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H Lüllmann

Publications and source records attributed to H Lüllmann.

At least 37 records · Page 2Linked to original sources
PubMed1987

Critical remarks on the Ca-flux determinations in smooth and cardiac muscle.

The commonly used methods of determining Ca fluxes in smooth and cardiac muscle are scrutinized for their appropriateness. These methods include an incubation of the tissue in 45Ca, followed by a washout period either in ice-cold EGTA-containing Ca-free solutions or in lanthanum-containing Ca-free solutions. The amount of 45Ca remaining in the tissue at the end of the washout phase is taken as Ca2+ influx during the labeling period. Procedures including longer washout periods cannot yield information on Ca2+ influx, since the Ca store relevant for contractile activation rapidly adapts to changes in the extracellular Ca2+ concentrations.

Animals↗
PubMed1987

High and concentration-proportional accumulation of [3H]-nitrendipine by intact cardiac tissue.

The binding of [3H]-nitrendipine to intact, electrically driven isolated left atria of guinea-pigs was investigated over the concentration range 10(-10) M to 3 X 10(-5) M. A high affinity binding site saturable in the nM range as found in ventricular homogenates could not be detected. Instead the accumulation of nitrendipine in intact atria was found to be proportional to the concentration from 10(-10) M to 10(-6) M; beyond 10(-6) M the binding started to become saturated. Nitrendipine was highly accumulated in atrial tissue. The cell:medium ratios amounted to about 120 in the range from 10(-10) M to 10(-6) M. The concentration-response curve for the negative inotropic action of nitrendipine yielded an ED50 of 3 X 10(-7) M, thus lying within the range of concentration-proportional accumulation. The reduction of the contractile force proceeded faster (t1/2 less than 10 min) than the uptake process t1/2 approximately 40 min) suggesting that it is the binding of nitrendipine into a superficial compartment, which interferes with the excitation-contraction coupling. The results suggest that the high concentration of nitrendipine present in hydrophobic cellular compartments such as the plasmalemma might be involved in its pharmacological action.

Animals↗
PubMed1986

Responses to hypertonic solutions in guinea-pig atria: changes in action potentials, force of contraction and calcium content.

In left atria of guinea-pig hearts we studied the effects of Tyrode solution made hypertonic by the addition of mannitol (50 to 300 mosm/l). Electrical and mechanical performance were investigated at 0.1, 1 and 3 Hz. Up to 150 mosm/l a positive inotropic effect was observed, addition of 300 mosm/l caused a positive inotropic response followed by a long lasting negative inotropic effect. The positive inotropic effect depended on the frequency of stimulation: at the low frequency of 0.1 Hz the increase in force of contraction was so large, that in hypertonic solution the absolute value of developed tension at 0.1 Hz was actually larger than at 3 Hz. With 150 mosm/l mannitol the time to peak tension and the twitch duration were prolonged. These effects were also most prominent at 0.1 Hz. The action potential duration was shortened; the membrane hyperpolarized. The observed changes in action potential duration and the membrane hyperpolarization may reflect changes in cation concentration due to cellular dehydration. The propagation velocity of excitation was reduced in the absence of a detectable decrease in maximum rate of depolarization during the upstroke of the action potential. The cells did not behave as perfect osmometers because loss of tissue water as estimated from wet weight and dry weight measurements was smaller than expected for a 1.5-fold increase in tonicity. After having established complete exchange of tissue calcium with 45Ca, hypertonicity-induced changes in the cellular calcium content could be determined by changes in 45Ca content. At both frequencies of stimulation, the cellular calcium content increased to the same extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1985

On the cooperativity of ouabain-binding to intact myocardium.

