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Biomedical subjects

H Kögler

Publications and source records attributed to H Kögler.

12 recordsLinked to original sources
PubMed2003

The functional effect of adenoviral Na+/Ca2+ exchanger overexpression in rabbit myocytes depends on the activity of the Na+/K+-ATPase.

OBJECTIVES: The functional consequences of Na+/Ca2+ exchanger (NCX) overexpression in heart failure have been controversially discussed. NCX function strongly depends on intracellular sodium which has been shown to be increased in heart failure. METHODS AND RESULTS: We investigated the Na+/K+-ATPase (NKA) inhibitor ouabain (0.5-16 micromol/l) in electrically stimulated, isotonically contracting adult rabbit cardiocytes overexpressing NCX after adenoviral gene transfer (Ad-NCX-GFP, 48 h culture time). Myocytes transfected with adenovirus encoding for green fluorescent protein (Ad-GFP) served as a control. Contractions were analyzed by video-edge detection. In the Ad-NCX-GFP group, the maximum inotropic response was significantly reduced by 50.7% (P<0.05). This was a result of an enhanced susceptibility to contracture after exposure to the drug (median concentration (25-75%): 4 (4-8) vs. 8 (6-16) micromol/l, P<0.05). When analyzing relaxation before contracture, the maximum relaxation velocity was reduced (0.15+/-0.04 vs. 0.27+/-0.04 microm/s, P<0.05) and the time from peak shortening to 90% of relaxation was increased (298+/-39 vs. 185+/-15 ms, P<0.05). No differences in systolic and diastolic parameters were observed with the Na+ channel modulator BDF9198 (1 micromol/l). CONCLUSIONS: Inhibition of NKA by ouabain induces a combined diastolic and systolic dysfunction in NCX overexpressing rabbit myocytes. This may be the consequence of cytoplasmic Ca2+ overload due to inhibition of forward mode or induction of reverse mode Na+/Ca2+ exchange. In end-stage failing human myocardium and during digitalis treatment this mechanism may be of major importance.

Adenoviridae↗
PubMed2001

FK506 does not affect cardiac contractility and adrenergic response in vitro.

FK506 (tacrolimus) is a new immunosuppressant being used in cardiac allograft transplantation. While cyclosporine A has been shown to exert an acute negative inotropic effect on isolated heart muscle preparations, little is known of the inotropic influence of FK506. The Ca(2+) release channel of human skeletal muscle and cardiac muscle is associated with FK506 binding proteins (FKBP), FKBP12 and FKBP12.6, respectively. FKBPs can be dissociated by treatment with FK506. As a consequence of FK506 exposure, isolated skeletal muscle and cardiac muscle ryanodine receptors show altered gating characteristics. Therefore, we analyzed the direct inotropic effect of FK506 exposure to isolated, intact heart muscle preparations from the human and rabbits. Experiments were performed on isolated, electrically stimulated right atrial auricular muscle strips obtained from human myocardium during elective open heart surgery and on intact right ventricular trabeculae from rabbit hearts. The human preparations were exposed to concentrations of 8 x 10(-9), 8 x 10(-8) and 8 x 10(-6) M FK506 followed by a cumulative dose-response curve with isoprenaline as a non-selective beta-adrenoceptor agonist. Our data suggest that FK506 does not exert any positive or negative inotropic effect in either human or rabbit myocardium.

Adrenergic beta-Agonists↗
PubMed2001

Maintained contractile reserve in a transgenic mouse model of myocardial stunning.

Cardiac excitation-contraction (E-C) coupling is impaired at the myofilament level in the reversible postischemic dysfunction known as "stunned" myocardium. We characterized tension development and calcium cycling in intact isolated trabeculae from transgenic (TG) mice expressing the major proteolytic degradation fragment of troponin I (TnI) found in stunned myocardium (TnI(1-193)) and determined the ATPase activity of myofibrils extracted from TG and non-TG mouse hearts. The phenotype of these mice at baseline recapitulates that of stunning. Here, we address the question of whether contractile reserve is preserved in these mice, as it is in genuine stunned myocardium. During twitch contractions, calcium cycling was normal, whereas tension was greatly reduced, compared with non-TG controls. A decrease in maximum Ca2+-activated tension and Ca2+ desensitization of the myofilaments accounted for this contractile dysfunction. The decrease in maximum tension was paralleled by an equivalent decrease in maximum Ca2+-activated myofibrillar ATPase activity. Exposure to high calcium or isoproterenol recruited a sizable contractile reserve in TG muscles, which was proportionately similar to that in control muscles but scaled downward in amplitude. These results suggest that calcium regulatory pathways and beta-adrenergic signal transduction remain intact in isolated trabeculae from stunned TG mice, further recapitulating key features of genuine stunned myocardium.

