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Biomedical subjects

K Werdan

Publications and source records attributed to K Werdan.

At least 127 records · Page 7Linked to original sources
PubMed1991

A basic program for calculation of APACHE II and Elebute scores and sepsis evaluation in intensive care medicine.

This paper describes a program for bedside-practicable calculation of APACHE II score, providing an additional option for both a rapid and sensitive screening as well as for a more specific sepsis assessment by the Elebute score in case of a putative diagnosis of sepsis. Thus, diagnostic and prognostic evaluation of septic patients and the assessment of disease progression and classification of "responders" to therapy can be promptly available in the ICU setting. The program is written in BASIC and therefore can easily be adapted to most microcomputers available on the market.

Bacterial Infections↗
PubMed1991

Regulation of adenylyl cyclase by noradrenaline and tumour necrosis factor alpha in rat cardiomyocytes.

The regulation of adenylyl cyclase components and of adenylyl cyclase activity by noradrenaline and tumour necrosis factor alpha (TNF alpha) was studied in rat cardiomyocytes. Long-term treatment of rat cardiomyocytes in the presence of noradrenaline leads, in addition to a down-regulation of beta 1-adrenoceptors, to an increase in the level of inhibitory G protein alpha-subunits and to a heterologous desensitization of adenylyl cyclase stimulation. Similar to the noradrenaline exposure, incubation of the cardiomyocytes in the presence of the cytokine TNF alpha (10 U.ml-1) also increases the level of Gi alpha proteins. However, in contrast to the noradrenaline treatment, which apparently induces a selective up-regulation of Gi alpha, the TNF alpha exposure also increases the level or activity of other components of adenylyl cyclase, such as the level of membrane beta 36-subunits of G proteins and, most likely, the level of the alpha-subunits of the stimulatory G protein (Gs alpha) and the activity of adenylyl cyclase catalytic subunit. While noradrenaline treatment desensitizes receptor-dependent and independent adenylyl cyclase activity, treatment of the cells with TNF alpha induces a sensitization of adenylyl cyclase stimulation. The data indicate that only a selective increase in the level of inhibitory G protein alpha subunits decreases adenylyl cyclase activity. The hypersensitivity of adenylyl cyclase induced by TNF alpha exposure may be due to concomitant alterations of other components of the adenylyl cyclase signal transduction system.

Adenylyl Cyclases↗
PubMed1991

A cardiodepressant factor isolated from blood blocks Ca2+ current in cardiomyocytes.

A cardiodepressant factor (CDF) was isolated (salt free) from the plasma of dogs after hypovolemic-traumatic shock by column chromatography. CDF was found to exert a concentration-dependent negative inotropic effect in guinea pig papillary muscle; it reduced the amplitude of cell wall motion, the contraction and relaxation velocity, and the frequency of spontaneously beating rat cardiomyocytes in culture, effects that were rapidly reversible upon washout. By means of electrophysiological methods (whole cell recording with patch electrodes and voltage clamp) we tested the effect of CDF on adult guinea pig cardiomyocytes: application of CDF initially decreased the plateau by 7 mV (150 ms after peak of action potential) and reduced the action potential duration by 93 ms (76% of control action potential duration) at 50% and 88 ms (79%) at 90% of repolarization. The plateau was further reduced by 13 mV and the action potential duration was prolonged by 25 ms (106%) at 50% and was prolonged drastically by 156 ms (137%) at 90% of repolarization compared with control. Voltage-clamp experiments have shown that the most prominent effect of CDF is a strong reduction of ICa accompanied by inhibition of IK and subsequent repolarization. Similar results have been obtained with neonatal rat cardiomyocytes. Blockage of the calcium inward current can explain the negative inotropic and chronotropic effect of CDF in cardiomyocytes.

Action Potentials↗
PubMed1991

Effect of positive inotropic agents on myosin isozyme population and mechanical activity of cultured rat heart myocytes.

To examine whether catecholamines have a direct effect on myosin heavy chain expression of heart myocytes or whether they act via an altered work load, myocytes from neonatal rat hearts were cultured in thyroid hormone-free media containing various positive inotropic and chronotropic agents. The velocity and frequency of contraction of the myocytes were monitored using an optoelectronic system. After 3-5 days of culture, myosin isozyme populations, cellular cAMP content, and 2-deoxy-D-glucose uptake of the myocytes were determined. Compared with myocytes cultured in the absence of inotropic agents (32.6 +/- 3.5% V1), the proportion of myosin V1 was significantly (p less than 0.05) increased in the case of 1 microM isoproterenol (48.2 +/- 5.9% V1), 1 microM forskolin (57.1 +/- 11.7% V1), and 1 mM dibutyryl cAMP (79.1 +/- 2.0% V1). Dibutyryl cAMP increased V1 to a similar level as 30 nM triiodothyronine did (70.2 +/- 13.0% V1). Only a small increase was observed in myocytes cultured in the presence of 10 microM phenylephrine (40.4 +/- 8.4% V1), 10 microM ouabain (40.6 +/- 11.9% V1), or 10 microM Bay K 8644 (40.7 +/- 11.7% V1). The agents with a marked effect on myosin heavy chain expression resulted in a higher cAMP content; isoproterenol and forskolin also stimulated 2-deoxy-D-glucose uptake. All agents resulted in a higher velocity of contraction; with the exception of ouabain, frequency of contraction was also increased. A change in Ca2+ concentration in the medium from 1.3 to 2.4 mM resulted in a small increase in V1 (40.7 +/- 5.2% V1) but had the same effect on contraction velocity as dibutyryl cAMP did. Furthermore, 10 nM isoproterenol also increased V1 in myocytes that were arrested with 10 microM verapamil. The increase in V1 in the case of dibutyryl cAMP, isoproterenol, and forskolin is thus most probably not a correlate of the increased mechanical activity but of the high cellular cAMP content.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

