PubMed Health⌕ Search

Biomedical subjects

H Pagel

Publications and source records attributed to H Pagel.

At least 19 recordsLinked to original sources
PubMed2001

Effects of angiotensin II and the AT(1) receptor antagonist losartan on the renal excretion of urodilatin.

BACKGROUND: The precise mechanisms regulating the natriuretic peptide urodilatin (ANP-95-126) remain to be defined. Renal excretion of urodilatin (U(URO)V) has been shown to be modified by variations in plasma sodium and renal perfusion pressure. This suggests a relationship between urodilatin and the renin-angiotensin system. METHODS: We investigated the effects of angiotensin II (AII, 0.1 nmol/l) and the AT(1) receptor antagonist losartan (LS, 1 micromol/l) on U(URO)V and renal function in isolated rat kidneys perfused for 180 min in a closed circuit system. A further series employing a vasoconstricting concentration of endothelin-1 (ET-1, 0.01 nmol/l) was performed to explore the effects of vasoconstriction and glomerular filtration rate (GFR) on U(URO)V. RESULTS: Urine flow (UV) and urinary sodium excretion (U(Na)V) decreased and renal vascular resistance (RVR) increased after treatment with AII (n = 5) in comparison with a control group (n = 6; p < 0.05). Treatment with LS (n = 5) and AII+LS (n = 5) had no significant effect on these parameters. GFR decreased after AII (p < 0.05) and was not significantly altered by other interventions. U(URO)V decreased after AII (p < 0.05) and was comparable to the control group after LS and AII+LS. ET-1 (n = 5) induced a significant increase in RVR and decreased UV and U(Na)V (p < 0.05). Point-to-point analysis revealed that the ET-1-induced vasoconstriction and the subsequent decrease in GFR had no effect on U(URO)V. CONCLUSIONS: This suggests that vasoconstrictory concentrations of AII decrease U(URO)V in the isolated perfused rat kidney. The lack of effect of ET-1 on U(URO)V suggests that the AII-induced alterations in urodilatin excretion cannot be explained by vasoconstriction per se.

Angiotensin II↗
PubMed2001

Effects of posture and positive airway pressure on plasma atrial natriuretic peptide and renal urodilatin excretion.

AIMS: To determine whether a coupling of plasma atrial natriuretic peptide (ANP) and renal excretion of urodilatin (U(URO)V)--recently observed during supraphysiological concentrations of ANP--may also be detected during moderate changes in ANP levels, i.e. if ANP is increased by supine positioning and decreased by applying continuous positive airway pressure (CPAP). MATERIAL AND METHODS: We investigated 10 healthy male volunteers, orally hydrated with 200 ml water/h, in a randomized crossover study for periods of 1 hour following 2 protocols. Protocol 1: sitting and supine position. Protocol 2: sitting with and without a CPAP of 8 cm H2O. RESULTS: ANP increased ongoing from the sitting to the supine position (SIT-1: 13.2 +/- 4.7; SUP: 27.9 +/- 21.9 pg x ml(-1); p < 0.01) during protocol 1 and decreased after the onset of CPAP in seated subjects (SIT-2: 16.9 +/- 7.9; SIT-CPAP: 13.9 +/- 6.5 pg x ml(-1); p < 0.05) during protocol 2. U(URO)V decreased slightly, but not significantly, during protocol I (SIT-1: 63.9 +/- 21.7; SUP: 49.9 +/- 13.2 fmol x min(-1)) and remained unchanged after institution of CPAP in the sitting position (SIT-2: 68.5 +/- 25.2; SIT-CPAP: 68.5 +/- 50.2 fmol x min(-1)). Correlation analysis revealed no relationship between plasma ANP and U(URO)V. CONCLUSIONS: Moderate variations in the levels of ANP in water-loaded volunteers do not induce parallel changes in the urinary excretion of urodilatin.

Adult↗
PubMed2000

Quality of salivary tears following autologous submandibular gland transplantation for severe dry eye.

