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Biomedical subjects

B Mühlbauer

Publications and source records attributed to B Mühlbauer.

At least 37 records · Page 2Linked to original sources
PubMed1998

Urinary dopamine and renal handling of L-DOPA in fasted spontaneously hypertensive rats.

A defective renal dopaminergic system has been suggested to contribute, via impaired sodium excretion, to the pathogenesis of hypertension. Data according renal dopamine (DA) release in hypertension, however, are inconsistent. In the present study, we compared urinary DA excretion (UDAV), plasma free DA (PDA), and renal tissue DA contents (TDA) of young spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. Since the protein intake dominantly controls UDAV, fasted animals were used to exclude the influence of feeding. Conscious WKY and SHR had a similar UDAV which was lower compared to SD rats. Thiopental anesthesia increased UDAV in SHR and WKY but not in SD rats. TDA was higher in SHR compared to SD and WKY rats. To investigate the tubular capacity to generate DA, the response to L-DOPA infusion was assessed in two doses. 1 nmol/min/100 g body weight L-DOPA increased UDAV approximately 30-fold in all strains but did not affect tubular sodium excretion or renal hemodynamics. In contrast, infusion of 3 micromol/min/100 g body weight L-DOPA increased UDAV by five orders of magnitude and induced natriuresis, diuresis, and tachycardia. These effects were assigned to an increase in PDA and no significant differences were observed among the strains. We conclude that, regarding renal DA, (1) the differences among SHR, WKY, and SD rats rather appear to be strain related than hypertension associated; (2) the renal capacity of DA generation from L-DOPA is not impaired in SHR; (3) tubular DA at physiological concentrations does not alter sodium excretion significantly in normo- or hypertensive rats, and (4) the influence of anesthesia on UDAV should be considered in comparative studies.

Animals↗
PubMed1998

Evaluation of cytomegalovirus retinitis management. Outcome of four years of cytomegalovirus therapy.

Cytomegalovirus (CMV) is the most common pathogen of opportunistic viral infections in patients with the acquired immunodeficiency syndrome. In this study, we assessed the therapeutic outcome of our treatment regimen of CMV retinitis by analysing retrospectively 33 consecutive patients. The clinical utility of CMV cultures from blood, urine and throat specimens obtained at the time of diagnosis was additionally evaluated. Treatment started with ganciclovir (GCV) therapy. In case of relapsing retinitis, re-induction therapy was initiated, and if unsuccessful, the patient was switched to foscarnet. Patients developing resistant retinitis despite foscarnet therapy were offered a GCV-foscarnet combination therapy. Under primary GCV therapy, the median first stable interval of the whole group was 202 days (mean 238 days). Twenty-five out of 33 CMV retinitis patients (76%) responded to initial GCV therapy. Eleven of these patients showed relapsing retinitis that could be stabilised in 3 patients solely with combination therapy. Eight patients did not respond to primary GCV therapy. Three of them improved with foscarnet, but 3 patients did not respond to either treatment. In 18 (56%) out of 32 patients, CMV cultures yielded positive results. Considering our series, we may conclude that in the majority of patients primary or secondary viral resistance can be overcome by dose increase, switching to the alternative drug or a combination therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

The IQGAP-related protein DGAP1 interacts with Rac and is involved in the modulation of the F-actin cytoskeleton and control of cell motility.

DGAP1 of Dictyostelium discoideum is a cell cortex associated 95 kDa protein that shows homology to both RasGTPase-activating proteins (RasGAPs) and RasGAP-related proteins. When tested for RasGAP activity, recombinant DGAP1 protein did not promote the GTPase activity of human H-Ras or of Dictyostelium RasG in vitro. Instead, DGAP1 bound to Dictyostelium Rac1A and human Rac1, but not to human Cdc42. DGAP1 preferentially interacted with the activated GTP-bound forms of Rac1 and Rac1A, but did not affect the GTPase activities. Since Rho-type GTPases are implicated in the formation of specific F-actin structures and in the control of cell morphology, the microfilament system of mutants that either lack or overexpress DGAP1 has been analysed. DGAP1-null mutants showed elevated levels of F-actin that was organised in large leading edges, membrane ruffles or numerous large filopods. Expression of actin fused to green fluorescent protein (GFP) was used to monitor the actin dynamics in these cells, and revealed that the F-actin cytoskeleton of DGAP1-null cells was rapidly re-arranged to form ruffles and filopods. Conversely, in DGAP1-overexpressing cells, the formation of cellular projections containing F-actin was largely suppressed. Measurement of cell migration demonstrated that DGAP1 expression is inversely correlated with the speed of cell motility.