[Supplemental infection therapy with i.v. immunoglobulins (polyvalent IgG and Pseudomonas IgG)--results of an observational case study with 163 patients].

The impact of i.v. immunoglobulin (IVIG) therapy on the survival of adult septic patients cannot yet be considered either proved or disproved. To define optimal criteria for a large multicenter placebo-controlled trial, a multicenter observational study was carried out in 163 medical and surgical patients exhibiting a total of 173 episodes of sepsis and septic shock [Elebute (El) sepsis score; 19 +/- 0.5). The effects of supplemental IVIG treatment (unmodified polyvalent IgG, pH 4.25, n = 123; for Pseudomonas sepsis, n = 50, Pseudomonas IgG) on multiple-organ failure (MOF) were investigated according to changes in the APACHE II score (AP) (pretreatment value 23.7 +/- 0.6). In 44% of the cases ("responders"), a prompt improvement in AP (defined as a decrease of greater than or equal to 4) was evident from day 0 to day 4 after the onset of therapy, thus showing a close temporal relationship to IVIG administration. This improvement, associated with an improved prognosis (mortality, 24% vs 55%), was found in all subgroups, most importantly, polyvalent IgG vs Pseudomonas IgG treatment; medical vs surgical patients; moderate vs severe MOF; and gram-positive vs gram-negative septicemia. Thus, all of these patients should be included in future placebo-controlled, randomized IVIG trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Hormonal regulation of Gi alpha level and adenylyl cyclase responsiveness.

Prolonged exposure of cells to adenylyl cyclase stimulatory hormonal factors can cause an increase in the level of membrane inhibitory G protein (Gi) alpha-subunits, while inhibitory receptor agonists have been reported to induce the opposite response. As studied in cultured rat cardiomyocytes, the beta-adrenoceptor-induced increase in the level of Gi alpha proteins is protein synthesis-dependent, is apparently not accompanied by an increase in G protein beta-subunits and results in a decreased adenylyl cyclase responsiveness. On the other hand, a decrease in Gi alpha level apparently results in sensitization of adenylyl cyclase stimulation. These data suggest that the up- or down-regulation of the level and activity of Gi protein alpha-subunits is a rather general cellular response, providing an intracellular negative feedback control against prolonged receptor activation.

ADP Ribose Transferases↗
PubMed1990

Pseudomonas exotoxin A prevents beta-adrenoceptor-induced upregulation of Gi protein alpha-subunits and adenylyl cyclase desensitization in rat heart muscle cells.

Exposure of rat heart muscle cells to noradrenaline (1 microM) for 48 hr led to a decrease in the number of beta 1-adrenoceptors of 50% and a concomitant decrease in adenylyl cyclase stimulation by isoprenaline and forskolin of about 60 and 30%, respectively. In addition, the levels of two inhibitory guanine nucleotide-binding protein (Gi protein) alpha-subunits (Gi alpha 40 and Gi alpha 41) were increased in membranes of noradrenaline-treated cells. Evidence is presented that noradrenaline induces this increase by activation of beta-adrenoceptors. First, the noradrenaline action was mimicked by the beta-adrenoceptor agonist isoprenaline. Second, beta-adrenoceptor blockade by timolol but not alpha-adrenoceptor blockade by prazosin prevented the noradrenaline-induced up-regulation of Gi alpha proteins. Furthermore, timolol but not prazosin abolished the noradrenaline-induced down-regulation of beta 1-adrenoceptors and the decreases in receptor-dependent (isoprenaline) and -independent (forskolin) adenylyl cyclase stimulation. The specific protein synthesis inhibitor Pseudomonas exotoxin A was used to study whether the noradrenaline-induced up-regulation of Gi alpha subunits depends on increased synthesis of these proteins. This toxin inhibits peptide chain elongation by ADP-ribosylating elongation factor 2. Treatment of rat heart muscle cells with Pseudomonas exotoxin A (1 ng/ml) completely prevented the noradrenaline-induced increase in Gi alpha proteins, measured by both pertussis toxin-catalyzed ADP-ribosylation and immunoblotting with anti-Gi alpha antibodies. Most importantly, Pseudomonas exotoxin A also completely prevented the noradrenaline-induced decrease in forskolin-stimulated adenylyl cyclase activity. Furthermore, the noradrenaline-induced decrease in isoprenaline-stimulated adenylyl cyclase activity was significantly attenuated by the toxin, although the down-regulation of beta 1-adrenoceptors caused by noradrenaline treatment was not affected. The data presented suggest that prolonged activation of beta-adrenoceptors in rat heart muscle cells, in addition to causing a receptor down-regulation, induces the synthesis of Gi alpha proteins, which then apparently mediate a decreased adenylyl cyclase responsiveness. The data, additionally, suggest that the synthesis of Gi alpha proteins is under control of the activity of the adenylyl cyclase system and that altered levels of these proteins may play a major role in long term regulation of signal transduction by this enzyme.

