The binding of the calcium transport inhibitors reserpine, chlorpromazine and prenylamine to the lipids of the membranes of the sarcoplasmic reticulum

Balzer, H.; Makinose, Madoka; Fiehn, W.; Hasselbach, Wilhelm

doi:10.1007/bf00537360

Cited by 63 publications

(11 citation statements)

References 7 publications

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“…Other studies (Huunan-Seppala, 1972) have suggested the existence of a binding process to phospholipids, similar to that reported by Balzer, Makinose, Fiehn & Hasselbach (1968) for various lipophilic amines: chlorpromazine, prenylamine, reserpine. The same hypothesis was invoked in the case of imipramine concentration in the lung (Junod, 1972a), and the interrelations between drugs of similar nature are consistent with that concept.…”

Section: Discussionsupporting

confidence: 76%

“…A similar observation was reported by Huunan-Seppala (1972) for binding of propranolol to mitochondria, by Kwant & Seeman (1969) for binding of chlorpromazine to red cells, by Balzer et al (1968) (1974) extended their studies on the nature of the concentration process of imipramine, amphetamine, chlorcyclizine and methadone. They were able to find evidence for the presence of two components of accumulation: a linear one and a saturable one, for high and low substrate concentrations respectively.…”

Section: Discussionsupporting

confidence: 65%

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Concentration of (±)‐propranolol in Isolated, Perfused Lungs of Rat

Dollery¹,

Junod²

1976

British J Pharmacology

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The metabolism and the accumulation of (±)-propranolol have been studied in isolated lungs of the rat, perfused with an artificial medium. 2 Little or no metabolism took place during the perfusion periods (up to 10 minutes). 3 Accumulation was observed with high tissue/medium ratios for substrate concentrations of 0.2 giM to 1 mM; there was evidence for saturability, but no real plateau could be seen. The presence of two binding sites with different affinities was established. 4 Cold greatly inhibited the accumulation process at low substrate concentrations, but had no effect at 1 mM propranolol. 5 Inhibition of accumulation was measured in the presence of imipramine, desmethylimipramine, nortryptiline, chlorpromazine and of Na+-free medium. Cocaine, 5-hydroxytryptamine and noradrenaline had no effect. Lidocaine enhanced the accumulation process. Release of previously bound propranolol was accelerated in the presence of propranolol and imipramine, unaffected by a Na+-free medium and decreased by cold and by lidocaine. 6 Experiments on lung tissue slices yielded qualitatively similar results to those obtained with perfused lungs. Ouabain and KCN had no or little effect on propranolol accumulation. IntroductionPrevious studies on the distribution of (±)propranolol in tissues have shown that the lungs were able to concentrate (±)-propranolol to a remarkable extent since a tissue/medium ratio of up to 250 was observed (Black, Duncan & Shanks, 1965). Further analysis (Hayes & Cooper, 1971) showed that in rats, dogs and monkeys, large amounts of metabolites of propranolol could also be detected in the lungs. It was not known if the presence of these metabolites was the result of the local pulmonary metabolism of propranolol or of their accumulation after production elsewhere in the body.The present studies were therefore undertaken to investigate the mechanism of concentration and the possible metabolism of (±)-propranolol in isolated perfused lungs of the rat. In view of their similar physicochemical properties, it was also interesting to compare the mode of accumulation of propranolol with that of imipramine and other basic amines, whose concentration in the lungs has already been the object of recent studies (Junod, 1972a, Andersen, Orton, Pickett & Eling, 1974 Iwasawa & Gillis (1974), propranolol had no effect on noradrenaline uptake by the lung. Methods Medium and materialsThe perfusion medium consisted of Krebs-Ringer bicarbonate buffer, containing 5 mM glucose and 4.5% bovine serum albumin; to obtain a Na+-free medium, sucrose was substituted for NaCl and Tris HCI for NaHCO3, while the albumin was made Na+-free according to the procedure already described (Junod, 1972b Unless otherwise specified, drugs were added to the perfusion medium and were therefore present during the entire perfusion. In the experiments where the effects of drugs on the efflux of propranolol were studied, drugs were added to the perfusion medium only during the period when efflux of 14C was measured. Experimental proceduresDetails of t...

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 65%

Concentration of (±)‐propranolol in Isolated, Perfused Lungs of Rat

Dollery¹,

Junod²

1976

British J Pharmacology

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“…Under the conditions, stated in Table 4, 500/, inhibition is produced at a total concentration of 75 pM prenylamine in the splitting medium. The effect on the native and phospholipase-A-treated vesicles is assumed to result from an interaction of the drug with the fatty acids, because the binding of the drug is strongly reduced by delipidation [30]. This explanation may get some support from the observation, that half-maximal inhibition occurs a t a drug concentration range similar to that of the activating oleic acid, …”

Section: Pig 9 Inhibition Of Dodecylsulfate-activated Atpase Bymentioning

confidence: 99%

Properties of the Calcium‐Independent ATPase of the Membranes of the Sarcoplasmic Reticulum Delipidated by the Nonionic Detergent Triton X‐100

