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Biomedical subjects

A Heidland

Publications and source records attributed to A Heidland.

At least 91 records · Page 5Linked to original sources
PubMed1995

Low-dose calcitriol prevents the rise in 1,84-iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial).

BACKGROUND: Higher doses of calcitriol are effective in lowering markedly elevated 1,84 PTH levels of patients with renal secondary hyperparathyroidism. It has not been established, however, whether prophylactic administration of low doses of calcitriol prevents an increase of 1,84 PTH without causing side-effects, i.e. hypercalcaemia, hypercalciuria, or hyperphosphataemia. STUDY DESIGN: We carried out a placebo-controlled, double-blind prospective multicentre trial over 12 months in 45 patients with mild to moderate renal failure. Criteria for inclusion were S-creatinine 1.4 mg/dl and 1,84 PTH > 6 pmol/l (normal 6). Calcitriol 0.125 microgram/day per os was compared with placebo. The patients received calcium carbonate per os if serum P exceeded 1.7 mmol/l. RESULTS: Baseline 1,84 iPTH concentrations were not significantly different, i.e. 14.0 pmol/l (6.7-63.3) on placebo vs 16.2 (6.85-82.0) on calcitriol. Intention to treat analysis revealed a significant difference of final 1,84 iPTH, i.e. 27.8 (4.2-68.5) on placebo vs 18.2 (4.45-75.5) on calcitriol. On post-hoc analysis the difference was even more pronounced at S-creatinine concentrations above 3 mg/dl. S-calcium, S-phosphate, and urinary excretion of calcium did not change significantly on either placebo or on calcitriol. There were no episodes of hypercalcaemia or hyperphosphataemia. There was no significant difference of final S-creatinine or change in S-creatinine between placebo and calcitriol. One patient on calcitriol and two on placebo progressed to terminal renal failure. Bone alkaline phosphatase as a non-invasive index of bone metabolism was not decreased to subnormal levels. CONCLUSION: The results document that a therapeutic window exists in patients with moderate renal failure and elevated of 1,84 iPTH, where low-dose calcitriol (0.125 microgram/day) prevents the increase in 1,84 iPTH without causing side-effects. This observation suggests that the parathyroid is more sensitive to calcitriol than intestine and bone.

Adult↗
PubMed1995

Function of endocrine organs in hemodialyzed patients of long-term erythropoietin therapy.

Endocrine abnormalities in patients with chronic renal failure are well documented. The present study aimed to assess the influence of long-term erythropoietin (EPO) therapy on endocrine abnormalities in hemodialyzed patients. Two groups of hemodialyzed patients, each of which comprised 17 subjects, were examined. The first group was treated by EPO (EPO group) while the second one did not receive this hormone (No-EPO group). A complete biochemical and hormonal check-up was performed before and at the 3, 6, 9, and 12 month points of the study period. Normal values for the estimated parameters were obtained in appropriately selected sex- and age-matched healthy subjects. After EPO therapy, an increase of the hematocrit value from 21.8 +/- 0.9 to 32.6 +/- 0.9% was observed, which was accompanied by a significant decline of plasma ferritin and saturation of transferrin. In patients of the No-EPO group, a significant although less marked rise of the hematocrit value (21.4 +/- 0.4 to 24.2 +/- 0.6%) was also noticed. EPO therapy did not change plasma levels of electrolytes (Na, K, Ca, inorganic phosphate), osteocalcin, creatinine, glucose, and alkaline phosphatase as well as plasma concentrations of calcium-related hormones (PTH, calcitonin, 1,25[OH]2D3), vasopressin, and triiodothyronine. EPO treatment induced a significant decrease in somatotropin, prolactin, follitropin, lutropin, ACTH, cortisol, plasma renin activity, aldosterone, noradrenaline, adrenaline, dopamine, glucagon, pancreatic polypeptide, and gastrin plasma levels and an increase in plasma insulin, estradiol, testosterone, atrial natriuretic peptide, thyrotropin, and thyroxine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Suppressing role of transforming growth factor-beta 1 on cathepsin activity in cultured kidney tubule cells.

