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Biomedical subjects

M Wehling

Publications and source records attributed to M Wehling.

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

[Guidelines for lowering lipids are too infrequently observed. Results of a retrospective study of coronary heart disease patients].

UNLABELLED: The aim of this retrospective analysis was to investigate adherence to treatment guidelines in the secondary prevention of coronary heart disease. 3720 CHD patients treated in 591 doctor's offices throughout Germany were investigated. End points were serum lipid levels at week-6, i.e. screening investigation, and 5 weeks after discontinuation of the lipid-lowering medication (week-1). 3383 of the 3720 (90.9%) patients had LDL-C levels > = 115 mg/dl, and 3563 (95.8%) > = 100 mg/dl. At week-6 mean LDL-C was 167.7 +/- 43.5 and mean total cholesterol was 258.8 +/- 47.8 mg/dl. 5 weeks after discontinuation of lipid-lowering treatment, mean LDL-C increased by 5.6%, and mean total cholesterol by 3.7% in comparison with baseline at week-6. 2346 (69.3%) of the patients with LDL-C > = 115 at week-6 did not receive any prior lipid-lowering medication. Also, patients receiving lipid-lowering medication demonstrated an insufficient lipid decrease (only 14.4% of all treated patients had LDL-C levels < 115 mg/dl, and only 6.8% had levels < 100 mg/dl. CONCLUSION: So far, lipid-lowering guidelines for the secondary prevention of CHD are not being adequately implemented. Appropriate action to remedy this situation (e.g. establishment of Disease Management Programs) is needed. The aggressive use of lipid-lowering drugs is a must if the goals of the treatment guidelines are to be met, and morbidity and mortality of CHD lowered.

Anticholesteremic Agents↗
PubMed2000

Dominant negative myostatin produces hypertrophy without hyperplasia in muscle.

Myostatin, a TGF-beta family member, is a negative regulator of muscle growth. Here, we generated transgenic mice that expressed myostatin mutated at its cleavage site under the control of a muscle specific promoter creating a dominant negative myostatin. These mice exhibited a significant (20-35%) increase in muscle mass that resulted from myofiber hypertrophy and not from myofiber hyperplasia. We also evaluated the role of myostatin in muscle degenerative states, such as muscular dystrophy, and found significant downregulation of myostatin. Thus, further inhibition of myostatin may permit increased muscle growth in muscle degenerative disorders.

Animals↗
PubMed2000

Rapid, nongenomic steroid actions: A new age?

In the traditional theory of steroid action, steroids bind to intracellular receptors and modulate nuclear transcription after translocation of steroid-receptor complexes into the nucleus. Due to similarities of molecular structure, specific receptors for steroids, vitamin D(3) derivatives, and thyroid hormone are considered to represent a superfamily of steroid receptors. While genomic steroid effects characterized by their delayed onset of action and their sensitivity to blockers of transcription and protein synthesis have been known for several decades, rapid actions of steroids have been more widely recognized and characterized in detail only recently. Rapid effects of steroids, thyroid hormones, and the steroid hormone metabolite of vitamin D(3), 1alpha, 25-dihydroxyvitamin D(3), on cellular signaling and function may be transmitted by specific membrane receptors. Binding sites in membranes have been characterized, exposing binding features compatible with an involvement in rapid steroid signaling. Characteristics of putative membrane receptors are completely distinct from intracellular steroid receptors, a fact which is further supported by the inability of classic steroid receptor antagonists to block nongenomic steroid actions. A putative progesterone membrane receptor has been cloned and functionally expressed with regard to progesterone binding. Development of drugs that specifically affect nongenomic action alone or even both modes of action may find applications in various, areas such as in the cardiovascular and central nervous systems and treatment of preterm labor, infertility, and electrolyte abnormalities.

Animals↗
PubMed2000

Nongenomically initiated steroid actions.

The classical theory of steroid hormone action comprises binding to an intracellular receptor followed by modulation of transcriptional and translational events. These cumbersome model explains the characteristic latency of these genomic steroid effects. Over the past two decades, increasing evidence for rapid nongenomic effects of steroids, incompatible with the traditional model, has accumulated. These alternative steroid effects have been described for all classes of steroids and a multitude of species and tissues with different mechanisms of action.