Adrenergic beta-Agonists↗
PubMed2000

Transgenic mouse model of stunned myocardium.

Stunned myocardium is a syndrome of reversible contractile failure that frequently complicates coronary artery disease. Cardiac excitation is uncoupled from contraction at the level of the myofilaments. Selective proteolysis of the thin filament protein troponin I has been correlated with stunned myocardium. Here, transgenic mice expressing the major degradation product of troponin I (TnI1-193) in the heart were found to develop ventricular dilatation, diminished contractility, and reduced myofilament calcium responsiveness, recapitulating the phenotype of stunned myocardium. Proteolysis of troponin I also occurs in ischemic human cardiac muscle. Thus, troponin I proteolysis underlies the pathogenesis of a common acquired form of heart failure.

Actin Cytoskeleton↗
PubMed1999

Force responses of skinned molluscan catch muscle following photoliberation of ATP.

Isometric force responses following flash photolysis of caged-ATP were measured from skinned preparations of the catch muscle anterior byssus retractor of Mytilus (ABRM). When fibres were transferred from Ca(2+)-free to Ca(2+)-containing rigor solution (pCa < 4) the force remained low, but flash photolysis produced an extended force increase (half-time, 0.30 +/- 0.07 s, n = 6). When Ca(2+)-activated fibres were transferred to a Ca(2+)-free rigor solution, their force remained at a high level. Flash photolysis produced a rapid force decay (half-time, 0.28 +/- 0.06 s, n = 9) to about 19% of the initial Ca(2+)-activated force. In the presence of 0.5 mM MgADP, the force increase was slowed down by a factor of 3 and the force decay by a factor of 5. These effects of MgADP on crossbridge kinetics are comparable to those observed in vertebrate smooth muscle and are thought to cause "latch", a catch-like state (Fuglsang et al. J Muscle Res Cell Motil 14:666-677, 1993). They are consistent with a model implicating competition between MgADP and MgATP for the nucleotide-binding site on crossbridges. Considering the relatively fast force responses induced by caged-ATP photolysis, even in the presence of MgADP, it appears unlikely that the detachment of crossbridges from the rigor state can account for catch-related processes. In view of the low myosin ATPase under maximal activating conditions (0.6 s-1, Butler et al. Biophys J 75:1904-1914, 1998), neither crossbridge attachment nor detachment of rigor crossbridges seems to be the rate-limiting processes of the crossbridge cycle.

Adenosine Diphosphate↗
PubMed1999

Ca2+ sensitivity of stunned myocardium after skinning using retrograde infusion of detergent.

Myofilament Ca2+ desensitization contributes to the contractile dysfunction of ischemic/reperfused ("stunned") myocardium. We examined the presence of reduced Ca2+ sensitivity of isometric force in chemically skinned fibers obtained from stunned myocardium using different modes of applying the detergent Triton X-100. Langendorff-perfused rat hearts underwent 20 min ischemia/20 min reperfusion, which caused a 35 +/- 3% decrease in left ventricular developed pressure, compared to continuously perfused control hearts. Stunned and control hearts were randomly allocated to two different permeabilization protocols: In group A, trabeculae were dissected and immersed in skinning solution containing 1% Triton X-100 for 20 min. Group B hearts remained fixed to the aortic cannula and skinning solution was infused retrogradely for 6 min prior to dissection of trabeculae. Extraction of cytosolic marker proteins was more complete in group-B than in group-A preparations. Group-A preparations from stunned hearts exhibited significant Ca2+ desensitization (pCa50 = 5.07 and 5.15 in stunned and control myocardium, respectively). In group B no such difference was observed, all preparations showing higher Ca2+ sensitivity and maximum force than group-A preparations (pCa50 = 5.32 in stunned versus 5.33 in control hearts). Prolonging group-A skinning to 150 min also abolished the difference in Ca2+ sensitivity between stunned and control myocardium. In conclusion, compared to a conventional protocol, skinning by perfusion results in more complete permeabilization and better preservation of myocardial contractile function. Ischemia/reperfusion at this moderate degree of contractile dysfunction induces Ca2+ desensitization at least partially by factors that can be extracted by thorough skinning.

