1999

The ET(A) receptor blocker LU 135252 prevents chronic transplant nephropathy in the "Fisher to Lewis" model.

The effect of the orally highly bioavailable and specific endothelin A (ET(A)) receptor antagonist LU 135252 was assessed in a model of chronic renal allograft nephropathy. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Fisher autografts and kidneys after uninephrectomy served as controls. All animals received low-dose cyclosporin A (CsA; 1.5 mg/kg body wt) for 10 d after surgery. Allotransplanted animals were then randomized to receive standard diet or a diet designed to deliver 30 mg of LU 135252/kg body wt per d for 35 wk. BP was monitored telemetrically. Treatment with LU 135252 did not affect systolic or diastolic pressure. Indices of glomerulosclerosis (GSI), and tubulointerstitial and vascular damage were measured. Chronic transplant nephropathy was almost completely prevented by LU 135252 compared with untreated allografts or kidneys of uninephrectomized controls, i.e., GSI 0.7 +/- 0.12 versus 1.6 +/- 0.25 (P < 0.001) versus 0.7 +/- 0.06 (P < 0.001). Allograft weight and serum creatinine were significantly lower in treated versus untreated animals. The results are consistent with the notion that ET(A) receptor-mediated events play a role in the genesis of chronic transplant nephropathy.

Animals↗
PubMed1999

[Clinical study of 8 patients with round atelectasis associated with asbestos exposure].

Matsubase town (where our hospital is located) has a history of environmental exposure to asbestos. We reviewed the clinical and radiological features of 8 patients with round atelectasis associated with asbestos exposure who had been examined at our hospital between 1988 and 1997. The subjects were followed up over a period ranging from 6 months to 10 years (mean: 54 months). Round tumors were detected in 6 of the patients by chest CT scans but not by chest X-ray films. Five of those patients underwent transbronchial lung biopsies, and 1 was examined by bronchography. Two patients had a history of pleural effusion. Seven of the patients exhibited round atelectasis in their lower lung fields. The clinical course of round atelectasis was unchanged in all patients. Although round atelectasis is sometimes suspected of being bronchial carcinoma, it can be diagnosed without thoracotomy, on the basis of the patient's medical history and a careful examination of radiological findings.

Aged↗
PubMed1998

Memory for duration: role of hippocampus and medial prefrontal cortex.

In this task rats had to learn that a three-dimensional object stimulus (a rectangle) that was visible for 2 s would result in a positive (go) reinforcement for one object (a ball) and no reinforcement (no go) for a different object (a bottle). However, if the rectangle stimulus was visible for 8 s then there would be no reinforcement for the ball (no go), but a reinforcement for the bottle (go). After rats learned this conditional discrimination by responding differentially in terms of latency to approach the object, they received large (dorsal and ventral) lesions of the hippocampus, lesions of the medial prefrontal cortex (anterior cingulate and precentral cortex), lesions of the cortex dorsal to the dorsal hippocampus, or served as sham-operated controls. Following recovery from surgery they were retested. The results indicate that there were major impairments following hippocampal lesions, in contrast to cortical control and medial prefrontal cortex lesions, as indicated by smaller latency differences between positive and negative trials on postsurgery tests. In order to ensure that the deficits observed with hippocampal lesions were not due to a discrimination problem, new rats were trained in an object (gray cylinder) duration discrimination task. In this go/no go procedure, the rats were reinforced for a 2-s exposure (duration) of the gray cylinder, but not a 10-s duration, or vice versa. The results indicate that after hippocampal lesions, there was an initial deficit followed by complete recovery. There were no significant changes for the medial prefrontal, cortical control, or sham-operated animals. It appears that the hippocampus, but not the medial prefrontal cortex, is actively involved in representing in short-term memory temporal attribute information based on the use of markers for the beginning and end of the presence (duration) of a stimulus (object).

Animals↗
PubMed1998

Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats.