BACKGROUND: This study aimed to characterise the composition of the pre-ocular fluid after transplantation of the autologous submandibular gland (SMG) for patients with severe dry eye. METHODS: Stimulated and unstimulated pre-ocular fluid from 15 patients (17 eyes) with a viable SMG graft ("SMG-salivary tears"), as well as normal tears and SMG saliva (20 normal subjects/ 20 eyes), was sampled. As global tear parameters, fern pattern analysis and SDS gel electrophoresis were performed. As specific quality parameters, total protein content, secretory immunoglobulin A (SIgA), lysozyme, amylase, sodium, potassium and osmolality were measured using routine laboratory methods. The flow rate of SMG-salivary tears was determined in 5 patients by means of sequential scintillography. RESULTS: The fern pattern of SMG-salivary tears was coarse and thus more similar to normal SMG saliva than tears. SDS gel electrophoresis of the SMG-salivary tears showed albumin and two unidentified proteins in addition to the normal tear pattern. Osmolality and total protein content of SMG-salivary tears were higher than in normal SMG saliva, but still lower than in normal tears. High activities of normal tear antibacterial proteins (SIgA, lysozyme and amylase) were detected in the salivary tears. Stimulation of the secretion did not alter the composition of SMG-salivary tears. The flow rate of SMG-salivary tears was closer to that of normal tears than normal SMG saliva. CONCLUSION: Salivary tears resulting from SMG-transplantation represent condensed SMG saliva. Thus their quality is intermediate between normal tears and normal SMG saliva. High levels of secretory proteins demonstrate that the gland maintains an active function. Surgical denervation and residual tear components from the ocular surface are the most likely factors to cause the complex differences between normal SMG saliva and SMG-salivary tears. The effects of this secretion on the ocular surface are currently being evaluated in a clinical and laboratory study.

Adolescent↗
PubMed2000

Pentoxifylline improves circulatory and metabolic recovery after cardiopulmonary resuscitation.

BACKGROUND: To evaluate the effectiveness of a bolus application of pentoxifylline (PTXF) at the beginning of CPR in a standardized resuscitation animal model. METHODS AND RESULTS: In a laboratory model of cardiac arrest, 12 Wistar rats (382-413 g) were randomized into two groups. Both groups underwent 4 min of cardiopulmonary arrest induced by a transthoracic application of a fibrillating current of 10 mA. At the beginning of CPR, group one (n=6) received a bolus injection of 10 mg kg(-1) body weight PTXF versus sodium chloride in group two (controls: n=6). All animals developed a severe lactate acidosis during and after CPR but in PTXF treated animals acid-base values returned to baseline pattern. During return of spontaneous circulation (ROSC) in the PTXF group lactate concentration decreased from 13.4+/-2.1 to 1.9+/-0.7 mmol l(-1) within 60 min (P<0.01). In control animals, lactate values remained high (10.8+/-3.5 by 60 min, P<0.01). After bolus injection of PTXF pH increased from 6.93+/-0.06 to 7.29+/-0.13 within 60 min of ROSC versus 6.85+/-0.05 to 6.97+/-0.23 in sodium chloride treated animals (P<0.01). Within 5 min of ROSC, PTXF treated animals achieved higher oxygenation values (PTXF P(a)O(2)=216.9+/-62.5 mmHg, control 132. 2+/-15.1 mmHg, P<0.01). CONCLUSIONS: Administration of PTXF at the beginning of CPR improved macrocirculation, acid-base status and arterial oxygenation.

Acid-Base Imbalance↗
PubMed1999

Quality of salivary tears following autologous submandibular gland transplantation for severe dry eye.