Animals↗
PubMed1998

Replacement of troponin-I in slow-twitch skeletal muscle alters the effects of the calcium sensitizer EMD 53998.

We extracted troponin-I (TnI) from skinned rat and rabbit soleus muscle fibres using a modification of the method described by Strauss et al. (FEBS Lett 310:229-234, 1992) for replacement of TnI in cardiac preparations. Incubation of soleus muscle fibres with 10 mmol/l vanadate virtually completely abolished the Ca2+dependence of force. Immunoblot analysis revealed that more than 80% of TnI had been extracted from the preparations. The Ca2+dependence of force was restored by incubation with a complex of cardiac TnI (cTnI) and troponin-C (cTnC). We examined the effects of the Ca2+-sensitizing compound EMD 53998 on isometric tension in native porcine cardiac and rabbit soleus skinned fibres as well as soleus in which the endogenous slow skeletal TnI (ssTnI) had been replaced by cTnI (soleus-cTnI). It was found that 10 micromol/l EMD 53998 in native soleus increased maximum Ca2+-activated force to 120+/-1.4% of control. In soleus-cTnI fibres, maximum force was increased to only 105+/-0.9%, which was similar to the effect observed in cardiac muscle (108+/-0.6%). In cardiac muscle, 10 micromol/l EMD 53998 induced a leftward shift of the pCa-tension relation by 0.65 log units. In native soleus, DeltapCa was only 0.40. Again, the effect of EMD 53998 on soleus-cTnI (DeltapCa=0.56) more closely resembled the response found in cardiac muscle than that observed in native soleus muscle. The apparent TnI-isoform dependence of the effects elicited by EMD 53998 suggests that its actions are modulated by the regulatory proteins of the thin filament.

Animals↗
PubMed1997

Cardiac contractility: modulation of myofibrillar calcium sensitivity by beta-adrenergic stimulation.

Under conditions of beta-adrenergic receptor stimulation, cardiac performance is enhanced. cAMP-dependent phosphorylation of proteins located in the sarcolemma, in the membrane of the sarcoplasmic reticulum (SR), and in the myofibrils of the cardiomyocytes, mediates the effects of catecholamines on the heart. Altered Ca2+ handling leads to increased levels of intracellular free Ca2+. This is mainly responsible for the enhanced contractility of the myocardium that can be observed following beta-adrenergic receptor stimulation. Phosphorylation of the thin filament regulatory protein troponin I (TnI), on the other hand, decreases the Ca2+ sensitivity of the myofilaments, which means that the Ca2+ concentration necessary for the development of half-maximal force is increased. Cardiac TnI has a 26-33 amino acid N-terminal extension that is not present in fast and slow skeletal muscle TnI isoforms. Within this segment, two adjacent serine residues can be phosphorylated by a cAMP-dependent protein kinase. Replacement of endogenous TnI by different mutants obtained using site-directed mutagenesis of one or both of the serine residues has shown that only the bis-phosphorylated form decreases the Ca2+ sensitivity. This Ca2+ desensitizing effect, together with an increased rate of Ca2+ uptake into the SR due to phosphorylation of the SR membrane protein phospholamban, is responsible for the relaxation-enhancing effect (lusitropic action) of catecholamines. The latter is an important determinant of coronary perfusion and rapid diastolic filling of the ventricles, and is also a prerequisite for the elevation of heart rate that accompanies beta-adrenergic receptor stimulation.

Animals↗
PubMed1991

Peptide competition of actin activation of myosin-subfragment 1 ATPase by an amino terminal actin fragment.

The amino-terminal region of actin participates in the binding of myosin subfragment 1 (S1) during cross-bridge cycling, thereby assisting in the activation of the magnesium-dependent myosin ATPase. Effects of three actin fragments on the magnesium-dependent S1 and acto-S1 ATPase activities in solution were studied. One of the peptides, containing residues actin 1-44, mimicked the S1 ATPase-activating properties of actin and in turn inhibited acto-S1 ATPase both in a concentration-dependent manner. This suggests peptide competition for the actin binding site on myosin. The other fragments, residues actin 1-18 and 82-119, respectively, had no detectable effect on S1- and acto-S1 ATPase activity.

Actins↗
PubMed1987

[Computer-assisted implementation of the MMPI test].

In a research programme lasting one year a computer-supported technique for the MMPI-Test has been developed in co-operation of the Clinical-Psychology and the Bio-Medical. Engineering Departments. The use of the microelectronically operated test apparatus has proved extremely economic.

Computers↗