Elevated expression and activity of transforming growth factor-beta 1 (TGF-beta 1) have been indicated in various renal diseases, implicating the potential involvement of this growth factor in the accumulation of extracellular matrix. To assess its potential role on protein turnover in tubule cells, we investigated in LLC-PK1 cells the effects of TGF-beta 1 on the activities of lysosomal cysteine proteinases cathepsins B, H, and L + B, which play a major role in the degradation of both cellular protein and extracellular matrix. The results show that 1-10 ng/ml TGF-beta 1 exerted inhibitory effects on cathepsin B and L + B activities, when applied to either the basolateral or apical membrane of these cells (basolateral side: B -23.2%, L + B -19.9%; apical side: B -28.2%, L + B -22.6%). Application of TGF-beta 1 to both sides enhanced suppression of the enzyme activities (B -37.8%, L + B -37.4%). This suppression of cathepsin activities was accompanied by a reduction of cellular protein degradation rate by 20.0% after 24 h and 51.7% after 48 h. Furthermore, TGF-beta 1 stimulated cellular protein synthesis by 50.0% after 48 h. The combined effects on protein turnover resulted in cellular hypertrophy: increases of both protein content and cell size after 48 h. Concerning the underlying mechanism, TGF-beta 1 did not induce a rise in intracellular Ca2+ concentration nor did Ca2+ channel blocker verapamil (10(-6) M) ameliorate the TGF-beta 1-induced inhibition of cathepsin activities. However, TGF-beta 1 raised the pH in lysosomes, which obviously impaired the acidic cysteine proteinases. In conclusion, the TGF-beta 1-induced cellular hypertrophy is caused by both enhanced protein synthesis and reduced protein breakdown. Suppression of cathepsin B and L + B activities mediated probably by an alkalinization in lysosomes is involved in the decreased protein degradation.

Animals↗
PubMed1995

Prevention of cardiac hypertrophy in experimental chronic renal failure by long-term ACE inhibitor administration: potential role of lysosomal proteinases.

The pathogenesis of cardiac hypertrophy in chronic uremia is poorly understood. In the present study, the long-term effects of chronic uremia on cardiac morphology and various cysteine proteinases of the heart were investigated in rats with and without antihypertensive therapy by the angiotensin converting enzyme inhibitor enalapril or by the calcium channel blocker verapamil. 16 weeks after subtotal nephrectomy considerable uremia had developed associated with arterial hypertension, rise in heart weight and heart weight/body weight ratio. Morphologically myocardial cells developed marked hypertrophy. Determination of various cysteine proteinases by fluorometry revealed a significant decline of cathepsin B activity while the activities of cathepsin H and L were unchanged. Antihypertensive treatment with enalapril and verapamil normalized the blood pressure and improved renal function significantly. Myocardial cell hypertrophy and the enhanced heart weight/body weight ratio were normalized under treatment with enalapril but not with verapamil. Simultaneously, the impaired cathepsin B activity returned to the normal range after enalapril treatment. It is concluded that the cardiac hypertrophy in uremia is at least partly caused by an activation of the circulating and/or cardiac renin-angiotensin system. Impaired proteinase activity in the uremic state may be involved in the development of cardiac hypertrophy.

Animals↗
PubMed1995

Effects of urodilatin and diltiazem on renal function in ischemic acute renal failure in the rat.