ADP Ribose Transferases↗
PubMed1989

Intrinsic sympathomimetic activity of beta-adrenoceptor antagonists: down-regulation of cardiac beta 1- and beta 2-adrenoceptors.

Prolonged treatment of cultured rat heart muscle cells containing beta 1- and non-muscle cells containing beta 2-adrenoceptors with beta-adrenoceptor antagonists devoid of intrinsic sympathomimetic activity had no effect on beta-adrenoceptor density. In contrast, antagonists with intrinsic sympathomimetic activity decreased beta-adrenoceptor density and response (adenylate cyclase stimulation) in both heart muscle (beta 1) and non-muscle cells (beta 2) by a maximum of about 50%. An even larger down-regulation of beta-adrenoceptors and loss of receptor-stimulated adenylate cyclase activity was induced by the full endogenous agonist, noradrenaline, with the beta-adrenoceptors of heart muscle cells (beta 1) being much more sensitive to the beta 1-selective noradrenaline than the heart non-muscle cell beta 2-adrenoceptors. When combined with noradrenaline, the antagonists with intrinsic sympathomimetic activity prevented the action of noradrenaline at both beta 1- and beta 2-adrenoceptors, thereby leading to an apparent up-regulation of receptor density and response. This apparent reversal from an agonist to an antagonist action was observed at much lower concentrations of noradrenaline at beta 1- than at beta 2-adrenoceptors. The data presented indicate that the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity, but not those without, upon prolonged treatment decrease the density and responsiveness of both beta 1- and beta 2-adrenoceptors in cultured rat heart cells. This suggests that the intrinsic sympathomimetic activity of these agents is not a subtype-selective component. Furthermore, the agonist and antagonist activity of these agents apparently depends on the concomitant presence of an endogenous full agonist and an its own affinity and that of the partial agonist for the beta-adrenoceptor subtype.

Adenylyl Cyclases↗
PubMed1989

Mechanism of noradrenaline-induced heterologous desensitization of adenylate cyclase stimulation in rat heart muscle cells: increase in the level of inhibitory G-protein alpha-subunits.

The mechanism of heterologous desensitization of adenylate cyclase stimulation was studied in cultured neonatal rat heart muscle cells. After culturing of the cells for 3 days in the presence of 1 microM noradrenaline there was in addition to a 52% decrease in isoproterenol-stimulated adenylate cyclase activity, a lessening of the stimulation of beta-adrenoceptor-independent adenylate cyclase by guanosine-5'-O-(thiotriphosphate) and forskolin by 24 and 34%, respectively. The decrease in receptor-independent adenylate cyclase stimulation by forskolin, but not the attenuation of isoproterenol-stimulated adenylate cyclase activity, was abolished by pertussis toxin (PTX) pretreatment of the cells. Gi, the inhibitory G-protein of adenylate cyclase was therefore quantitated. Labelling of the Mr approximately 40 kDa PTX substrates in membranes of noradrenaline-treated cells was increased by 70% as shown by pertussis toxin-catalyzed ADP ribosylation of heart cell membranes. This increase was also seen in the presence of an excess of purified beta gamma-subunits of transducin and of GTP, suggesting that the increased labelling was not due to elevation of the level of beta gamma-subunits or increase in the concentration of GTP in the membranes of noradrenaline-treated cells. Analysis of the PTX substrates on high resolution urea/SDS-polyacrylamide gels revealed that at least two distinct PTX substrates (40 and 41 kDa) were present in rat heart cell membranes. The labelling of both substrates was increased in membranes of desensitized cells. Immunoblotting of heart cell membranes with anti-Gi alpha-antibodies demonstrated a marked increase in the amount of Gi alpha in membranes of noradrenaline-treated cells. In contrast, immunoblotting with anti-beta-antibodies showed that the level of the beta-subunit of G-proteins (36 kDa) was unchanged after noradrenaline exposure. The data indicate that prolonged treatment of rat heart muscle cells with noradrenaline leads to an increase in the level of alpha-subunits of Gi-proteins. This suggests that this increase is responsible for the observed heterologous desensitization of adenylate cyclase stimulation.

Adenosine Diphosphate↗