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Biomedical subjects

H Lüllmann

Publications and source records attributed to H Lüllmann.

At least 55 records · Page 3Linked to original sources
PubMed1980

Accumulation of drugs by guinea pig isolated atria. Quantitative correlations.

The time course of the tissue accumulation of 16 neutral, cationic, and anionic drugs by resting and 2-Hz stimulated atria of the guinea pig was measured. The accumulation of the substances was quantified by means of their tissue to medium ratios (T/M). Auricles driven with 2 Hz accumulated the drugs faster and during a long period of time to a greater extent than resting atria. By extrapolation of the binding characteristics, the final equilibrium T/M values were estimated. The variance in these accumulation data at equilibrium (log T/M) Could be best described by a linear combination of log P (octanol/water) and the ability of the drugs to bind to atrial homogenate (log percent bound/percent free). A parameter calculated from protein binding appeared less significant. Comparable results were obtained for the accumulation data measured in resting and 2-Hz stimulated atrial muscles. It is suggested that the degree of accumulation of drugs into atrial tissue is determined by the facility of their penetration of the plasma membrane and the extent of their intracellular binding.

Animals↗
PubMed1979

Accumulation of drugs by resting or beating cardiac tissue.

The rate and degree of accumulation of 12 neutral, anionic and cationic drugs were studied in resting and 2 Hz-stimulated isolated left auricles of the guinea pig. The uptake process was accelerated in muscles driven electrically. The time needed to reach equilibrium was related to the extent of accumulation which in turn corresponded with the lipophilicity of the drug. The frequency-induced changes in the kinetics of the accumulation disappeared under reduced mechanical activity of the muscle. It is suggested that the increased mechanical activity enhances drug disposition within the extracellular space, so that more drug is available for transmembrane penetration.

Animals↗
PubMed1978

Perhexiline induces generalized lipidosis in rats.

Administration of perhexiline (Pexide) to rats causes generalized occurrence of lamellated and crystalloid cytoplasmic inclusions which resemble those described in patients with perhexiline-induced polyneuropathy. It is concluded that perhexiline being an amphiphilic cationic compound is a potent inducer of generalized lipidosis.

Animals↗
PubMed1977

Interdependence of ion transport and the action of quabain in heart muscle.

1 The influence of ouabain (0.4 muM) on contractile force and cellular Na and K concentrations was investigated in isolated left atria of the guinea-pig at rest and at different beat frequencies. Simultaneously the binding of ouabain to the tissue was determined.2 Strict dependence of rates of onset of positive iontropic action and of binding of ouabain on beat frequency are limited to conditions where no alterations of cellular Na and K concentrations occur. A correlation was observed between sodium flux per unit time and the development of positive inotropism and binding to the receptors of ouabain.3 Ouabain exerts its positive inotropic effect without affecting the intracellular Na and K concentrations in spite of the fact that under these conditions even the majority of binding sites, i.e. Na-K-adenosine triphosphatases (Na-K-ATPases), are occupied by the drug. The positive inotropic effect may be explained by a ouabain-induced conformational alteration of the Na-K-ATPase which leads to structural alterations of the plasmalemma connected with an increased availability of coupling calcium.4 Increasing the frequency of stimulation over a critical value, which appears to be determined by an overloading of the Na pump, induces a decrease in contractile force, cellular accumulation of Na and loss of K, and eventually contracture.5 The rate of binding of ouabain appears to depend on the actual concentration of particular conformations of the Na-K-ATPase with high affinity for ouabain. These conformations transiently occur during a pumping cycle and their concentration may therefore be dependent on the frequency of cycling which in turn is determined by the frequency of contraction.6 Ouabain can easily be washed out from the tissue irrespective of the condition of the muscle. If, however, the intracellular Na and K homeostasis is impaired, the inhibition of the pump persists even if ouabain is released from the binding sites upon wash-out. It is suggested that the inhibition of the pump is maintained by an increased intracellular Ca ion concentration and a depletion of ATP.7 A kinetic model is proposed for the interaction between cardiac glycosides and the Na-K-ATPase in intact heart muscle cells.

Animals↗
PubMed1976

Stereoselective binding in cardiac tissue of the enatiomers of benzetimide, and antimuscarinic drug.

1 Benzetimide, possessing two stable enantiomers, dexetimide and levetimide, has been investigated in guinea-pig atria with respect to its atropine-like action and its tissue distribution. 2 The antagonistic potency of dexetimide was found to be over 6000 times higher than that of levetimide, the pA2 values being 9.82 and 6.0 respectively. 3 The tissue accumulation was investigated for both isomers in the concentration range from 1.5 X 10(-9) M to 10(-6) M yielding tissue to medium ratios (T/M) of between approximately 50 and 10. The highest values were found for the lowest concentrations. At any concentration investigated, dexetimide exhibited a higher uptake than the levoisomer. 4 The rate of uptake and washout of dexetimide was extremely slow, that of levetimide being considerably faster at equimolar concentrations. The same pattern held true for the onset and decline of the antagonistic action. 5 The high accumulation was found to be almost entirely due to unspecific binding. Even in the case of dexetimide the relative size of the receptor compartment could not be determined. The unspecific binding sites displayed a certain stereoselectivity but to a much lesser extent than the specific receptor binding sites.