In humans as well as in experimental models the hallmark of ischemic acute renal failure (ARF) is a profound diminution in glomerular filtration rate (GFR) and renal blood flow. Both calcium antagonists and a-ANP have been reported to exert beneficial effects in ischemic ARF. No data, however, exist about combined administration of the natriuretic peptide urodilatin and calcium channel blockers. We therefore investigated the effects of urodilatin (URO, 40 micrograms/kg/h, i.v.) and diltiazem (DIL, 300 micrograms/kg/h, i.v.) in the rat given immediately after clamping of both renal arteries for 40 min. Compared to controls (0.07 +/- 0.01) depressed GFR (ml/min/100 g) was clearly elevated with URO (0.16 +/- 0.03), DIL (0.13 +/- 0.03) and URO + DIL (0.14 +/- 0.02) after the ischemic lesion. After cessation of drug delivery the beneficial effects were blunted in the URO group, in contrast to the DIL and URO + DIL group, where GFR was significantly elevated compared to controls even 3 h after starting reperfusion. Besides that also urine flow, sodium excretion and blood pressure were examined. In conclusion both URO and DIL exert beneficial effects in ischemic ARF in the rat while infused. In contrast to URO DIL showed prolonged beneficial effects even after cessation of drug delivery. An additional effect of both drugs could not be observed.

Acute Kidney Injury↗
PubMed1995

Insulin-like growth factor I induced reduction in cysteine proteinase activity in freshly isolated proximal tubule cells of the rat.

The potential effects of insulin-like growth factor I (IGF-I) on lysosomal cysteine proteinases (cathepsin B, H and L+B activities) were investigated in the freshly isolated proximal tubule cells of rats. IGF-I significantly inhibited these enzyme activities after an incubation time of 80 min. This effect was associated with a dose-dependent increase in cellular protein content. The study suggests that, besides the established enhanced protein synthesis, IGF-I-induced cellular hypertrophy is mediated by a suppression of the proteolytic enzyme activity in proximal tubular cells.

Animals↗
PubMed1995

Angiotensin II-induced hypertension: effects on central and peripheral atrial natriuretic peptide.

Angiotensin (Ang) II and atrial natriuretic peptide (ANP) have opposing effects on blood pressure, sympathetic activity, vasopressin and ACTH secretion, salt appetite, and drinking. We observed their interaction by infusing Ang II (7.2 nmol/h) into the peritoneum (i.p.) or into the lateral ventricle (i.c.v.) of rats with osmotic minipumps for seven days. At sacrifice, rats receiving Ang II-i.c.v. had a systolic blood pressure of 184 +/- 3 (SEM) mmHg, those receiving Ang II-i.p. had 159 +/- 5 mmHg (p < 0.05), while controls had 109 +/- 2 and 110 +/- 2 mmHg, respectively (p < 0.05). Drinking and urine volume increased similarly in rats receiving Ang II by either route, while Uosm decreased. Renin (PRA) values were lower (p < 0.05) in rats receiving Ang II-i.c.v. (0.7 +/- 0.2 ng Ang l/ml/h) or Ang II-i.p. (0.9 +/- 0.2) than in the respective controls (2.3 +/- 0.7 and 2.0 +/- 0.3). Plasma ANP values with Ang II-i.c.v. (18 +/- 1.6 pg/ml) or with Ang II-i.p. (49 +/- 6) were also lower (p < 0.05) than respective controls (89 +/- 12, 76 +/- 4). Vasopressin (AVP) concentrations in the plasma were not influenced by the regimens. In the brain, the ANP contents in areas of the so-called AV3V-region (organum vasculosum laminae terminalis, preoptic periventricular nucleus, medial preoptic nucleus) were similarly and significantly reduced by both Ang II-i.c.v. and Ang II-i.p.. ANP values were also reduced in the median eminence by both types of Ang II-treatment, while ANP concentrations in the supraoptic nucleus were increased. The data show that Ang II infusions producing a chronic rise in blood pressure exert similar effects on drinking behavior, PRA, and ANP concentrations in blood and brain. The AV3V area may be pivotal to both models.

Angiotensin II↗
PubMed1995

Role of proteinases in renal hypertrophy and matrix accumulation.