BACKGROUND: This study aimed to characterise the composition of the pre-ocular fluid after transplantation of the autologous submandibular gland (SMG) for patients with severe dry eye. METHODS: Stimulated and unstimulated pre-ocular fluid from 15 patients (17 eyes) with a viable SMG graft ("SMG-salivary tears"), as well as normal tears and SMG saliva (20 normal subjects/20 eyes), was sampled. As global tear parameters, fern pattern analysis and SDS gel electrophoresis were performed. As specific quality parameters, total protein content, secretory immunoglobulin A (SIgA), lysozyme, amylase, sodium, potassium and osmolality were measured using routine laboratory methods. The flow rate of SMG-salivary tears was determined in 5 patients by means of sequential scintillography. RESULTS: The fern pattern of SMG-salivary tears was coarse and thus more similar to normal SMG saliva than tears. SDS gel electrophoresis of the SMG-salivary tears showed albumin and two unidentified proteins in addition to the normal tear pattern. Osmolality and total protein content of SMG-salivary tears were higher than in normal SMG saliva, but still lower than in normal tears. High activities of normal tear antibacterial proteins (SIgA, lysozyme and amylase) were detected in the salivary tears. Stimulation of the secretion did not alter the composition of SMG-salivary tears. The flow rate of SMG-salivary tears was closer to that of normal tears than normal SMG saliva. CONCLUSION: Salivary tears resulting from SMG-transplantation represent condensed SMG saliva. Thus their quality is intermediate between normal tears and normal SMG saliva. High levels of secretory proteins demonstrate that the gland maintains an active function. Surgical denervation and residual tear components from the ocular surface are the most likely factors to cause the complex differences between normal SMG saliva and SMG-salivary tears. The effects of this secretion on the ocular surface are currently being evaluated in a clinical and laboratory study.

Adolescent↗
PubMed1999

Effects of neopterin and 7,8-dihydroneopterin on hypoxia-induced renal erythropoietin production.

Activation of the human cellular immune system is associated with greatly increased formation of the pteridines neopterin and 7,8-dihydroneopterin. It has been postulated that pteridines play a role in the pathogenesis of the anaemia of inflammation. Herein, we studied effects of pteridines on renal function, primarily on the synthesis of erythropoietin (Epo). The experiments were performed with isolated rat kidneys which were perfused hypoxically (pO2 26 mmHg) at constant pressure (100 mmHg) in a serum-free recirculation system for 3 h. The results show that the rate of the production of Epo was significantly lowered when neopterin or 7,8-dihydroneopterin were added to the perfusate. Neopterin (200 microM) also reduced the renal Epo mRNA level. Both pteridines increased renal vascular resistance. 7,8-Dihydroneopterin lowered urine flow and glomerular filtration rate more potently than neopterin. Renal O2 consumption and parameters of exocrine renal function (fractional reabsorption rates of sodium, glucose and water) were not altered by the pteridines, while the glomerular permeability was greatly increased. These results suggest that activated macrophages may not only inhibit the synthesis of Epo by generating cytokines and reactive O2 species but also by the release of pteridines. In vivo, high concentrations of pteridines in renal tissue may aggravate the anaemia of inflammation.

Animals↗
PubMed1999

Urinary excretion of urodilatin is increased during pressure natriuresis in the isolated perfused rat kidney.

The findings about mechanisms regulating production and excretion of urodilatin [ANP-(95-126)], a member of the atrial natriuretic peptide (ANP) family, are controversial. To elucidate a possible relationship between arterial blood pressure and renal urodilatin excretion, we studied the effects of different perfusion pressures on urine flow (UV), urinary sodium (U(Na)V), urinary potassium (U(K)V), and urodilatin excretion (U(URO)V), and the concentration of urodilatin in the perfusate (P(URO)) of isolated perfused rat kidneys. Kidneys were perfused for 180 min with constant perfusion pressures (80 and 120 mmHg, respectively; each, n = 4) in a closed circuit system. Samples of urine and perfusate were taken every 30 min. Mean UV, U(Na)V, U(K)V, and U(URO)V values were significantly higher with a perfusion pressure of 120 mmHg than with 80 mmHg, whereas P(URO) did not change significantly. Serial measurements revealed no direct relation of U(URO)V with either U(Na)V or UV. This suggests that renal perfusion pressure is a determinant of U(URO)V and that urinary and venous effluent concentrations of urodilatin (probably production) are not coupled directly and that U(URO)V and U(Na)V may dissociate during acute variations of sodium excretion and UV.