Actin Cytoskeleton↗
PubMed1998

Dopamine D2 receptors mediate glomerular hyperfiltration due to amino acids.

Renal dopamine has been proposed to be involved in the regulation of glomerular filtration rate (GFR). Because inhibition of dopamine D2 receptors abolishes the renal hyperfiltration due to amino acid load, we tested the hypothesis that pharmacological activation of D2-like receptors mimicked this renal response. In anesthetized rats, quinpirole (0.3 microgram . 100 g-1 . min-1), an agonist for receptors of the D2-like family, caused an increase in GFR by 20 +/- 2%, which corresponded to that provoked by infusion of an 10% amino acid solution. The D2 receptor antagonist S(-)-sulpiride that acts both centrally and peripherally completely abolished the renal hemodynamic response to quinpirole and to amino acids whereas domperidone, a peripherally acting D2 receptor antagonist, inhibited this hyperfiltration only in part. Urinary dopamine excretion increased in response to amino acid infusion whether GFR increased or not. We conclude that, in anesthetized rats, dopamine D2 receptors contribute to the amino acid-induced hyperfiltration and that both central and peripheral receptors might be involved, whereas dopamine excreted into the urine does not appear to play a functional role in this renal hemodynamic response.

Amino Acids↗
PubMed1997

Microfilament dynamics during cell movement and chemotaxis monitored using a GFP-actin fusion protein.

BACKGROUND: The microfilament system in the cortex of highly motile cells, such as neutrophils and cells of the eukaryotic microorganism Dictyostelium discoideum, is subject to rapid re-organization, both spontaneously and in response to external signals. In particular, actin polymerization induced by a gradient of chemoattractant leads to local accumulation of filamentous actin and protrusion of a 'leading edge' of the cell in the direction of the gradient. In order to study the dynamics of actin in these processes, actin was tagged at its amino terminus with green fluorescent protein (GFP) and observed with fluorescence microscopy in living cells of D. discoideum. RESULTS: Purified GFP-actin was capable of copolymerizing with actin. In the transfected cells of D. discoideum studied, GFP-actin made up 10-20% of the total actin. Microfilaments containing GFP-actin were capable of generating force with myosin in an in vitro assay. Observations of single living cells using fluorescence microscopy showed that the fusion protein was enriched in cell projections, including filopodia and leading edges, and that the fusion protein reflected the dynamics of the microfilament system in cells that were freely moving, being chemotactically stimulated, or aggregated. When confocal sections of fixed cells containing GFP-actin were labeled with fluorescent phalloidin, which binds only to filamentous actin, there was a correlation between the areas of GFP-actin and phalloidin fluorescence, but there were distinct sites in which GFP-actin was more prominent. CONCLUSIONS: Double labeling with GFP-actin and other probes provides an indication of the various states of actin in motile cells. A major portion of the actin assemblies visualized using GFP-actin are networks or bundles of filamentous actin. Other clusters of GFP-actin might represent stores of monomeric actin in the form of complexes with actin-sequestering proteins.

Actin Cytoskeleton↗
PubMed1997

Renal response to infusion of dopamine precursors in anaesthetized rats.