Walter

Hasselbach

1973

European Journal of Biochemistry

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1.When the sarcoplasmic reticulum membranes are solubilized in Triton X-100 their ATPases are modified : the calcium-dependent ATPase is activated whereas the basic ATPase is inhibited.2. Phospholipids are removed from the solubilized sarcoplasmic membranes completely by chromatography on a sepharose column equilibrated with Triton X-100. Thereby the activity of the calcium-dependent ATPase is abolished and cannot be restored by addition of phospholipids.3. The delipidated ATPase preparation, exhibits only low activity, which is not dependent on calcium but on magnesium alone. This calcium-independent ATPase is activated to the level of the calcium-dependent ATPase both by unsaturated and saturated fatty acids, by anionic phospholipids and various synthetic lipids.4. The enhancement of the ATPase activity produced by lipids is related to the binding of these compounds to the membrane protein in amounts comparable with those of bound Triton as demonstrated by dialysis experiments with dodecylsulfate. When the concentration of Triton in the medium is lowered, the dodecylsulfate/protein binding ratio increases, while Triton is detached from the protein.5. The activation of the calcium-independent ATPase by saturated fatty acids is dependent upon the chain-length of these aliphatic compounds. Only the long-chain fatty acids are strong activators. Moreover, the hydrophilic group of lipids affects maximal activities. No activation is observed with lecithin or dodecanol, while alkyl-sulfates or -phosphates activate most effectively.6. The calcium-independent ATPase differs from the calcium-dependent ATPase in that it is insensitive to N-ethylmaleimide, dinitrodithiobenzoic acid or salyrgan. The enzyme is strongly inhibited by prenylamine, sodium azide and silver ions. Similarly low alkali salt concentrations produce a strong reduction of the activity.7. The relative rates, with which the nucleoside triphosphates are split by the calcium-independent ATPase, differ considerably. As observed for the calcium-activated ATPase. The dependence on the substrate concentration suggests a positive cooperativity concerning Mg * ATP (Hill coefficient 1.46). 5001, of maximal activity is obtained a t 0.25 mM Mg * ATP. The enzyme is strongly inhibited by Mg * ADP.Kielley and Meyerhof have characterized a magnesium-activated ATPase found in aqueous muscle extracts, which was later identified as the ATPase of the membrane fragments of the sarcoplasmic reticulum [ 11. They demonstrated that treatment of the enzyme with phospholipase C caused inactiva- I n this paper a preparation is described from which essentially all phospholipids have been removed by use of the nonionic detergent TritonX-100 [8].

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“…According to Balzer et al [11] The following buffers were used: a t pH 5.2 and pH 6 Trismaleate, a t pH 7 and at pH 9 histidine and at pH 8 Tris-HC1. The concentration of the buffers was 20 mM.…”

Section: Phosphoprotein Formationmentioning

confidence: 99%

Properties of the Sarcoplasmic ATPase Reconstituted by Oleate and Lysolecithin after Lipid Depletion

Hasselbach

1972

European Journal of Biochemistry

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1. The ATPase activity of the sarcoplasmic membranes and the phosphoryl transfer reaction from ATP to the membranes depend on the composition of their lipid phase.2. Lipid depletion leads to a drastic (-60°/,,) reduction of phosphoprotein formation. Oleate raises and lysolecithin decreases phosphoprotein formation. I n absence of calcium and/or magnesium neither the native nor the delipidated vesicular preparations are phosphorylated.3. The ATPase activity of lipid-depleted vesicular preparations reactivated by oleate or lysolecithin and that of the preparation containing the lipid hydrolysis products after phospholipase A treatment reaches half-maximal activation a t concentrations of ionized calcium between 0.2 and 0.3 pM. The maximal ATP-splitting rates, however, differ considerably.4. Half-maximum activation by Mg ATP for the oleate and lysolecithin-reactivated ATPase is reached a t 10 pM and 100 pM, respectively. The corresponding Hill coefficients are 0.5 and 0.6. 5. For the oleate-reactivated ATPase an activation energy of about 35 kcal/mol has been calculated which is similar to that of the extra ATPase of native vesicles. The activation energy of the lysolecithin-reactivated ATPase is about 8 kcal lower.6. The ATPase activity of the reconstituted vesicular preparations shows an identical steep decline at pH values >7. An irreversible damage of the vesicular preparations a t higher values could be excluded.7. The properties of the reconstituted sarcoplasmic ATPase are discussed in relation to the sarcoplasmic calcium transport.

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The binding of the calcium transport inhibitors reserpine, chlorpromazine and prenylamine to the lipids of the membranes of the sarcoplasmic reticulum

Cited by 63 publications

References 7 publications

Concentration of (±)‐propranolol in Isolated, Perfused Lungs of Rat

Concentration of (±)‐propranolol in Isolated, Perfused Lungs of Rat

Properties of the Calcium‐Independent ATPase of the Membranes of the Sarcoplasmic Reticulum Delipidated by the Nonionic Detergent Triton X‐100

Properties of the Sarcoplasmic ATPase Reconstituted by Oleate and Lysolecithin after Lipid Depletion

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