Animals↗
PubMed1999

Effects of pro- and antioxidative compounds on renal production of erythropoietin.

The most important stimulus for the enhanced synthesis of erythropoietin (Epo) is a lowered O2 tension in the tissue. However, the mechanism by which an impaired O2 supply is transduced into appropriate Epo production is still not fully understood. Recently, studies in human hepatoma cells (line HepG2) indicate that reactive O2 species are involved in the signal transduction from the cellular O2 sensor to the Epo gene. To clarify the role of reactive O2 species in the regulation of Epo synthesis in the kidney, the principal Epo-producing organ in vivo, we investigated the influence of potent pro- and antioxidants on Epo production in isolated perfused rat kidneys. Under normoxic conditions, the iron chelator desferrioxamine and the antioxidant vitamin A increased renal Epo production, mimicking hypoxic induction. In contrast, supplementation of the perfusion medium of hypoxically perfused kidneys with the prooxidant compounds H2O2 or pyrogallol caused a significant reduction of Epo synthesis. The inhibition of Epo formation by reactive O2 species could be completely antagonized by desferrioxamine and the hydroxyl radical-(OH*)-scavenger tetramethylthiourea. Vitamin A also antagonized the H2O2-dependent inhibition of hypoxically induced Epo synthesis. Interestingly, the addition of the antioxidant vitamin A to hypoxically perfused kidneys also induced Epo production significantly. Our data strongly support the idea that reactive O2 species, especially H2O2, are part of the signaling chain of the cellular O2-sensing mechanism regulating the renal synthesis of Epo.

Animals↗
PubMed1998

Whole-body hyperthermia combined with ifosfamide and carboplatin causes hypotension and nephrotoxicity.

It was previously postulated on the basis of clinical data that the cardiovascular sequelae of extracorporeal whole-body hyperthermia (e-WBH), i.e., hypotension (which requires catecholamine support) results in unique nephrotoxicity in combination with select chemotherapeutic agents. In an attempt to explain this phenomenon, we mimicked e-WBH physiological conditions in a rat model. Animals were treated with and without ifosfamide (IFO) and/or carboplatin (CBDCA) at 37 degrees C or 41.5-41.8 degrees C, with blood pressure monitoring and catecholamine support comparable to the clinical setting. Ex vivo post-treatment data (24 h) from artificially perfused kidneys (i.e., histology, urine volume, perfusion rate, glomerular filtration rate, and the reabsorption of sodium, glucose, and water) demonstrated unique toxicity including proximal tubular necrosis for the combination of WBH and IFO, for WBH and CBDCA and for WBH and IFO plus CBDCA, but not for IFO and CBDCA without WBH. These data, considered together with results derived from a subsequent clinical trial and the laboratory work of others were consistent with the hypothesis.

Animals↗
PubMed1997

Effects of antioxidant vitamins on renal and hepatic erythropoietin production.

An important role in O2 sensing has been assigned to microsomal and membrane-bound b-type cytochromes which generate regulatory reactive O2 species (ROS). Recently, ROS have been shown to suppress the in vitro synthesis of erythropoietin (Epo). We investigated the potential of the antioxidant vitamins A, E and C to enhance renal and hepatic Epo production. Renal effects were studied in isolated serum-free perfused rat kidneys. In control experiments without antioxidant vitamins, Epo secretion amounted to 441 +/- 23 mU/g kidney (mean +/- SEM, N = 5) during the three hour period of hypoxic perfusion (arterial pO2 35 mm Hg). Epo secretion significantly increased to 674 +/- 92 mU/g kidney (N = 7) when vitamins A (0.5 microgram/ml), E (0.5 microgram/ml) and C (10 micrograms/ml) in combination were added to the perfusion medium. The effects of the single vitamins were studied in Epo-producing hepatoma cell cultures (lines HepG2 and Hep3B). Vitamin A induced a dose-dependent increase (half-maximal stimulation at 0.2 microgram/ml) in the production of immunoreactive Epo during 24 hours of incubation (such as 680 +/- 51 U Epo/g cell protein in HepG2 cultures with 3 micrograms/ml retinol acetate compared to 261 +/- 15 U/g in untreated controls; N = 4). In contrast, vitamin E (tested from 0.05 to 500 micrograms/ml) and vitamin C (tested from 2 to 200 micrograms/ml) did not increase Epo production in hepatoma cell cultures. Thus, while vitamins E and C may have the potential to protect cells from oxidative damage, vitamin A exerts a specific stimulation of Epo production. Preliminary evidence suggests that this effect of vitamin A involves increased mRNA levels of hypoxia-inducible factor 1 alpha (HIF-1 alpha).