Aldosterone↗
PubMed2000

Specific nongenomic actions of aldosterone.

BACKGROUND: According to the traditional model, steroid hormones modulate gene transcription and protein synthesis. The considerable latency of these genomic steroid effects is the consequence of these time-consuming steps of action. Over the years, it has become increasingly clear that rapid actions of steroids exist that are incompatible with this "classic" genomic model of action. These rapid, nongenomic effects, which recently have been shown for virtually all groups of steroids, are likely to be transmitted by specific membrane receptors. METHODS: A review of data mainly focusing on the nongenomic in vitro and in vivo effects of aldosterone is presented. RESULTS: For rapid aldosterone effects, a prominent example of a receptor/effector cascade for nongenomic steroid effects has been described in various cell types. Nonclassic membrane receptors with a high affinity for aldosterone, but not for cortisol, seem to be involved. As an important second messenger, [Ca2+]i is consistently increased within minutes after the addition of aldosterone. The effects are half maximal at physiological concentrations of free aldosterone (approximately 0.1 nmol/L), while the classic mineralocorticoid antagonist canrenone is ineffective in blocking the action of aldosterone. In addition, cortisol is active only at supramicromolar concentrations. Aldosterone rapidly acts on further cell signaling systems, for example, phosphoinositide hydrolysis and cAMP generation. CONCLUSIONS: For a better understanding of nongenomic aldosterone action even in a clinical context, future research will have to target the cloning of the first membrane receptor for aldosterone and the evaluation of the clinical relevance of rapid steroid effects in general.

Aldosterone↗
PubMed2000

Modulation of myostatin expression during modified muscle use.

Previous findings have provided strong evidence that myostatin functions as a negative regulator of muscle mass during development and growth. In the present study, we test the hypothesis that myostatin may serve a similar function in fully differentiated muscle experiencing modified loading. Our findings show that myostatin expression can be modulated in fully differentiated, nonpathological skeletal muscle in a manner that is inversely related to changes in muscle mass. Atrophy of rat hind limb muscles induced by 10 days of unloading resulted in a 16% decrease in plantaris mass, a 110% increase in myostatin mRNA, and a 37% increase in myostatin protein. Immunohistochemical observations showed a detectable increase in myostatin concentration at myotendinous junctions during muscle unloading. The concentration of myostatin mRNA and protein returned to values not significantly different from ambulatory controls after 4 days of reloading, during which time plantaris mass also returned to control values. However, the results also show that periods of 30 min of daily muscle loading during the unloading period were sufficient to prevent significant losses of muscle mass caused by unloading, although myostatin mRNA still showed a 55% increase in concentration. Thus, significant increases in myostatin expression are not sufficient for muscle mass loss, although muscle mass loss during unloading is accompanied by increases in myostatin.

Animals↗
PubMed2000

Mannheim classification of nongenomically initiated (rapid) steroid action(s).

There is increasing evidence for rapid effects of steroids that are incompatible with the classical model of genomic steroid action. To address the diversity of mechanisms for rapid steroid signaling described over the past years, a classification of rapid steroid effects has been proposed to promote the discussion and understanding of nongenomic steroid action.

Animals↗
PubMed2000

Aldosterone- and progesterone-membrane-binding proteins: new concepts of nongenomic steroid action.

n the classical theory of steroid action steroids penetrate into cells and bind to intracellular receptors resulting in modulation of nuclear transcription and protein synthesis within hours. In addition, rapid actions of steroids have been identified, which are incompatible with the classic model of steroid action. Specific binding sites for aldosterone and progesterone have been reported in membrane preparations of liver, vascular smooth muscle cells and kidney. These sites are discussed to be involved in rapid nongenomic steroid actions, such as the rapid activation of the Na(+)/H(+) exchanger and elevation of [Ca(2+)]i in vascular smooth muscle cells by aldosterone. In addition, rapid progesterone-induced increases of [Ca(2+)]i have been reported in spermatozoa. A high affinity progesterone-membrane binding protein from porcine liver has been identified and cloned. The derived amino acid sequence showed no significant identity with any functional protein suggesting a binding site completely different to classic progesterone receptors. These binding sites are possibly involved in rapidly induced meiotic maturation of amphibian oocytes and the spermatozoan acrosome reactions as evidenced by recent studies, where the progesterone induced acrosome reactions and calcium signaling was blocked by a specific antibody raised against the membrane binding site for progesterone. In addition to data on specific steroid binding and rapid steroid signaling in vitro, results of nongenomic steroid effects in vivo are presented and their physiological relevance are discussed in the review.

