Die Wirkung des k-Strophanthins und Prednisolonbisguanylhydrazons auf die Membran-ATPase des Herz- und Skeletmuskels

Ohne Zusammenfassung     

Die Beeinflussung des durch verschiedene fiebererzeugende Stoffe erregten Temperaturzentrums durch lokale Applikation von Ca,K und Na

Ohne ZusammenfassungMit 8 Textabbildungen.     

Die Empfindlichkeit der Nebennieren von Katzen auf Cholin und Azetylcholin

Naunyn-Schmiedeberg's Archives of Pharmacology -     

Die Wirkung von Phenobarbital und Diphenylhydantoin auf verschiedene Fettfraktionen der Leber

Ohne Zusammenfassung     

Unterschiede in der Empfindlichkeit verschiedener RNS-Synthese-Reaktionen gegenüber Actinomycin C1

Ohne Zusammenfassung     

Involvement of tropomyosin in the sensitivity of Na+ + K+ ATPase to ouabain

The Na⁺/K⁺ ATPase sensitivity to ouabain was shown to be increased by 300 to 1000-fold after treatment of the plasma membrane by EDTA. Addition of proteins detached from the plasma membrane with Ca²⁺ ions to EDTA treated membranes reconstituted the original Na⁺/K⁺ ATPase resistance to ouabain inhibition. Tropomyosin with Ca²⁺ ions (not with Mg²⁺ ions) induced the same effect. When suboptimal doses of tropomyosin were used for such a reconstitution, the dose-response curve indicated a full reconstitution of a given percentage of enzyme molecules. This observation led us to assume a direct or indirect effect of tropomyosin on Na⁺/K⁺ ATPase functions.     

Die Blutdruckwirkung des Protocatechualdehyds der Protocatechusäure und des Vanillins

Zusammenfassung Es wird an Hand von Kurven die blutdrucksteigernde Wirkung des Protocatechualdehyds, der Protocatechusäure und des Vanillins nachgewiesen und auf die gleiche Eigenschaft des Oxyhydrochinons verwiesen. Konstitution, Blutdruckeffekt und paradoxe Reaktion der genannten Substanzen weisen darauf hin, daß es sich um Stoffe der Adrenalinreihe handelt. Außerdem wird gezeigt, daß bei dem Abbau des Protocatechualdehyds zur -säure im Organismus auch die Blutdruckwirksamkeit abnimmt.Mit 12 Textabbildungen.     

Affinity and dose-dependent digoxin Na+K+ATPase dissociation by monoclonal digoxin-specific antibodies

The effect of three monoclonal digoxin-specific antibodies and of polyclonal Digidot^® as reference on digoxin dissociation from rat brain Na⁺K⁺ATPase microsomes was studied to determine the role of the affinity constant (Ka) and dose of the antibody on the rate of digoxin dissociation from Na⁺K⁺ATPase. Stoichiometrical doses of 1C10, 6C9, 9F5 IgG, and Digidot^® (Ka = 6 10⁹, 3.1 10⁸, 2.5 10⁷, and 8.5 10⁹ M⁻¹, respectively) resulted in digoxin dissociation related to Ka. When the IgG:digoxin molar ratio increased from 0.25 to 10, digoxin dissociation from Na⁺K⁺ATPase sites also increased according to the Hill equation, allowing comparative parameters among the three antibodies to be determined. 1C10 IgG was 2- and 10-fold more efficacious than 6C9 and 9F5, respectively. This in vitro model appears to be a useful predictive screening assay before in vivo experimentation.     

Physiological functions of (Na+ + K+)-adenosinetriphosphatase (ATPase) isozymes

Since Sweadner demonstrated that there are two isozymes (alpha and alpha(+) isoforms) of (Na+ + K+)-adenosine triphosphatase (ATPase) in the brain about 10 years ago, the isozymes have been extensively studied at biochemical and molecular levels. We started the studies on the isozymes of (Na+ + K+)-ATPase soon after finding that pyrithiamin, an antimetabolite of thiamin is a selective inhibitor of the alpha(+)isoform. This review summarizes the previous studies on the isozymes of (Na+ + K+)-ATPase, which are now classified into alpha 1, alpha 2, and alpha 3.     