Graded compensatory renal growth was induced either by unilateral (UNX) or 5/6 nephrectomy (5/6-NX). Over the experimental period of 16 weeks, kidney weight increased by 59% in SHAM animals, while the remaining kidney in UNX rats more than doubled its initial weight. The hypertrophic response was most pronounced in the remnant kidney after 5/6-NX with a four fold increment in kidney weight. Morphologically glomerular volume increased moderately after UNX (+27%), while 5/6-NX was associated with marked glomerular hypertrophy (+87%). Significant focal sclerosis was found in 11% of glomeruli in the remaining kidney after UNX. By contrast 83% of glomeruli wre sclerosed in the remnant kidney after 5/6-NX. In parallel, there was a significant increase in the glomerular protein/DNA ratio (+23%) in 5/6-NX but not in UNX animals. These glomerular alterations were associated with lower glomerular cysteine and metalloproteinase activities (collagenase, -57%; gelatinase, -49%) in 5/6-NX rats, while UNX rats had normal glomerular proteinase activities. In terms of tubular proteinases, cathepsin activities were significantly lower in UNX rats (cath. L+B, -38%; cath. B, -37%; cath. H, -27%) and more so after 5/6-nephrectomy (cath. L+B, -72%; cath. B, -73%; cath. H, -73%), while metalloproteinase activities were only reduced in 5/6-NX rats (collagenase, -35%; gelatinase, -58%). These findings demonstrate that kidney hypertrophy is associated with reduction in renal proteinase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed1995

Antihypertensive treatment with a vasodilating beta-blocker, carvedilol, in chronic hemodialysis patients.

Carvedilol is an antihypertensive agent which displays unselective beta-blocking, alpha 1-blocking and antioxidant properties. It is primarily metabolized by the liver and excreted via the biliary system. The compound is highly lipophilic and strongly bound to plasma proteins. Consequently, there is no elimination during hemodialysis. The efficacy, safety, and pharmacokinetic profile of carvedilol titrated to effect were investigated in an open clinical trial in 15 long-term hemodialysis patients with arterial hypertension over a period of 12 weeks. The drug was administered only on days without dialysis. After a wash-out phase of one week, carvedilol was started in a dose of 12.5 mg per day. All 15 patients were titrated according to the antihypertensive effect to a daily dose of 25 mg of carvedilol. Carvedilol was effective in lowering blood pressure in hemodialysis patients (RR systolic: 170 +/- 11 vs. 144 +/- 9 mmHg; RR diastolic: 98 +/- 10 vs. 85 +/- 10 mmHg). The pharmacokinetic parameters of carvedilol and its active metabolite M2, assessed in 12 of the 15 patients, were not influenced by the lack of renal function or intermittend haemodialysis. In particular, there was no accumulation of carvedilol or its metabolite M2. In terms of side effects, three patients had to be withdrawn from the trial, because of hypoglycemia (n = 1), insufficient blood pressure control (n = 1) and prolonged hypotension (n = 1). Taken together, these results indicate that carvedilol is a safe and efficacious antihypertensive agent which can be used in patients maintained by maintenance dialysis treatment.

Adrenergic beta-Antagonists↗
PubMed1995

Angiotensin-II-induced cell hypertrophy: potential role of impaired proteolytic activity in cultured LLC-PK1 cells.