Animals↗
PubMed1997

Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats.

Proinflammatory cytokines play an important role in the pathogenesis of anemia in inflammatory diseases. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) have been reported to inhibit the synthesis of erythropoietin (EPO) in vitro. To evaluate the in vivo significance of this observation, we have investigated effects of the administration of bacterial lipopolysaccharide (LPS) and IL-1 beta on renal EPO production in rats. Measurements by competitive reverse-transcription polymerase chain reaction showed that EPO mRNA levels were significantly reduced in the kidneys of normoxic rats 6 h after the injection of LPS (0.1 or 1 mg/kg). In addition, LPS and IL-1 beta (1 microgram/kg) inhibited the increase in EPO mRNA and plasma EPO levels when administered to rats before hypoxia exposure (8% O2 in the inspiratory gas). Evidence for an inflammatory reaction in the kidneys of LPS-treated rats was provided by measurements of greatly elevated renal TNF-alpha mRNA levels. Furthermore, kidneys isolated from LPS-created rats produced less immunoreactive EPO when perfused hypoxically in vitro for 2 h. Thus mediators of the immune response inhibit renal EPO gene expression in vivo, which is relevant with respect to the impaired synthesis of EPO in inflammatory diseases in humans.

Animals↗
PubMed1995

Increased production of erythropoietin after application of antidiuretic hormone. A consequence of renal vasoconstriction?

The renal glycoprotein hormone erythropoietin (Epo) is the key element in the feedback control of the production of red blood cells (RBC) in bone marrow. Excess of antidiuretic hormone (ADH) increases the RBC mass by increasing the synthesis of Epo. The mechanism of the Epo stimulating effect of ADH is not fully understood. Rats were treated with ADH with or without prior injection of a V1a-receptor antagonist. Additional experiments were carried out by stimulating the V2-receptor by desmopressin (DDAVP). Epo level in plasma was doubled following injections of ADH. Blockade of the V1a-receptor completely abolished the Epo stimulating effect of ADH. Neither ADH alone nor the combined giving of V1a-antagonist and ADH had an influence on the glomerular filtration rate or the renal plasma flow. Therefore, the increased Epo synthesis after application of ADH cannot be explained by a constriction of renal blood vessels with consecutive ischemic hypoxia. There is rather a direct stimulation of Epo synthesis by ADH via its receptors. Since a selective stimulation of the V2-receptor by DDAVP did not increase to Epo level in plasma, the observed increase of Epo is mediated by the V1a-receptor.

Animals↗
PubMed1994

Inhibition of erythropoietin production by cytokines. Implications for the anemia involved in inflammatory states.

In patients with the anemia of chronic diseases, the plasma level of EPO is often low in relation to the blood hemoglobin concentration. Because infectious and inflammatory processes cause activation of cytokine-producing macrophages and lymphocytes, we investigated whether isolated inflammatory cytokines influence the synthesis of EPO in vitro. IL-1 and TNF-alpha were shown to inhibit EPO mRNA levels and EPO formation in the human hepatoma cell cultures HepG2 and Hep3B, and to lower EPO formation in isolated perfused rat kidneys. IFN-alpha and IFN-beta also induced some inhibition of EPO production in HepG2 cultures. IL-3, TGF-beta 2, and IFN-gamma did not inhibit. IL-6 stimulated the production of EPO in Hep3B cells but was ineffective in HepG2 cells and lowered EPO production in isolated perfused rat kidneys. IL-1, TNF-alpha, and possibly other cytokines could contribute to defective EPO production in renal and nonrenal immune responses.