Aldosterone↗
PubMed2000

Effects of the mineralocorticoid fludrocortisone on fibrinolytic function in healthy subjects.

Recent evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the regulation of fibrinolytic function. Angiotensin II (Ang II) is the primary candidate to mediate this inter-relationship, since this peptide is capable of stimulating plasminogen activator inhibitor-1 (PAI-1) in vitro and in vivo. It has been suggested that aldosterone may also modulate fibrinolysis, possibly by interacting with Ang II. The present study therefore investigates the effect of short-term treatment with the synthetic mineralocorticoid fludrocortisone (F) on fibrinolytic function. Ten healthy male volunteers, aged 25 to 30 years, on a constant intake of 160-180 mmol Na(+) and 60-80 mmol K(+), were studied on a control day (C1), after two days of oral administration of F (0.1 mg b.d.), and again three days after cessation of F (C2). F was associated with a marked decrease in plasma renin activity (PRA) from 0.91 +/- 0.45 ng ml(-1) h(-1) to 0.34 +/- 0.29 ng ml(-1) h(-1) (p=0.005), which returned to the baseline range at C2 (0.65 +/- 0.45 ng ml(-1) h(-1); p=0.032). The experimental protocol was not associated with significant changes in the activity or antigen concentration of tissue plasminogen activator (t-PA). PAI-1 exhibited a circadian rhythm with highest values at 0800 hours (41.8 +/- 9.1 ng/ml), decreasing by 1230 hours (22.6 +/- 5.9 ng/ml), with a further decrease at 1630 hours (12.3 +/- 3.1 ng/ml). At all three time points, PAI-1 remained unchanged by the mineralocorticoid. Our results therefore do not support a major mineralocorticoid effect on PAI-1. However, our study does not exclude a modulatory role of F, since unchanged PAI-1 could be observed in spite of a marked suppression of the RAAS.

Adult↗
PubMed2000

Multiple actions of steroid hormones--a focus on rapid, nongenomic effects.

According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. Based upon similarities in molecular structure, specific receptors for steroids, vitamin D(3) derivatives, thyroid hormone, retinoids, and a variety of orphan receptors are considered to represent a superfamily of steroid receptors. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized that are clearly incompatible with the genomic model. These rapid, nongenomic steroid actions are likely to be transmitted via specific membrane receptors. Evidence for nongenomic steroid effects and distinct receptors involved is presented for all steroid groups including related compounds like vitamin D(3) and thyroid hormones. The physiological and clinical relevance of these rapid effects is still largely unclear, but their existence in vivo has been clearly shown in various settings including human studies. Drugs that specifically affect nongenomic steroid action may find applications in various clinical areas such as cardiovascular and central nervous disorders, electrolyte homeostasis, and infertility. In addition to a short description of genomic steroid action, this review pays particular attention to the current knowledge and important results on the mechanisms of nongenomic steroid action. The modes of action are discussed in relation to their potential physiological or pathophysiological relevance and with regard to a cross-talk between genomic and nongenomic responses.

Animals↗
PubMed1999

Recognition of a human sperm surface protein involved in the progesterone-initiated acrosome reaction by antisera against an endomembrane progesterone binding protein from porcine liver.

Antisera against a porcine liver endomembrane progesterone (P4)-binding protein inhibited the P4-initiated acrosome reaction (AR) but not the ionomycin-initiated AR of human sperm. Indirect immunofluorescence studies detected antigen in the sperm head that moved during capacitation from a posterior head region to a midhead region. Moreover, the antisera detected a 44.6 kDa protein in western blots of sperm digitonin extracts. These results suggest that a sperm protein with at least partial homology to the liver endomembrane P4-binding protein, is a putative P4-receptor on the sperm plasma membrane involved in the P4-initiated AR.