In the present study the renal response to intravenous infusion of the catecholamine precursors L-dihydroxyphenylalanine (L-DOPA) or L-tyrosine was investigated in thiopentone sodium-anaesthetized Sprague-Dawley rats. Glomerular filtration rate (GFR) was assessed by renal clearance of inulin, urinary concentration of dopamine (U(DA)V) by HPLC and sodium excretion (U(Na)V) by flame photometry. We found that basal U(DA)V was 6.5 +/- 0.5 pmol/min per 100 g body weight (mean +/- SEM). Intravenous infusion of L-tyrosine at 0. 1-3.0 micromol/min dose dependently enhanced U(DA)V (17 +/- 3 to 144 +/- 14 pmol/min respectively) with higher doses of L-tyrosine resulting in no further increase in U(DA)V. Compared with L-tyrosine administration significantly lower doses of L-DOPA (0.07 to 35 nmol/min) caused increases in U(DA)V which were orders of magnitude higher (18 +/- 1 to 7800 +/- 470 pmol/min, respectively) and did not show saturation characteristics. GFR did not change in response to L-tyrosine or L-DOPA infusion. No variations in urinary flow rate or in U(Na)V could be observed which were significantly correlated to changes in U(DA)V. In contrast, intravenous infusion of dopamine at a dose of 6 nmol/min significantly increased GFR by 35 +/- 6.2% and urinary flow rate by over 2-fold. Immunohistochemistry with light microscopy revealed no tyrosine hydroxylase in the kidney. Therefore, dopamine synthesis in the tubular cells mainly depends on the renal supply of L-DOPA. The unchanged GFR and U(Na)V in spite of large variations of U(DA)V argue against the hypothesis that intratubular dopamine plays a functional role in the regulation of hemodynamics or sodium transport in the kidney. Renal dopamine excretion may rather represent an effective pathway for the elimination of catecholamine precursors from the plasma.

Adrenal Glands↗
PubMed1997

Disprocynium24 induces a dopamine-independent, eukaliuric diuresis and natriuresis in the anaesthetized rat.

In the anaesthetized rat, intravenous administration of the isocyanine 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) at doses up to 600 microg/kg resulted in marked diuresis and natriuresis without affecting urinary potassium excretion. Fractional sodium excretion was increased over 10-fold indicating a high ceiling-diuretic action. The effects of disprocynium24 on renal function were accompanied by a dose-dependent reduction in heart rate (HR) and mean arterial blood pressure (MAP). Acute administration of 600 microg/kg disprocynium24 decreased MAP by 25% and, in addition, caused a fall in glomerular filtration rate (GFR). Since i) disprocynium24 has been shown to interfere with urinary dopamine excretion (UDAV) and ii) dopamine has been implicated with the regulation of renal sodium excretion, we hypothesized that the effects of disprocynium24 might be mediated by its effects on renal dopamine handling. The following findings, however, argue against this hypothesis. First, administration of disprocynium24 in single doses up to 600 microg/kg caused a diuresis and natriuresis, but did not significantly affect U(DA)V. Second, neither the systemic nor the renal response to disprocynium24 were markedly altered by pretreatment with the dopamine D1- or D2-receptor blockers SCH23390 (10 microg x kg(-1) x min[-1]) or S(-)sulpiride (15 microg x kg(-1) x min[-1]), respectively.

Animals↗
PubMed1997

Progressive multifocal leukoencephalopathy in AIDS: initial and follow-up CT and MRI.

We sought to determine the value of follow-up CT and MRI in patients with acquired immuno-deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). We reviewed 50 CT and 19 MRI examinations performed in 21 biopsy- or autopsy-proven cases of PML; 17 patients had follow-up examinations (mean time 5.9 weeks). The radiological examinations were correlated with pathological findings at autopsy. On initial imaging studies, 73 lesions were found. On follow-up, the most striking feature was rapid progression in both size and number of the lesions (from a mean of 3.2 to 6.9 per patient). One third of the patients showed increasing mass effect. A central area suggesting necrosis, of variable size, was found in 12/16 patients. Autopsy revealed macroscopic necrotic changes in the lesions in 11/16 patients.

AIDS Dementia Complex↗
PubMed1997

Protein-induced increase in urinary dopamine in normal and diabetic rats: role of catecholamine precursors.