BACKGROUND: Angiotensin II-induced hypertrophy of both mesangial and tubular cells has been shown to be caused by enhanced protein synthesis. There are no data about its role on protein breakdown. Therefore, protein turnover and proteolytic activities were investigated in LLC-PK1 cells. METHODS: Protein turnover was measured by determining the incorporation and release of [14C]phenylalanine; collagenolytic and gelatinolytic activities were assayed by using fluorogenic peptidyl substrates. RESULTS: Angiotensin II (10(-8)-10(-6) M) exerted a dose-dependent inhibition of collagenolytic and gelatinolytic activities, associated with reduction of protein degradation rate. In addition angiotensin II stimulated protein synthesis in the cells. These combined effects on protein turnover resulted in an increase in both cell size and cell protein content (31.7% after 48 h). However, the rise of cell protein content was only partly (48.0%) prevented by the protein synthesis inhibitor cycloheximide (10(-5)M), which supports the role of decreased protein degradation in the angiotensin-II-induced cell hypertrophy. The angiotensin-II-induced effects on proteolytic activities as well as on cell protein content could be abolished by coincubation with the angiotensin II type I-receptor antagonist DuP 753 (10(-6)M). The calcium-channel blocker verapamil (10(-6)M) ameliorated the impairment of collagenolytic activity. On the contrary the calcium ionophore A23187 (10(-6)M) mimicked the action of angiotensin II on this enzyme activity (control 34.5 +/- 1.9; angiotensin II 24.0 +/- 2.0; A23187 23.0 +/- 2.2 and angiotensin II+verapamil, 33.8 +/- 2.6 pmol/min/micrograms DNA). The role of cytosolic [Ca2+] in the actions of angiotensin II could be finally shown by a dose-dependent rise which was partly blunted by verapamil. CONCLUSION: The angiotensin-II-induced hypertrophy in LLC-PK1 cells is caused not only by enhanced protein synthesis but also by reduced protein degradation. The concomitant decline of collagenolytic and gelatinolytic activities may contribute to the accumulation of extracellular matrix, and presumably also to cell hypertrophy. These effects are obviously mediated via angiotensin II type I receptors and seem to be [Ca2+] dependent.

Analysis of Variance↗
PubMed1994

Renal proteinases and kidney hypertrophy in experimental diabetes.

IDDM is associated with an increase in kidney size, which is due to cellular hypertrophy and progressive matrix accumulation within the glomerulus and throughout the tubulo-interstitium. The present study addressed the potential role of cysteine and metalloproteinases in renal hypertrophy of short-term diabetes. Three weeks after induction of streptozotocin diabetes in rats, intraglomerular gelatinase activity (streptozotocin: 23 +/- 4 vs control: 44 +/- 3 mU/microgram DNA) and cathepsin L+B activity (streptozotocin: 6.7 +/- 0.8 vs control: 9.3 +/- 0.7 U/microgram DNA) were significantly decreased. Insulin treatment completely prevented the decline in glomerular proteinase activity (gelatinase: 37 +/- 6 mU/microgram DNA; cathepsin L+B: 9.6 +/- 0.9 U/microgram DNA). In isolated proximal tubules a similar pattern of enzyme activity could be observed. Three weeks of diabetes caused a significant decline in cathepsin L+B activity (streptozotocin: 28 +/- 2 vs control: 37 +/- 3 U/microgram DNA). Insulin treatment again prevented the decline in these tubular proteinase activities. In parallel, kidney weight increased by 22% and glomerular protein/DNA ratio rose by 17% in untreated diabetic rats. Diabetic rats receiving insulin displayed a normal glomerular protein/DNA ratio and the kidney weight was increased by only 5%. These results show that renal hypertrophy of early diabetes is closely associated with a decline in both glomerular and tubular proteinase activity. Adequate insulin substitution prevented renal hypertrophy and the reduction in proteinase activity.

Animals↗
PubMed1994

Lovastatin ameliorates depressed intraglomerular proteolytic activities in experimental nephrotic syndrome.

Lipid abnormalities have been implicated in the pathogenesis of glomerulosclerosis in experimental models of kidney disease. In previous studies it has been shown that Adriamycin-induced nephropathy is associated with reduced activities of glomerular proteinases. This observation led to the hypothesis that reduced proteolytic activities may be responsible for mesangial protein accumulation, which ultimately leads to global sclerosis of the glomerular tuft. The aim of the present study was to investigate whether lovastatin treatment, which prevents progressive glomerulosclerosis in experimental nephrotic syndrome, would also have an effect on glomerular proteinase activities. Adriamycin administration resulted in a persistent nephrotic syndrome with gross proteinuria (377 +/- 26 mg/24 h), hypoalbuminemia (2.1 +/- 0.12 vs. 2.8 +/- 0.02 g/dl), hypercholesterolemia (575 +/- 74 vs. 68 +/- 1.5 mg/dl) and elevated triglyceride levels (1,155 +/- 78 vs. 57 +/- 8 mg/dl). Glomerular azocaseinolytic activities both at pH 5.4 (-21%) and 7.4 (-37%) were significantly reduced. In contrast to human subjects, nephrotic rats that were treated with lovastatin displayed reduced triglyceride levels (767 +/- 134 mg/dl); their serum cholesterol, however, remained unchanged. In terms of glomerular proteolytic enzyme activities, the decline in azocaseinolysis at both pH values was, at least partly, prevented by lovastatin. On the basis of these data, it appears that the beneficial effect of lovastatin on the evolution of glomerulosclerosis in the nephrotic rat is associated with the conservation of glomerular proteolytic activities.

