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Biomedical subjects

S Hvidt

Publications and source records attributed to S Hvidt.

At least 19 recordsLinked to original sources
PubMed1992

Effects of actin filaments on fibrin clot structure and lysis.

The muscle and cytoskeletal protein actin is released from cells as a consequence of cell death and interacts with components of the hemostatic and fibrinolytic systems, including platelets, plasmin, and fibrin. We report here that incorporation of actin filaments into fibrin clots changes their viscoelastic properties by increasing their shear modulus at low deforming stresses and by nearly eliminating their tendency to become more rigid with increasing deformation (ie, exhibit strain-hardening). The viscoelastic effects depended on the length of the actin filaments as shown by the effects of the plasma filament-severing protein, gelsolin. Binding of actin to fibrin clots also varied with actin filament length. The plasma actin-binding proteins gelsolin and vitamin D-binding protein reduced, but did not eliminate, the incorporation of actin in the clot. Fluorescence microscopy showed a direct association of rhodamine-labeled actin filaments with the fibrin network. Incubation of clots containing long actin filaments in solutions containing physiologic concentrations of gelsolin (2 mumol/L) released 60% of the actin trapped in the clot. Reduction of the actin content of a fibrin clot by incubation in a gelsolin-containing solution resulted in an increased rate of clot lysis. The ability of plasma gelsolin to shorten actin filaments may therefore be of physiologic and potentially of therapeutic importance insofar as gelsolin-mediated diffusion of actin from the clot may restore the clot's rheologic properties and render it more sensitive to the lytic action of plasmin.

Actins↗
PubMed1992

Thermally induced chain exchange of frog alpha beta-tropomyosin.

The thermally induced unfolding of the alpha-helix of Rana esculenta alpha alpha, alpha beta and beta beta tropomyosin and two tryptic fragments approximately corresponding to the N- and C-terminal halves of alpha beta have been investigated by use of optical rotation, circular dichroism and UV difference spectroscopy. Reversible unfolding transitions of alpha alpha and beta beta occur around 49 degrees C and 32 degrees C, respectively. The helix unfolding of alpha beta shows two major transitions at 36 degrees C and 48 degrees C, with only the latter being reversible. The major unfolding transitions of each of the N- and C-terminal alpha beta peptides roughly correspond to the low and high temperature transitions of intact alpha beta, respectively. This suggests that the unfolding of alpha beta could be due to unfolding of two independent domains in alpha beta. UV difference data, crosslinking and chromatography results show, however, that the unfolding of alpha beta at 36 degrees C is due to chain exchange with the formation of alpha alpha homodimers and largely unfolded beta monomers, and that the transition at 48 degrees C is due to unfolding of alpha alpha dimers.

Animals↗
PubMed1990

Effect of ATP on actin filament stiffness.

Actin is an adenine nucleotide-binding protein and an ATPase. The bound adenine nucleotide stabilizes the protein against denaturation and the ATPase activity, although not required for actin polymerization, affects the kinetics of this assembly Here we provide evidence for another effect of adenine nucleotides. We find that actin filaments made from ATP-containing monomers, the ATPase activity of which hydrolyses ATP to ADP following polymerization, are stiff rods, whereas filaments prepared from ADP-monomers are flexible. ATP exchanges with ADP in such filaments and stiffens them. Because both kinds of actin filaments contain mainly ADP, we suggest the alignment of actin monomers in filaments that have bound and hydrolysed ATP traps them conformationally and stores elastic energy. This energy would be available for release by actin-binding proteins that transduce force or sever actin filaments. These data support earlier proposals that actin is not merely a passive cable, but has an active mechanochemical role in cell function.

Actins↗
PubMed1990

Resemblance of actin-binding protein/actin gels to covalently crosslinked networks.

The maintainance of the shape of cells is often due to their surface elasticity, which arises mainly from an actin-rich cytoplasmic cortex. On locomotion, phagocytosis or fission, however, these cells become partially fluid-like. The finding of proteins that can bind to actin and control the assembly of, or crosslink, actin filaments, and of intracellular messages that regulate the activities of some of these actin-binding proteins, indicates that such 'gel-sol' transformations result from the rearrangement of cortical actin-rich networks. Alternatively, on the basis of a study of the mechanical properties of mixtures of actin filaments and an Acanthamoeba actin-binding protein, alpha-actinin, it has been proposed that these transformations can be accounted for by rapid exchange of crosslinks between actin filaments: the cortical network would be solid when the deformation rate is greater than the rate of crosslink exchange, but would deform or 'creep' when deformation is slow enough to permit crosslinker molecules to rearrange. Here we report, however, that mixtures of actin filaments and actin-binding protein (ABP), an actin crosslinking protein of many higher eukaryotes, form gels rheologically equivalent to covalently crosslinked networks. These gels do not creep in response to applied stress on a time scale compatible with most cell-surface movements. These findings support a more complex and controlled mechanism underlying the dynamic mechanical properties of cortical cytoplasm, and can explain why cells do not collapse under the constant shear forces that often exist in tissues.