Anemia↗
PubMed1994

Thyroid hormones enhance hypoxia-induced erythropoietin production in vitro.

Effects of thyroid hormones on the production of erythropoietin (Epo) were investigated in isolated perfused rat kidneys and in the human hepatoma cell line, HepG2. Epo protein was measured by radioimmunoassay. L-triiodothyronine and L-thyroxine stimulated hypoxia-induced Epo formation both in the kidney and in HepG2 cells in a dose-dependent fashion. Quantitation of Epo mRNA by competitive polymerase chain reaction (PCR) showed that hypoxic HepG2 cells had three-fold higher Epo messenger RNA levels when treated with thyroid hormones for 3 hours. Measurements of oxygen consumption revealed that this effect was not due to an increase in the degree of hypoxia. Thus, apart from the known direct effect on erythroid precursors, thyroid hormones appear to stimulate erythropoiesis by a noncalorigenic increase in Epo production.

Animals↗
PubMed1992

Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys.

The blood level of erythropoietin (Epo) is often anomalously low in anemic patients with inflammatory or malignant diseases. Therefore, we studied effects of pure recombinant immunomodulatory peptides on Epo formation in cultures of the human hepatoma cell line, HepG2. Interleukin (IL)-1 beta, IL-1 alpha, and tumor necrosis factor alpha lowered Epo production with half-maximal inhibition at 2, 5, and 20 U/ml, respectively. IL-6, transforming growth factor beta 2 and interferon gamma did not inhibit. Furthermore, IL-1 beta (10 U/ml) proved to block Epo formation in isolated serum-free perfused rat kidneys. Proposedly, monokines play a role in the pathogenesis of Epo deficiency in various diseases.

Animals↗
PubMed1991

Isolated serum-free perfused rat kidneys release immunoreactive erythropoietin in response to hypoxia.

The renal glycoprotein hormone erythropoietin (Epo) interacts with erythrocytic progenitors to stimulate their proliferation and differentiation in the bone marrow. The renal O2-sensing mechanism in the control of the synthesis of Epo is still poorly understood. Therefore, the capacity of isolated rat kidneys to produce Epo during hypoxic and anemic perfusion was studied. The kidneys were perfused at a constant perfusion pressure of 100 mm Hg with a substrate-enriched Krebs-Henseleit solution containing 60 g/liter BSA and freshly drawn human erythrocytes. Epo was measured by RIA. When the kidneys were perfused at an arterial pO2 of 720 or 150 mm Hg (hematocrit, 5%), Epo production was very low (0.1-0.2 U/g kidney within 3 h of perfusion). When the arterial pO2 was lowered to 35 or 20 mm Hg, Epo production increased to 0.4 and 0.9 U/g kidney, respectively. The release of Epo during hypoxic perfusion (pO2 35 and 20 mm Hg) was little affected by changes in the hematocrit, i.e. the O2-carrying capacity of the perfusion medium over a wide range (0-40%). These results indicate that the production of Epo in the isolated perfused kidney depends on the availability of O2 and can be modulated by changes in the arterial pO2.

Anemia↗
PubMed1990

Erythropoietin production in the isolated perfused kidney.

In order to further investigate the dependency of the production of erythropoietin (Epo) on the renal O2 supply, experiments were carried out in the isolated perfused rat kidney (IPRK). The kidneys were perfused with a substrate enriched Krebs-Henseleit solution containing 60 g/l bovine serum albumin at a constant perfusion pressure of 100 mmHg. When the kidneys were perfused at an arterial pO2 of 720 or 150 mmHg (hematocrit 5%), Epo production measured by RIA was very low (0.1-0.2 U/g kidney after 3 h of perfusion). At a pO2 of 20 mmHg, Epo production increased markedly up to 0.9 U/g kidney. However, the production of Epo was little affected by changes in the hematocrit of the perfusion medium from zero to 40%, even if severe anemia was mimicked. These results indicate that Epo production in the IPRK is mainly under the control of the arterial pO2.

Anemia↗