Acrosome Reaction↗
PubMed1999

Simultaneous assay of morphine, morphine-3-glucuronide and morphine-6-glucuronide in human plasma using normal-phase liquid chromatography-tandem mass spectrometry with a silica column and an aqueous organic mobile phase.

Morphine (MOR) is an opioid analgesic used for the treatment of moderate to severe pain. MOR is extensively metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). A rapid and sensitive method that was able to reliably detect at least 0.5 ng/ml of MOR and 1.0 ng/ml of M6G was required to define their pharmacokinetic profiles. An LC-MS-MS method was developed in our laboratory to quantify all three analytes with the required sensitivity and a rapid turnaround time. A solid-phase extraction (SPE) was used to isolate MOR, M3G, M6G, and their corresponding deuterated internal standards from heparinized plasma. The extract was injected on a LC tandem mass spectrometer with a turbo ion-spray interface. Baseline chromatographic separation among MOR, M3G, and M6G peaks was achieved on a silica column with an aqueous organic mobile phase consisting of formic acid, water, and acetonitrile. The total chromatographic run time was 3 min per injection, with retention times of 1.5, 1.9 and 2.4 min for MOR, M6G, and M3G, respectively. Chromatographic separation of M3G and M6G from MOR was paramount in establishing the LC-MS-MS method selectivity because of fragmentation of M3G and M6G to MOR at the LC-MS interface. The standard curve range in plasma was 0.5-50 ng/ml for MOR, 1.0-100 ng/ml for M6G, and 10-1000 ng/ml for M3G. The inter-day precision and accuracy of the quality control (QC) samples were <7% relative standard deviation (RSD) and <6% relative error (R.E.) for MOR, <9% RSD and <5% R.E. for M6G, and <3% RSD and <6% R.E. for M3G. Analyte stability during sample processing and storage were established. Method ruggedness was demonstrated by the reproducible performance from multiple analysts using several LC-MS-MS systems to analyze over one thousand samples from clinical trials.

Chromatography, Liquid↗
PubMed1999

Rapid nongenomic effects of aldosterone in mineralocorticoid-receptor-knockout mice.

In addition to genomic effects of aldosterone, rapid nongenomic effects of steroids have been reported in various tissues that were clearly incompatible with a genomic action of aldosterone. Rapid effects of aldosterone involve second messengers such as calcium and cAMP. Specific high affinity binding sites for aldosterone have been characterized in membranes for different cells, which probably transmit those rapid steroid effects. To date, it is unclear if these binding sites are modified classical mineralocorticoid receptors (MR) or if they represent an unrelated receptor protein. The aim of the present study was to investigate whether rapid aldosterone action still occurs in the absence of the classical MR. For this purpose we used the model of MR knockout mice. Rapid effects were analyzed in skin cells, measuring intracellular calcium and cAMP levels after stimulation with aldosterone. We found that rapid effects are not only present in MR knockout mice, but that the effects are even larger than in wild-type mice cells. The results of the present study demonstrate that the classic MR is dispensable for rapid aldosterone action. The study, thus, proves that a receptor different from the classic intracellular receptor is involved in rapid aldosterone signaling.

Aldosterone↗
PubMed1999

Nitric-oxide synthase is a mechanical signal transducer that modulates talin and vinculin expression.

Mechanical stimuli can cause changes in muscle mass and structure which indicate that mechanisms exist for transducing mechanical stimuli into signals that influence gene expression. Myotendinous junctions show adaptations to modified muscle loading which suggest that these are transcriptionally distinct domains in muscle fibers that may experience local regulation of expression of structural proteins that are concentrated at these sites. Vinculin and talin are cytoskeletal proteins that are highly enriched at myotendinous junctions that we hypothesize to be subject to local transcriptional regulation. Our findings show that mechanical stimulation of muscle cells in vivo and in vitro causes an increase in the expression of vinculin and talin that is mediated by nitric oxide. Furthermore, nitric oxide-stimulated increases in vinculin and talin expression occur through a protein kinase G-dependent pathway and therefore differ from other mechanisms through which nitric oxide has been shown previously to modulate transcription. Analysis of vinculin mRNA distribution in mechanically stimulated muscle fibers shows that the mRNA is highly concentrated at myotendinous junctions, which supports the hypothesis that myotendinous junctions are distinct domains in which the expression of cytoskeletal proteins is modulated by mechanical stimuli through a nitric oxide and protein kinase G-dependent pathway.