Die Beeinflussung des Kaliumefflux am denervierten Rattenzwerchfell durch verschiedene Pharmaka

Ohne Zusammenfassung     

Die Haftung verschiedener Cardenolide am Papillarmuskel und einer mikrosomalen ATPase des Meerschweinchenherzens

Summary In experiments on isolated electrically stimulated guinea pig papillary muscles and on isolated cardiac Na⁺-K⁺-activated ATPase preparations the action and the reversibility of action of 3 different cardenolides-digitoxin, k-strophanthidin and strophanthidin-3-bromoacetate (SBA) (supposed to be an irreversible inhibitor of the transport ATPase)-were studied.The equieffective concentrations for maximum positive inotropic effects (around 90%) were 2×10^–6, 2×10^–5 and 4×10^–5 M, respectively. In washout experiments the positive inotropic action of all these substances was found to be completely reversible: the rates of decline of the positive inotropic effects were about 2.7%/min with digitoxin, 24%/min with strophanthidin and 22%/min respectivety 5.7%/0/min (two components) with SBA.The equieffective concentrations for maximum inhibition (90–95%) of the Na⁺-K⁺-activated ATPase by digitoxin, strophanthidin and SBA were 10^–4, 2×10^–4 and 10^–4 M respectively. In washout experiments (repeated centrifugations) different degrees of reversibility of these inhibitory effects were observed depending upon the experimental conditions. Preincubation of the enzyme with the cardenolides in theabsence of Na⁺, Mg²⁺ and ATP resulted in a persisting inhibition of the Na⁺-K⁺-ATPase of 14% with digitoxin, 10% with k-strophanthidin and- significantly higher (p < 0.05)-33% with SBA. Corresponding experiments with preincubation of the enzyme in thepresence of Na⁺, Mg²⁺ and ATP, however, demonstrated a full reversibility of the inhibitory action of all these substances.These results are in contrast, in certain respects, with those obtained in previous experiments on brain ATPase.It is concluded that SBA is able to inhibit irreversibly only the non-phosphorylated form of the cardiac Na⁺-K⁺-activated ATPase, whereas the phosphorylated intermediate of this enzyme seems to be protected against the irreversible inhibition by this substance. Assuming that the latter state of the enzyme is predominant in the intact heart muscle cell, a complete reversibility of the pharmacological action of SBA would be expected if the inotropic effect is mediated by an inhibition of the enzyme. Our results are compatible with this hypothesis.

Wir danken der Deutschen Forschungsgemeinschaft für die Unterstützung durch Sachbeihilfen und der Volkswagenstiftung für die Geräteausstattung.     

Enzyme modifications that alter interactions of K+ and cardioactive steroids with (Na+ + K+)-dependent ATPase

Treatment of a purified (Na ⁺ + K ⁺-dependent ATPase preparation from dog kidney medulla with acetic anhydride or trinitrobenzene sulfonate (TNBS) produced a dose-dependent irreversible inactivation of the (Na ⁺ + K ⁺)-ATPase and K ⁺-phosphatase reactions catalyzed by the enzyme. Both K ⁺ and the cardioactive steroid strophanthidin protected against inactivation. Prior treatment with concentrations of acetic anhydride or TNBS that produced only partial inactivation also modified the residual activity of the enzyme, as manifested by an increase in the K_0.5 for K ⁺ as activator of the phosphatase reaction (mediated through the moderate-affinity α-sites for K ⁺) but not in the K_0.5, for K ⁺ as activator of the ATPase reaction (mediated through the high-affinity β-sites for K ⁺): correspondingly. the I ₅₀ values (concentrations required to produce 50 per cent inhibition) for ouabain and strophanthidin as inhibitors of the ATPase reaction were increased, and the binding of [³H]ouabain was decreased, by such treatment. Ouabain activated the phosphatase reaction in the absence of K ⁺ and. alter similar treatment, the apparent affinity for ouabain as activator was also decreased. These experiments demonstrate interactions between cardioactive steroids at their sites on the extracellular face of this transmembrane enzyme and K ⁺ at its moderate-affinity α-sites on the intracellular face. and further indicate that K ⁺ can modulate enzyme-drug interactions at such sites, as well as through K ⁺ -sites on the extracellular face of the enzyme.     

Membrane Na+ K+ ATPase inhibition related dyslipidemia and insulin resistance in neuropsychiatric disorders

There are several reports in literature implicating cholesterol metabolism in the pathogenesis of neuronal degenerations, oncogenesis, functional neuropsychiatric disorders and multiple sclerosis. Biosynthesis of cholesterol takes place by the isoprenoid pathway, which also produces digoxin, an inhibitor of membrane Na(+)-K+ ATPase. Inhibition of this enzyme results in intracellular Mg++ deficiency which can influence cholesterol metabolism. Digoxin also influences transport of tryptophan and tyrosine which are precursors of various neurotransmitters. Alterations in digoxin, membrane Na(+)-K+ ATPase and also in neurotransmitters have been reported in the disorders mentioned above. In view of this, serum lipid profile, activity of plasma HMG CoA reductase (the major rate limiting step in the isoprenoid pathway), RBC membrane Na(+)-K+ ATPase activity, serum Mg++ concentration, concentration of digoxin and concentration of serum neurotransmitters were studied in some neuropsychiatric disorders. The serum serotonin level was increased while that of serum dopamine and noradrenaline was reduced. Serum digoxin levels were high and RBC membrane sodium-potasium ATPase activity and serum magnesium were reduced. There was a reduction in HDL cholesterol and increase in plasma triglycerides (pattern similar to insulin resistance and syndrome X) in most of the disorders studied. The HMG CoA reductase activity was high, the serum total cholesterol was increased while RBC membrane cholesterol was reduced in most of the cases. The significance of increased digoxin with consequent inhibition of membrane Na(+)-K+ ATPase in relation to changes in cholesterol metabolism and insulin resistance type of dyslipidemia is discussed in this paper.     