A theoretical concept is presented which proposes that binding of ouabain to intact myocardium should be positive cooperative. It is based on the assumption that the myocardial Na/K-ATPases expose the ouabain-binding site only at a particular conformation adopted during a turnover cycle. The turnover rate and thus the ouabain-binding properties are regulated by the cytosolic Na-ion-concentration Nai. Any occupation of cellular Na/K-ATPases should affect the ouabain-binding properties of the unoccupied Na/K-ATPases, because their turnover rate is increased via an elevated Nai. A computer model which takes into account the interrelationships of the Na/K-ATPases both with Nai and with the ouabain-concentration predicts that ouabain-binding should proceed in a concentration-proportional fashion as long as the Na-load can be counterbalanced by non-occupied Na/K-ATPase molecules. The concentration-proportional binding reflects a positive cooperativity. Experimental results reveal that (3H)ouabain-binding to Na/K-ATPase of electrically stimulated guinea-pig left atria was in fact concentration-proportional under certain experimental conditions. The biological significance of the proposed concept remains to be elucidated.

Animals↗
PubMed1985

pH-dependent accumulation of fentanyl, lofentanil and alfentanil by beating guinea pig atria.

The influence of the pH of the incubation medium on the cellular accumulation of tritiated fentanyl, lofentanil, and alfentanil was investigated in isolated guinea pig atria. Fentanyl and lofentanil accumulated in atrial tissue up to about 30- and 50-fold, respectively. The amount of drug bound when equilibrium was attained was found to be dependent upon the pH of the medium. By plotting binding equilibria v. pH of the bath, curves were obtained which resembled titration curves. Half-maximal binding was attained at pH values close to the pKa values of fentanyl and lofentanil. Alfentanil was found to accumulate less. The uptake by the tissue was strongly proportional to the extracellular concentration. Atria equilibrated with fentanyl at pH 8.5 released the compound rapidly when exposed to a pH of 7.0, even in the continuous presence of fentanyl in the bath. The consequences of the findings for in vivo conditions are discussed with respect to a possible augmentation of the actions of fentanyl by respiratory acidosis.

Alfentanil↗
PubMed1985

Effects of aminoglycoside antibiotics on bound calcium and contraction in guinea-pig atria.

We studied the effect of three aminoglycoside antibiotics which have been shown to replace Ca from lipid monolayers on the superficially bound Ca of isolated beating left atria from guinea-pigs. The cellular Ca content was determined by means of 45Ca after having attained complete exchange. The antibiotics dibekacin, sisomicin, and gentamicin, all reduced the cellular Ca content by 10-20% in a dose-dependent manner. The loss of superficially bound Ca was accompanied by a decline of the contractile force by 40-90%. It is concluded that in isolated atrial muscle it is the amount of Ca bound to the outer surface of the cardiac plasmalemma, rather than the extracellular Ca2+ concentration, that determines contraction height.

Aminoglycosides↗
PubMed1984

Cardiac glycosides with different effects in the heart.

Remarkable differences exist between the effects of different cardiac glycosides (native and semi-synthetic) with respect to the affinity and to the magnitude of inotropic responses and their time courses. At glycoside concentrations which lead to identical Na-K-ATPase inhibitions, the inotropic responses vary widely. This finding contradicts the hypothesis that the increase of contractile force is the consequence of an ATPase inhibition and causally related to it. We propose the hypothesis that the inhibition of ATPase and the inotropic stimulation provoked by cardiac glycosides are two parallel events, not causally related but both mediated by the same receptor. The inhibition of the Na-K-ATPase is the consequence of the occupation and thus proportional to the concentration of the glycoside-ATPase complexes. In contrast, the inotropic response is determined by the frequency of glycoside-ATPase-interactions. Glycosides which possess high association and dissociation rate constants will interact with the ATPase with high frequencies and thus will evoke larger inotropic responses at a given ATPase inhibition than glycosides with low turnover rates.

Animals↗
PubMed1983

Influence of various cationic amphiphilic drugs on the phase-transition temperature of phosphatidylcholine liposomes.