Actinin↗
PubMed1989

Assembly of the native heterodimer of Rana esculenta tropomyosin by chain exchange.

Rana esculenta tropomyosin assembles in vivo into a coiled-coil alpha helix from two different subunits, alpha and beta, which are present in about equal concentrations. Although the native composition is alpha beta, a mixture of equal amounts of alpha alpha and beta beta is produced by refolding dissociated alpha and beta at low temperature in vitro. Refolding kinetics showed that alpha alpha formed first and was relatively stable with regard to chain exchange below approximately 20 degrees C. Equilibration of the homodimer mixture at 30 degrees and 34 degrees C for long times, however, resulted in the formation of the native alpha beta molecule by chain exchange. Biosynthesis of alpha beta from separate alpha and beta genes is, therefore, favored thermodynamically over the formation of homodimers, and biological factors need not be invoked to explain the preferred native alpha beta composition.

Animals↗
PubMed1988

Viscoelasticity of F-actin and F-actin/gelsolin complexes.

Actin is the major protein of eukaryote peripheral cytoplasm where its mechanical effects could determine cell shape and motility. The mechanical properties of purified F-actin, whether it is a viscoelastic fluid or an elastic solid, have been a subject of controversy. Mainstream polymer theory predicts that filaments as long as those found in purified F-actin are so interpenetrated as to appear immobile in measurements over a reasonable time with available instrumentation and that the fluidity of F-actin could only be manifest if the filaments were shortened. We show that the static and dynamic elastic moduli below a critical degree of shear strain are much higher than previously reported, consistent with extreme interpenetration, but that higher strain or treatment with very low concentrations of the F-actin severing protein gelsolin greatly diminish the moduli and cause F-actin to exhibit rheologic behavior expected for independent semidilute rods, and defined by the dimensions of the filaments, including shear rate independent viscosity below a critical shear rate. The findings show that shortening of actin filaments sufficiently to permit reasonable measurements brings out their viscoelastic fluid properties. Since gelsolin shortens F-actin, it is likely that the effect of high strain is also to fragment a population of long actin filaments. We confirmed recent findings that the viscosity of F-actin is inversely proportional to the shear rate, consistent with an indeterminate fluid, but found that gelsolin abolishes this unusual shear rate dependence, indicating that it results from filament disruption during the viscosity measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1986

Differences in thermal stability of frog and rabbit alpha alpha- and alpha beta-tropomyosins determined by optical rotatory dispersion.

Frog and rabbit alpha alpha- and alpha beta-tropomyosins were purified, and their thermal stabilities determined by use of optical rotatory dispersion. The tropomyosins were found to be virtually completely helical at 5 degrees C. Regions of different thermal stabilities were seen for all tropomyosins. Rabbit and frog alpha alpha-tropomyosin show very similar thermal properties, with main transitions near 47-49 degrees C. The main transition for frog alpha beta-tropomyosin is at 32 degrees C. The results show that the alpha beta-tropomyosins are less stable than the alpha alpha-forms. Only thermal transitions of the alpha beta-forms appear to be correlated with the body temperatures of the animals.

Animals↗
PubMed1986

Non-interaction between nifedipine and digoxin.

In order to evaluate a possible interaction between digoxin and nifedipine, we studied steady state digoxin pharmacokinetics before and during oral coadministration of nifedipine in eight healthy subjects. Mean plasma digoxin concentration was 0.68 +/- 0.15 ng/ml during control conditions versus 0.74 +/- 0.13 ng/ml (NS) after two weeks of nifedipine coadministration. Nifedipine caused no significant changes in either renal digoxin clearance (173.6 +/- 25.9 versus 173.1 +/- 33.2 ml/min) or 24-hour urinary recovery of digoxin (164.7 +/- 25.7 versus 183.8 +/- 29.2 micrograms/24 hrs). Our findings support earlier observations that nifedipine coadministration is not associated with any significant alteration of digoxin pharmacokinetics.

Adult↗
PubMed1985

Effect of quinine on plasma digoxin concentration and renal digoxin clearance.