Animals↗
PubMed1976

On the sarcolemmal site of action of cardiac glycosides.

An electron microscopic study of the guinea pig myocardial cell was conducted. By the use of LaC13, two morphologically distinct tubular systems could be demonstrated. The larger one represents the transverse tubular system which originates from the plasma membrane and is continous with the extracellular space (ECS). In the heart muscle cell it forms a three-dimensional network and it closely apposed to the myofilaments at the level of the Z and I bands. A comparatively small and sparsely developed tubular system which is not accessible from the ECS represents the sarcoplasmic reticulum (SR). By means of sucrose-density centrifugation in a discontinuous gradient two main microsomal fractions were obtained (F1 and F3). The pre-existing structure of F1 could be identified as the transverse tubular system, whereas F3 originates from the SR. The morphological features (e. g., an enclosed basement membrane) and the fact that after perfusion of hearts with [3H] inulin and preparation of microsomes the ECS marker is almost completely retained in F1 indicate that upon fractionation and vesiculation inside-out vesicles are formed which trap the former extracellular fluid. Moreover, the former extracellular surface is hidden and no longer accessible for membrane-impermeable compounds. After perfusion of hearts with [3H] ouabain and fractionation and centrifugation the radioactive material was found to accumulate in F1, the kinetics being identical with that of binding to the intact tissue and with the time course of the inotropic action of ouabain. The inside-out vesicles derived from the plasma membrane are characterized by the presence of a (Na+-K+)-ATPase activity, an outward Ca pump, a high binding capacity for Ca, and a low Ca pereability. Since the (Na+-K+)-ATPase is known to react with cardiac glycosides (CG) at the outer cell surface it was not surprising to find a complete lack of inhibition of the enzyme by the membrane-impermeable CG ouabain if administered to the intact sarcolemmal microsome. After disruption of the microsomes, however, a considerable inhibition of the (Na+-K+)-ATPase became demonstrable. Similarly, the Ca permeability of the plasma membranes could only be enhanced by CG if interacting with the former outside. Although ouabain again failed to exert any action, the membrane permeable digoxin increased the Ca pereability of the intact vesicular membrane. The rate of Ca transport as an indicator of the Ca pump activity remained unaffected by CG provided from either side of the membrane. The passive Ca binding to the plasma membrane, which results in a concentration up to 5 mM in this structure, is thought to represent the Ca pool essential for excitation-contraction coupling. The CG are thought to alter the Ca binding in this pool, thus rendering depolarization more effective in releasing Ca++.

Adenosine Triphosphatases↗
PubMed1975

Influence of ouabain and dihydroouabain on the circular dichroism of cardiac plasmalemmal microsomes.

1. The influence of ouabain on the tertiary structure of cardiac plasmalemmal proteins was investigated by means of circular dichroism measurement. Purified plasmalemmal microsomes were obtained by sucrose gradient centrifugation. The CD-spectra of the membranal proteins were shifted to the red and the amplitudes were smaller than those of the same proteins after solubilization. 2. Ouabain induced an increase of the ellipticity bands at 210 and 222 nm of about 50% above the level yielded with microsomes after sonication. At 222 nm ouabain exhibited the half maximum effect at a concentration of 5 X 10(-9) M. The effect could, however, only be exerted if the inside of the microsomes was exposed to ouabain by sonication, thus reflecting the inside-out nature of the plasmalemmal microsomes. 3. The high specificity of the ouabain effect was underlined by the following experiments: a) Dihydroouabain, a much less cardioactive derivative of ouabain proved to be ineffective in corresponding concentrations, b) ouabain had no influence upon the CD spectrum of microsomes derived from cardiac sarcoplasmic reticulum, c) a detergent-like action of ouabain underlying the observed effect can be excluded since highly active tensides, i.e. desoxycholate and dodecylsulfate, only influence the CD spectra at concentrations exceeding 10(-3) M, d) electronmicrographs of microsomes exposed to ouabain demonstrated no alteration of either the appearance or size of the microsomes. 4. The magnitude of the observed ouabain effect indicates that a large portion of the membrane-bound proteins is involved. The number of binding sites and their isolated structural alteration induced by ouabain are not sufficient to account quantitatively for the enhanced amplitudes of the CD spctra. This suggests that ouabain evokes structural changes of membrane proteins different from actual binding sites. It seems, therefore highly improbable that changes of the Na-K-ATPase present in the plasmalemmal microsomes are responsible for the observed effect.

Animals↗