The influence of 16 cationic amphiphilic compounds from various pharmacological groups on the phase-transition temperature (Tt) of dipalmitoyl-phosphatidylcholine (DPPC) liposomes was investigated using the method of differential scanning calorimetry. All drugs, the hydrophobicity of which varied in a wide range, depressed Tt. Biphasic dose-effect curves were obtained when the reduction of Tt (delta Tt) was plotted vs the molar ratio of drug/DPPC; beyond a plateau, Tt could again be reduced markedly by increasing the molar ratio. Concomitantly with the depression of Tt, the width of the transition peak changed in a characteristic way: it broadened during the (first) steep part of the dose-effect curves and became narrow like a control transition when the plateau of the dose-effect curves was reached. At still higher ratios the peak broadened again and eventually vanished, probably due to a detergent-like effect of the drug. Increasing hydrophobicity of the compounds shifted the dose-effect curves to lower molar ratios and enhanced the delta Tt attained at the plateau phase. It is proposed that the different potencies of the drugs to depress Tt result from different binding equilibria between the compounds and DPPC membranes, the individual equilibrium being determined by hydrophobic attraction and electrostatic repulsion.

Anions↗
PubMed1983

Influence of cationic amphiphilic drugs on the characteristics of ouabain-binding to cardiac Na+/K+-ATPase.

The influence of 12 cationic amphiphilic compounds on the equilibrium and kinetic characteristics of the binding of tritium-labelled ouabain to the lipoprotein Na+/K+-ATPase present in a crude membrane suspension of guinea pig myocardium was investigated. The drugs, e.g. local anaesthetic, antiarrhythmic and psychotropic agents, inhibited specific binding of ouabain in a concentration-dependent manner by reducing its affinity without affecting the number of binding sites. In the presence of chlorpromazine, propranolol and dibucaine, the decreased affinity of ouabain was due to both a diminished association rate and an increased dissociation rate, while in the presence of the weakly potent procaine only the association rate of ouabain was found to be reduced. The different potency of the catamphiphilic drugs was well correlated to the degree of their hydrophobicity. Evidence is presented that the protonized form of the drugs is the effective one. Concerning the mode of action, the catamphiphilic drugs are proposed to interact with the phospholipid part of the lipoprotein Na+/K+-ATPase, thereby indirectly altering the conformation of the embedded protein moiety and thus reducing the proper fit between ouabain and its receptor.

Animals↗
PubMed1983

Electrophysiological studies of some semisynthetic cardiac glycoside derivatives in isolated papillary muscle of the guinea-pig.

The effects of digitoxin, 3 alpha-methyl-digitoxigenin-3 beta-monoglucoside (3 alpha-MDM), 3 alpha-methyl-digitoxigenin (3 alpha-MD), proscillaridin, 4, 5-methylene-procillaridin (4, 5-MP), and 3 beta-hydroxy-4, 5-methylene-A, B-trans-scillarenin (3 beta-HMTS) on force of contraction and on the transmembrane action potentials were examined in isolated papillary muscles of guinea-pigs. All derivatives exhibited the typical cardiac glycoside effects: i.e. they increased the force of contraction and shortened the action potential duration at 20% (plateau phase) and 90% of repolarization. With digitoxin, 3 beta-HMTS and 4, 5-MP a transient prolongation in action potential duration was observed at the lower concentrations. The action potential amplitude and the resting membrane potential were reduced consistently only with the higher concentrations used. The onset of the positive inotropic effects of 3 alpha-MDM, 3 alpha-MD and 3 beta-HMTS was more rapid than that of digitoxin and proscillaridin. The increment in contractile force reached a maximum well before the full shortening effect on the action potential duration had developed. The shortening of the action potential is thought to be responsible for the biphasic nature of the positive inotropic effect. With 3 alpha-MD and 3 alpha-MDM even toxic effects, e.g. increase in baseline tension, were completely reversible after washing in drug-free solution. The dose-response curves for the positive inotropism can only be compared reliably once the equilibrium of drug action has been established. This steady state is probably reflected by the development of the full shortening in action potential duration.

Action Potentials↗
PubMed1982

An interaction of aminoglycoside antibiotics with Ca binding to lipid monolayers and to biomembranes.