In order to explore the digoxin-quinine interaction, digoxin steady state pharmacokinetics was studied before and during quinine coadministration in seven healthy subjects. Quinine (250 mg/day) increased mean plasma digoxin concentration from 0.64 +/- 0.12 to 0.80 +/- 0.18 ng/ml (p less than 0.05) within one week. Urinary digoxin recovery rose from 154.0 +/- 18.8 to 181.5 +/- 22.6 micrograms/24 h (p less than 0.01), whereas renal digoxin clearance was unaltered in the presence of quinine (181.5 +/- 24.2 vs. 174.1 +/- 26.5 ml/min). An increase in quinine dose (to 750 mg/day) caused further increments in plasma digoxin levels, whereas renal digoxin clearance remained unchanged. Quinine elevates plasma digoxin concentrations in a stepwise fashion probably due to an impairment of extrarenal digoxin clearance.

Adult↗
PubMed1983

Effects of physical activity and immobilization on plasma digoxin concentration and renal digoxin clearance.

Plasma digoxin concentration and renal digoxin clearance were determined during 2 hr of normal physical activity and during 2 hr of complete immobilization in eight healthy subjects on steady-state digoxin dosing. Mean plasma digoxin concentration rose from 0.64 +/- 0.13 ng/ml during physical activity to 1.04 +/- 0.19 ng/ml (63%) after 2 hr of rest. Resumption of physical activity resulted in gradual decline of plasma digoxin, and subsequent strenuous exercise reduced the value to preimmobilization level. Mean renal digoxin clearance was reduced from 168.4 +/- 18.7 ml/min during physical activity to 137.2 +/- 32.7 ml/min during rest whereas creatinine clearance was unchanged. The rise in plasma digoxin during rest is presumed to be due to changes in the binding of the drug to tissues such as skeletal muscles. Our findings indicate that attention should be given to the state of physical activity when kinetic studies are performed or when digoxin therapy is monitored by means of plasma digoxin analysis.

Adult↗
PubMed1983

The diagnostic value of determination of intraerythrocytic sodium and potassium concentrations versus plasma digoxin concentration in digoxin intoxication.

Plasma digoxin measurements have proved unserviceable as a means of differentiating between toxic and non-toxic patients. In order to assess the value of a biological effect of digoxin in this discrimination, intraerythrocytic sodium and potassium concentrations were determined in 55 chronically digitalized patients of whom 10 were digoxin-intoxicated according to ECG criteria. Digitoxicity was associated with elevated intraerythrocytic sodium concentration (mean +/- SEM 19.3 +/- 1.2 versus 11.3 +/- 0.3 mmol/l, p less than 0.001) and reduced intraerythrocytic potassium concentration (94.6 +/- 2.3 versus 100.0 +/- 0.6 mmol/l, p less than 0.001) compared to non-toxic patients. Mean (+/- SEM) plasma digoxin concentrations in the two groups were 3.14 +/- 0.41 and 1.57 +/- 0.09 nmol/l, respectively (p less than 0.001). When diagnosing toxicity in chronically digitalized patients, plasma digoxin and intraerythrocytic sodium determinations showed sensitivities of 60 and 100%, respectively. The predictive values of a positive test were 75% for plasma digoxin and 83% for intraerythrocytic sodium.

Aged↗
PubMed1982

Intraerythrocytic sodium and potassium concentrations during acute and chronic digitalization.

To assess the cellular effects of digoxin, intraerythrocytic sodium and potassium concentrations were measured in 17 patients during the early phase of digitalization, in 45 patients on long-term therapy and in 64 non-digitalized control patients. Acute digitalization raised intraerythrocytic sodium from 11.6 +/- 0.4 to 16.7 +/- 1.0 mmol/l (mean +/- SEM) (p less than 0.01) and reduced intraerythrocytic potassium from 100.1 +/- 1.3 to 95.9 +/- 1.8 mmol/l (p less than 0.01). These changes were strongly correlated with the steady-state plasma digoxin concentration. During a few weeks of digoxin therapy, the intraerythrocytic cation composition normalized gradually. In patients on chronic treatment, neither intraerythrocytic sodium (11.3 +/- 0.3 mmol/l) nor potassium concentrations (100.0 +/- 0.6 mmol/l) differed significantly from the values of the control group (11.4 +/- 0.2 and 99.9 +/- 0.5 mmol/l, respectively). The changes in intraerythrocytic cation concentrations, induced by acute digitalization, seem to disappear during chronic administration of the drug.

Aged↗