Vascular activation of K+ channels and Na+-K+ ATPase activity of estrogen-deficient female rats

The goal of the present study was to evaluate vascular potassium channels and Na⁺-K⁺-ATPase activity in estrogen deficient female rats. Female rats that underwent ovariectomy were assigned to receive daily treatment with placebo (OVX) or estrogen replacement (OVX + E2, 1 mg/kg, once a week, i.m.). Aortic rings were used to examine the involvement of K⁺ channels and Na⁺-K⁺-ATPase in vascular reactivity. Acetylcholine (ACh)-induced relaxation was analyzed in the presence of L-NAME (100 μM) and K⁺ channels blockers: tetraethylammonium (TEA, 5 mM), 4-aminopyridine (4-AP, 5 mM), iberiotoxin (IbTX, 30 nM), apamin (0.5 mM), charybdotoxin (ChTX, 0.1 mM) and iberiotoxin plus apamin. When aortic rings were pre-contracted with KCl (60 mM) or pre-incubated with TEA (5 mM), 4-aminopyridine (4-AP, 5 mM) and iberiotoxin (IbTX, 30 nM) plus apamin (0.5 μM), the ACh-induced relaxation was less effective in the ovariectomized group. Additionally, 4-AP and IbTX decreased the relaxation by sodium nitroprusside in all groups but this reduction was greater in the ovariectomized group. Estrogen deficiency also increased aortic functional Na⁺-K⁺ ATPase activity evaluated by K⁺-induced relaxation. L-NAME or endothelium removal were not able to block the increase in aortic functional Na⁺-K⁺ ATPase activity, however, TEA (5 mM) restored this increase to the control level. We also found that estrogen deficiency increased superoxide anion production and reduced nitric oxide release in aortic ring from ovariectomized animals. In summary, our results emphasize that the process underlying ACh-induced relaxation is preserved in ovariectomized animals due to the activation of K⁺ channels and increased Na⁺-K⁺ ATPase activity.     

Die jahreszeitliche Schwankung der Magnesiumempfindlichkeit und des Phosphatidgehaltes von Esculentenherzen

Zusammenfassung Als charakteristisches Zeichen der Magnesiumempfindlichkeit des nach der Straub-Fühnerschen Methode präparierten Esculentenherzens wurden zu einer bestimmten Jahreszeit neben Alternans und 21 Rhythmus Lucianische Perioden beobachtet. Die Konzentration an MgCl₂, die der normalen Ringerlösung zugesetzt wurde, betrug 0,01%. Dieser im Frühsommer beginnenden und im Frühherbst, in anderen Jahren auch später, abklingenden Magnesiumempfindlichkeit lief eine erhöhte Empfindlichkeit des Esculentenherzens gegen Sauerstoffmangel parallel.Gleichzeitig wurde der Phosphatidgehalt der Esculentenherzen zu verschiedenen Jahreszeiten bestimmt. Beimagnesiumempfindlichen Esculentenherzen war der Phosphatidgehalt hoch. Werte von 1600 mg aufwärts bis 1900 mg Phosphatid auf 100 g Herz berechnet, wurden für Mg-empfindliche Herzen gefunden. War das Herz Mg-unempfindlich, betrugen die Phosphatidwerte 1400 mg und weniger. Die niedrigsten Phosphatidwerte wurden in der Übergangszeit im Herbst mit 1000–1200 mg beobachtet. Dieser Sturz des Phosphatidgehalts unter die in der übrigen Jahreszeit gefundenen Werte, wurde regelmäßig in 3 Jahren beobachtet.Eine von anderer Seite gemachte Untersuchung über die jahreszeitliche Schwankung der Empfindlichkeit des Esculentenherzens gegenüber Digitaloiden aus Magnoliarinde zeigt eine auffällige Übereinstimmung im Kurvenverlauf mit den hier gefundenen Schwankungen der Phosphatidwerte.Mit 2 Textabbildungen.Die Arbeit wurde in Köln 1935 begonnen und in Bonn 1936 fortgesetzt.