Thirteen aminoglycoside antibiotics were investigated with respect to their ability to replace Ca from phosphatidylserine monolayers. The affinities of the glycosides for the Ca-binding sites depended on the pH and the Ca2+ concentration of the aqueous subphase. At a Ca2+ concentration of 1.2 X 10(-5)M and a pH of 7.5 the half maximum concentrations to replace Ca were found to range from 0.4 X 10(-6) (sisomicin) to 6 X 10(-6)M (streptomycin). The interaction between the streptomycins and Ca were of a competitive nature, whereas the aminoglycoside antibiotics with higher affinities displayed unusual steep dose-response curves suggesting positive cooperativity. The aminoglycoside antibiotics were also able to replace Ca from biomembranes (red cell ghosts and isolated sarcolemma of cardiac muscle) in a dose-dependent manner. The high affinity of aminoglycoside antibiotics to a phospholipid is considered to be involved in the toxic side effects of these antibiotics, e.g. nephrotoxicity and impairment of contractile force.

Aminoglycosides↗
PubMed1982

On the binding of a 3-alpha-methylated digitoxigenin-glucoside to ouabain receptors in heart muscle homogenate.

3-alpha-Methyl substituted digitoxigenin-3-beta-glucoside (methyl-dtg-gluc) displays unusual features, e.g. a high dissociation rate constant from its binding site leading to rapid reversibility of the inotropic and toxic effects, and a flat dose-response curve attaining higher inotropic maxima thus indicating an increased therapeutic index in animal experiments. In order to check whether or not methyl-dtg-gluc is specifically bound to the same receptors as classic cardiac glycosides we compared binding of ouabain and of methyl-dtg-gluc to guinea-pig heart muscle homogenate. For both compounds specific binding required the addition of ATP (2.5 mM). The binding curve for ouabain yielded half maximum binding at 1.3 x 10(-7) M and maximum number of binding sites of 6 pmole/mg protein; the corresponding values for methyl-dtg-gluc amounted to 1.4 x 10(-6) M and 6 pmole/mg protein, respectively. A mutual competition could be demonstrated between the two compounds. Since the provided data are equilibrium values they do not exclude higher turnover rates of methyl-dtg-gluc in comparison with ouabain at a given glycoside-ATPase complex concentration which can be expected from the fast dissociation rate constant of the methyl-dtg-gluc-ATPase complex. The results are briefly discussed with respect to the molecular mole of action of cardiac glycosides.

Animals↗
PubMed1982

Comparison of atropine and dexetimide in treatment of intoxications by selected organophosphates.

Mice and guinea pigs were intoxicated by three different organophosphates: DFP, paraoxon, and OMPA. After onset of intoxication the animals were treated by either a mixture of atropine plus obidoxim or dexetimide plus obidoxim. The combination of dexetimide plus reactivator proved to be superior to the combination of atropine plus reactivator in case of DFP intoxication. In guinea pig the LD50 of DFP could be increased from about 20 to 1300 micrometers/kg b.wt. by dexetimide plus obidoxim when applied after the onset of intoxication. Concerning the paraoxon intoxication both antidote mixtures were found to be equally potent, whereas the purely peripheral intoxication induced by OMPA could only be influenced to a minor degree. The tissue distribution of atropine and dexetimide differs markedly, dexetimide being accumulated faster and to a higher degree. Thus the higher penetration rate of dexetimide into the central nervous system is considered to be the reason of its superiority in the treatment of an organophosphate intoxication of rapid onset.

Animals↗
PubMed1981

Impairment of renal function in rats with generalized lipidosis as induced by chlorphentermine.

The purpose of this work was to study the impact of experimentally induced lipidosis upon renal function. Rats were orally treated up to 12 weeks with the anorectic drug chlorphentermine at dosages of 20 and 50 mg/kg, respectively. During the course of treatments the following parameters were determined: plasma urea level, creatinine clearance, ability of the kidneys to concentrate the urine after acute deprivation of drinking water, and to dilute the urine after acute water load. Morphological examination confirmed generalized lipidosis affecting kidney and many other organs. Chronic treatments with both drug dosages caused a rise of plasma urea level. Treatment with the high dosage caused a significant reduction of creatinine clearance and significant impairment of both abilities to concentrate and to dilute the urine. The findings demonstrate that serve generalized lipidosis as induced by high doses of chlorphentermine is associated with significant impairment of renal function.

Animals↗