Alkaloids↗
PubMed1999

Compatibility of plastics with cytotoxic drug solutions-comparison of polyethylene with other container materials.

In this study low density polyethylene (LDPE)-containers were compared to glass bottles and polyvinyl chloride (PVC) bags in view of adsorption effects with antineoplastic drugs. The infusion containers were supplemented with therapeutic doses of the nine common cytotoxic drugs carboplatin, carmustine, cytarabine, dacarbazine, fluorouracil, gemcitabine, melphalan, methotrexate and vinorelbine. 0.9% isotonic sodium chloride solution and 5% dextrose served as infusion solutions. The containers were stored at room temperature or at 4 degrees C, protected from light, for periods of up to 168 h. Turbidity, change of colour and visible crystallization were not observed. Samples were collected at different time intervals and drug contents were determined with high-performance liquid chromatography (HPLC). Preparations of carmustine showed no adsorption phenomena when stored in LDPE or in glass at 4 degrees C. At room temperature in LDPE, a slight decrease in concentration due to adsorption was monitored. However the drug loss in PVC bags was greater. Dacarbazine and melphalan showed decreases in concentration, which were independent on the type of container material. The remaining analyzed agents showed no drug loss at all. In conclusion, investigated drugs were stable in all three container types, with the best stability in glass bottles, followed by LDPE and PVC.

Adsorption↗
PubMed1999

Safety of low-density lipoprotein cholestrol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial).

Reduction in plasma lipids has been recognized as one of the primary cardiovascular risk reduction strategies in the secondary prevention of coronary heart disease (CHD). The primary end points of TARGET TANGIBLE were the safety (adverse events and laboratory measurements) and efficacy (responder rates) of therapy with atorvastatin versus simvastatin with the aim of achieving low-density lipoprotein (LDL) cholesterol lowering to < or =100 mg/dl (2.6 mmol/L). A total of 3,748 CHD patients with LDL cholesterol levels > or =130 mg/dl (3.4 mmol/L) entered a run-in diet phase of 6 weeks without any lipid-lowering drug therapy. At the end of the diet phase, 2,856 patients met the lipid criteria and were randomized to active treatment for 14 weeks. Patients received 10 to 40 mg of either drug in an optional titration design at 2:1 randomization for atorvastatin versus simvastatin. Adverse event rates were statistically equivalent (p<0.01) for simvastatin (35.7%) and for atorvastatin patients (36.3%). Both drugs were well tolerated; <5% of patients in both groups were withdrawn due to adverse events. In all, 37 atorvastatin patients (2%) and 27 simvastatin patients (3%) had serious adverse events. Drug-related side effects (elevations in creatine kinase, liver enzymes) occurred in both groups at similar rates with 10 atorvastatin patients (0.5%) and 5 simvastatin patients (0.5%) presenting confirmed transaminase elevations >3 x the upper limit of the normal range. Significantly fewer patients in the atorvastatin group (n = 724) required titration to 40 mg compared with the simvastatin group (n = 514) (38% vs. 54%, respectively; p<0.001). Atorvastatin resulted in a significantly greater number of patients reaching the LDL cholesterol goal than those treated with simvastatin, with 67% of atorvastatin patients and 53% of simvastatin patients reaching the target LDL cholesterol level of < or =100 mg/dl (2.6 mmol/L) (p<0.001). Both atorvastatin and simvastatin are safe for use by patients in the secondary prevention of CHD, with patients in both drug groups having similar adverse event rates. Despite the use of concomitant medications there was no drug-induced rhabdomyolysis with either atorvastatin or simvastatin.

Anticholesteremic Agents↗