Feeding and protein intake increase renal dopamine excretion (UDAV). Here the contribution of amino acids (AA), L-tyrosine (Tyr), and L-phenylalanine (Phe) to UDAV in conscious normal rats and in animals with streptozotocin (STZ)-induced (60 mg/kg) diabetes mellitus was investigated. Feeding a standard chow (17.3% protein) increased UDAV in normal rats over twofold compared with the fasted state, but the effect was completely abolished by feeding a low-protein (LP, 0.03%) diet. In STZ rats, UDAV was equal to that of normal rats during the fasted periods but was higher in fed animals, resulting most likely from the higher protein intake of STZ rats. In another series, rats on LP diet were given AA solutions (7, 14, and 21 g.kg-1.24 h-1) by gastric tube, which dose dependently increased UDAV to 67.3 +/- 4.3, 91.1 +/- 5.0, and 129 +/- 17 nmol.kg-1.day-1, respectively, compared with tap water as vehicle control (H2O, 55.6 +/- 7.0 nmol.kg-1.day-1). In rats kept without access to chow, administration of AA including Phe and Tyr (AAPT) increased UDAV twofold compared with H2O, whereas AA solution without Tyr and Phe did not change UDAV. Tyr or Phe alone increased UDAV to the same extent as observed in AAPT. Higher doses of Tyr further increased UDAV dose dependently but with saturation characteristics. UDAV of the animals that were in a slightly negative sodium balance was not correlated to renal sodium excretion. It is concluded that, in conscious rats, the increase in UDAV in response to feeding 1) depends on the supply of catecholamine precursors solely, 2) is dose dependent and saturable, and 3) is not affected by experimental diabetes mellitus.

Animal Feed↗
PubMed1997

Role of renal nerves and endogenous dopamine in amino acid-induced glomerular hyperfiltration.

The present study was performed to clarify whether urinary dopamine excretion (UDAV) and renal nerves are involved in the increase in glomerular filtration rate (GFR) induced by amino acid (AA) infusion. In thiopental-anesthetized rats, L-phenylalanine-free solutions of 10 AA (10%) either with (AATyr, n = 10) or without (AA0, n = 10) L-tyrosine (0.5%) were infused. Compared with baseline values, AATyr increased GFR from 0.83 +/- 0.05 to 1.00 +/- 0.04 ml.min-1.100 g-1 (P < 0.01) and UDAV almost fivefold from 5.81 +/- 0.46 to 28.1 +/- 7.4 pmol.min-1.100 g-1 (P < 0.01). In contrast, infusion of AAo increased GFR as did AATyr but did not significantly change UDAV. The DA2-receptor antagonist S(-)-sulpiride dose-dependently (0.5 to 15 micrograms.min-1.100 g-1) inhibited the GFR response to AA infusion but did not affect UDAV. In rats that had undergone chronic bilateral renal denervation (DNX), the AA-induced hyperfiltration was abolished completely, regardless of whether L-tyrosine was present. DNX did not affect basal UDAV, but the increase in UDAV in response to AATyr was attenuated compared with rats with innervated kidneys. Renal sodium excretion was increased almost twofold due to AA infusion and did not correlate with UDAV significantly. The data suggest 1) that urinary dopamine does not play a significant role in the regulation of kidney function, 2) that renal innervation is essential in the GFR response to systemic AA infusion, and 3) that a dopaminergic mechanism apart from tubular dopamine excretion is involved as well.

Amino Acids↗
PubMed1997

Adenosine and tubuloglomerular feedback.

During the past 16 years numerous studies have shown that adenosine is present in the normoxic kidney and accumulates when ATP hydrolysis prevails over ATP synthesis. Adenosine can induce renal vasoconstriction and a fall in glomerular filtration rate (GFR). The tubuloglomerular feed-back (TGF) mechanism refers to a series of events whereby changes in the NaCl concentration in the tubular fluid at the end of the thick ascending limb of Henle's loop are sensed by the macula densa which then elicits a twofold response in the juxtaglomerular apparatus: a change in the afferent arteriolar tone and GFR and an alteration in renin secretion from granular cells. While an increase in late proximal tubular flow rate, which increases the NaCl concentration and probably transport across the macula densa, lowers GFR and renin secretion, a low NaCl concentration at the macula densa elicits the opposite effects. One important role of the TGF response is to keep the fluid and electrolyte delivery to the distal tubule within certain limits, so that this part of the nephron can accomplish the fine adjustments in reabsorption to meet body needs. In this regard the TGF mechanism serves to establish an appropriate balance between nephron filtration rate and reabsorption in the proximal tubule and loop of Henle. Among several factors, adenosine is considered to be a potential candidate for mediating the TGF response from macula densa to extraglomerular mesangial cells, afferent arteriole, and granular cells. The TGF-mediated vasoconstriction and reduction in renin release following an elevation of the NaCl concentration at the macula densa can be blocked by theophylline and other adenosine-A1-receptor-specific antagonists. Furthermore, the TGF is potentiated by substances that can elevate extracellular adenosine concentrations such as dipyridamole. These and other findings support the concept that adenosine as a metabolic mediator may couple energy metabolism (ATP hydrolysis for tubular Na+ transport) with the control of renin secretion and GFR.