Albuminuria↗
PubMed1994

The aging rat kidney displays low glomerular and tubular proteinase activities.

The present study was conducted to investigate the relationship of age-related changes in renal function and structure with changes in glomerular and tubular proteinase activities in young (3 weeks), mature (3 months), and older (18 months) male Wistar rats. Glomerular filtration rate, expressed per 100 g body weight, remained unchanged during adolescence, but declined significantly (-44%) in aging animals. In parallel, albuminuria, which was barely detectable in young and mature rats, increased almost 10-fold in the aging animals. In comparison to young animals, the kidney weight in aging rats was 10-fold higher, signifying considerable tubular hypertrophy. The glomerular protein to DNA ratio increased by almost 70%, suggesting deposition of mesangial matrix within the glomerulus. These structural changes were associated with significant reductions in glomerular cysteine and metalloproteinase activities in the adolescent and older animals. Similarly, lower activities of both types of proteinases were observed in isolated proximal tubules. This behavior of proteolytic enzyme activities in the aging rat kidney corresponds well to the 10-fold increase in kidney weight (proximal tubular hypertrophy) and to the enhanced deposition of glomerular matrix. This study suggests a causal involvement of renal cysteine proteinases and metalloproteinases in the protein accumulation of the aging rat kidney.

Aging↗
PubMed1994

Human chronic kidney allograft rejection is accompanied by increased intraglomerular cathepsin B and L activity.

The major reason for late graft losses is chronic rejection. Recently, a large number of studies have indicated that proteolytic enzymes play an important role as mediators of glomerular injury. The cysteine proteinases cathepsins B and L degrade structural matrix proteins such as type I collagen and laminin. We investigated intraglomerular protease activities in 12 patients after kidney graftectomy because of end-stage renal disease following chronic rejection. A group of 12 patients undergoing nephrectomy because of cancer served as controls using only non-involved parts of the kidney. The activities of cathepsins B and L in homogenates of isolated glomeruli were measured fluorometrically methylcoumarylamide substrates and related to DNA content. In rejected kidney allografts we observed significantly enhanced intraglomerular cathepsin B activity and cathepsin B + L activity.

Adult↗
PubMed1994

Hypertension as cause and consequence of renal disease in the 19th century.

The pioneering work of Richard Bright, who introduced the concept of the renal origin of cardiovascular disease, initiated the continuous unfolding of knowledge on renal disease and its close interrelationship with arterial hypertension in the 19th century. Hypertension as a clinically and pathologically defined entity, however, was not established. The partial elucidation of the problem that the diseased kidney was sometimes the cause and sometimes the consequence of elevated blood pressure is not only fascinating but also remarkable, given the crude techniques available to physicians at that time. Subsequent workers came to regard 'Bright's disease' as consisting of several conditions differing in clinical manifestation and pathology. In particular, Johnson and Gull and Sutton drew attention to the small blood vessels in renal disease. Only the invention of a clinically applicable method of measuring blood pressure indirectly allowed Mahomed and Allbutt to show that hypertension may occur in the absence of renal disease. They paved the way for a clear separation of hypertensive renal disease from other forms of 'Bright's disease', culminating in the classification introduced by Fahr and Volhard.

England↗