In the past, there has been considerable concern that treatment with active vitamin D might accelerate progression independent of hypercalcemia and hypercalcuria. Nevertheless, 1,25(OH)2D3 has known antiproliferative properties and has also been shown to inhibit renal growth. Since glomerular growth is a permissive factor for the development of glomerulosclerosis, we reasoned that 1,25(OH)2D3 might even attenuate progression. To test this working hypothesis we performed two experiments of 8 and 16 weeks duration, respectively, to compare subtotally nephrectomized (SNX) rats treated with ethanol and SNX treated with 1,25(OH)2D3. Control animals were sham operated and pair-fed with SNX animals. 1,25(OH)2D3 (3 ng/100 g body wt/day) was administered by osmotic minipump. 1,25(OH)2D3 had no significant effect on systolic blood pressure and only a transient effect on weight gain. SNX reduced the number of glomeruli (left kidney) from an average of 3.3 x 10(4) to 1.2 x 10(4) per kidney. Mean glomerular volume was 3.87 +/- 0.71 x 10(6) microns 3 in sham operated animals and significantly (P < 0.05) higher (10.1 +/- 1.75 x 10(6) microns 3) in untreated animals 16 weeks after SNX. Glomerular volume was significantly (P < 0.05) less in 1,25(OH)2D3 treated SNX [10.1 +/- 1.75 in ethanol vs. 7.04 +/- 1.78 in 1,25(OH)2D3 treated SNX]. In parallel, there was significantly (P < 0.01) less glomerulosclerosis [glomerulosclerosis index 1.16 +/- 0.14 in the ethanol treated SNX vs. 0.80 +/- 0.16 in SNX treated with 1,25(OH)2D3] in the eight week experiment. Albuminuria was significantly (P < 0.01) lower in 1,25(OH)2D3 treated than in ethanol treated SNX (mean 0.785 mg/24 hr, range 0.43 to 1.80, vs. 3.75 mg/24 hr, 1.29 to 14.2). The morphological data were directionally analogous in a second 16 week experiment. Only slight changes of the vascular sclerosis index and tubulointerstitial index were seen in SNX and were not affected by 1,25(OH)2D3 further. To prove that the effect of 1,25(OH)2D3 was independent of PTH, parathyreoidectomized SNX rats without or with 1,25(OH)2D3 treatment were examined seven days post-SNX. PCNA staining showed suppression of cell proliferation. Furthermore, in situ hybridization for transforming growth factor-B (TGF-beta) showed less vascular and tubular expression in 1,25(OH)2D3 treated rats. We conclude that 1,25(OH)2D3 has antiproliferative actions during the compensatory growth of nephrons in response to subtotal nephrectomy. These effects are independent of PTH. The data document that 1,25(OH)2D3 reduces renal cell proliferation and glomerular growth as well as glomerulosclerosis and albuminuria as indicators of progressive glomerular damage.

Animals↗
PubMed1998

Left ventricular hypertrophy in renal failure.

In patients with terminal renal failure, left ventricular hypertrophy (LVH) is extremely common. It is found in approximately 60 to 80% of patients starting renal replacement therapy. The main causes of LVH are increased preload from hypervolemia and increased afterload from increased peripheral resistance, giving rise to a mixture of eccentric and concentric hypertrophy, but other factors (high cardiac output from anemia and arteriovenous (A-V) fistula, altered compliance of central arteries, and activation of local systems such as renin and endothelin) also play a role. The clinical importance of LVH derives from the fact that LVH is a predictor of cardiac death in dialyzed patients independent of blood pressure. LVH is accompanied by microvascular disease and by marked interstitial fibrosis (more than seen in non-renal patients with similar degrees of hypertension). Recent findings suggest that LV remodeling starts early and is seen even in normotensive patients with glomerulonephritis when GFR is still normal. The strategies to reduce LVH include reduction of hypervolemia, (near) normalization of hemoglobin and lowering of blood pressure, particularly by administration of angiotensin converting enzyme inhibitors.

Humans↗
PubMed1998

The sympathetic nervous system and the kidney: its importance in renal diseases.

There is a two-way relation between the sympathetic nerve system and the kidney. On the one hand the sympathetic nerve system affects renal function, i.e. renal hemodynamics, renin secretion and tubular sodium transport. On the other hand the kidney is the source of activating afferent signals, presumably via stimulation of chemoreceptors and baroreceptors. This concept is supported by clinical observations in endstage and pre-endstage renal disease, where sympathetic overactivity is present. It has been shown to depend on the presence of the diseased kidney and is abolished by bilateral nephrectomy. Experimentally, interruption of afferent nerve traffic by dorsal rhizotomy partially prevents hypertension in renal damage models. Imidazoline-preferring binding sites are found in the kidney. In the rat, natriuresis is elicited by injection of moxonidine into the renal artery. In humans, there is no definite evidence for a natriuretic effect, but some observations point in this direction. In renal disease, the issue arises whether sympathetic overactivity contributes to progression of renal failure. Indirect evidence in this direction could be the marked acceleration of progression by smoking, a state of known sympathetic overactivity. In experimental models of renal damage, treatment with moxonidine in antihypertensive doses markedly attenuated development of glomerulosclerosis. Preliminary observations show that even non-antihypertensive doses of moxonidine interfere with the development of glomerulosclerosis. Sympathicolytic agents are obviously rational in the antihypertensive therapy of the renal patient, because uraemia is a state of sympathetic overactivity and because blood pressure-independent effects of sympathetic activation on progression are likely.

Animals↗