Adenosine↗
PubMed1996

Erythropoietin production in healthy volunteers subjected to controlled haemorrhage: evidence against a major role for adenosine.

1. This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750 ml. 2. Healthy male nonsmokers received i.v. in a parallel, randomized, single-blind trial theophylline (loading dose 5 mg kg-1 over 20 min, followed by 0.5 mg kg-1 min-1), dipyridamole (0.21 mg kg-1 h-1) or placebo (0.9% NaCl) for 6 h following the phlebotomy. EPO concentrations were followed up to 72 h after phlebotomy. 3. Following blood loss EPO concentrations increased during all treatments. The AUCEPO (0,72 h) were not statistically significantly different (theophylline: 398 +/- 30, dipyridamole: 301 +/- 15, placebo: 332 +/- 57 [mu ml-1 h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activity was significantly increased during theophylline infusion. 4. In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.

Adenosine↗
PubMed1996

Role of adenosine in tubuloglomerular feedback and acute renal failure.

1. Adenosine (ADO) can induce renal vasoconstriction and a fall in glomerular filtration rate. When the rate of ATP hydrolysis prevails over the rate of ATP synthesis the kidney generates ADO at an enhanced rate. 2. Tubuloglomerular feedback (TGF) is the vascular response to changes of the NaCl concentration in the tubular fluid at the macula densa segment, which is the result of transepithelial electrolyte reabsorption by the proximal tubule and the loop of Henle. 3. TGF can be inhibited by ADO-A1 receptor antagonists and is potentiated by substances that can elevate extracellular ADO concentrations. These observations led to the hypothesis that ADO is an element of the signal transmission processes in the juxtaglomerular apparatus. 4. Renal ischaemia and nephrotoxic substances can induce acute renal failure (ARF). ADO receptor antagonists have been shown to ameliorate renal function in several different models of ARF in laboratory animals and humans. 5. A number of factors, such as extracellular volume contraction, low NaCl diet, angiotensin II and cyclooxygenase inhibitors enhance to a similar extent: (a) the renal vascular response to endogenous and exogenous ADO; (b) the TGF response of the nephron; and (c) the severity of ARF. All three phenomena are susceptible to antagonism by ADO receptor antagonists. 6. Therefore, we conclude that ADO plays a significant role in normal and pathological states of kidney function.

Acute Kidney Injury↗
PubMed1995

The pharmacological basis for the combination of calcium channel antagonists and angiotensin converting enzyme inhibitors in the treatment of hypertension.

IMPROVING THE TREATMENT OF HYPERTENSION: The results of basic and clinical research in hypertension over the last 30 years have shown that this disease cannot be treated merely by inducing vasodilation and a fall in blood pressure. The development of high blood pressure is associated with changes in carbohydrate and lipid metabolism and with the development of organ damage, mainly of the heart and kidneys. It is now clear that different elements of blood pressure control mechanisms can lead to hypertension, emphasizing the need to select the appropriate type of hypertensive drug in treating different patients. COMBINATION OF CALCIUM CHANNEL ANTAGONISTS AND ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: Calcium channel antagonists and ACE inhibitors have synergistic effects on sodium and fluid balance and on the renin-angiotensin-aldosterone system. Thus a combination of these two antihypertensive drug classes is likely to be beneficial in certain subgroups of patients with hypertension. Large clinical trials are needed to determine whether this is indeed the case.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

The in vivo role of annexin VII (synexin): characterization of an annexin VII-deficient Dictyostelium mutant indicates an involvement in Ca(2+)-regulated processes.

Dictyostelium discoideum cells harbor two annexin VII isoforms of 47 and 51 kDa which are present throughout development. In immunofluorescence and cell fractionation studies annexin VII was found in the cytoplasm and on the plasma membrane. In gene disruption mutants lacking both annexin VII isoforms growth, pinocytosis, phagocytosis, chemotaxis and motility were not significantly impaired under routine laboratory conditions, and the cells were able to complete the developmental cycle on bacterial plates. On non-nutrient agar plates development was delayed by three to four hours and a significant number of aggregates was no longer able to form fruiting bodies. Exocytosis as determined by measuring extracellular cAMP phosphodiesterase, alpha-fucosidase and alpha-mannosidase activity was unaltered, the total amounts of these enzymes were however lower in the mutant than in the wild type. The mutant cells were markedly impaired when they were exposed to low Ca2+ concentrations by adding EGTA to the nutrient medium. Under these conditions growth, motility and chemotaxis were severely affected. The Ca2+ concentrations were similar in mutant and wild-type cells both under normal and Ca2+ limiting conditions; however, the distribution was altered under low Ca2+ conditions in SYN-cells. The data suggest that annexin VII is not required for membrane fusion events but rather contributes to proper Ca2+ homeostasis in the cell.

Animals↗
PubMed1995

Therapeutic use of theophylline to antagonize renal effects of adenosine.

Experiments in laboratory animals clearly show that adenosine acts as a vasoconstrictive metabolite in the kidney. Adenosine receptor antagonists like theophylline can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine. Based on these findings a number of experiments have been performed to test whether the vasoconstrictive action of adenosine in the kidney might be important also in pathophysiological states. In various animal models theophylline and other methylxanthine derivatives have been successfully employed to improve renal function after induction of acute renal failure. Clinical implications of these experimental findings comprise the prevention of acute renal failure following the administration of radio contrast media by theophylline. Another therapeutic aspect derives from experimental and clinical data showing that theophylline controls erythropoietin production in erythrocytosis after renal transplantation.

Acute Kidney Injury↗
PubMed1994

Renal response to amino acid infusion in rats: effect of dopamine receptor antagonists and benserazide.

Previously, we have found that feeding is a dominant factor controlling urinary dopamine excretion (UDA) in conscious rats (Mühlbauer and Osswald 1992). Since the renal response to feeding is also characterized by an increase in glomerular filtration rate (GFR), we wanted to investigate in a first step whether the feeding-induced elevations of GFR and UDA could be causally related phenomena. Therefore, we studied the influence of dopamine synthesis and dopamine receptor blockade on the renal response to amino acid infusion (AA) in thiopental anesthetized rats. AA infusion (n = 7) increased GFR by 33 +/- 7% (P < 0.001) and UDA by 87 +/- 19% (P < 0.001). In the presence of benserazide (BZD, n = 5), an inhibitor of dopamine synthesis, infused i.v. at a dose of 30 micrograms/min/kg, UDA was suppressed to values below detection limit and the AA-induced GFR increase was abolished. Continuous intravenous infusion of the DA1 receptor antagonist SCH 23390 (SCH, n = 7) in a dose of 4.0 micrograms/kg/min did not prevent the AA-induced increase in GFR (33 +/- 3%, P < 0.001) and UDA (97 +/- 12%, P < 0.001). In contrast, S-sulpiride (SUL), a specific DA2 receptor antagonist, infused continuously i.v. in a dose of 5 micrograms/kg/min, completely abolished the AA-induced GFR increase, while UDA was increased 1.6-fold (P < 0.01). Like BZD, both dopamine receptor antagonists did not affect renal sodium excretion substantially. Our results suggest, that endogenous dopamine could act as a mediator in the renal response to amino acid infusion in the rat, most likely by activation of DA2 receptors.

Amino Acids↗