The membrane concentraton of a local anesthetic (Chlorpromazine)

Kwant, W.O.; Seeman, Philip

doi:10.1016/0005-2736(69)90167-9

Cited by 129 publications

(29 citation statements)

References 47 publications

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“…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: 67%

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: 67%

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

Dollery¹,

Junod²

1976

British J Pharmacology

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“…By removing the sialic acids, whether by neuraminidase or by trypsin (Figure 5d) this primary interaction is abolished so that even at lower concentrations chlorpromazine penetrates the lipid bilayer sufficiently to cause disorganization underlying haemolysis. This hypothesis would account also for observations (Harris & Saifer, 1962) on ionic bonding between positively charged phenothiazines and negatively charged carboxyl groups of N-acetyl neuraminic acid and on hydrogen bonding between phenothiazines and hydrophobic components of cell membranes, calculated from free energies of absorption (Kwant & Seeman, 1969).…”

Section: Discussionmentioning

confidence: 72%

Effects of modification of the membranes of intact erythrocytes on the anti‐haemolytic action of chlorpromazine

Born

Housley

1983

British J Pharmacology

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“…On the other hand, chlorpromazine (Kwant & Seeman, 1969;Kwant & van Steveninck, 1968), a large number of structurally unrelated anaesthetics (Seeman, 1966a;Seeman & Weinstein, 1966) and other compounds (Seeman, 1966c) were found to have a stabilizing effect on the erythrocyte membrane.…”

Section: Resultsmentioning

confidence: 99%

Biphasic interaction of Triton detergents with the erythrocyte membrane

Trägner

Csordás

1987

Biochemical Journal

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Octylphenoxy polyoxyethylene ethers (Triton detergents) interact with the erythrocyte membrane in a biphasic manner, i.e. they stabilize erythrocytes against hypo-osmotic haemolysis at low concentrations (0.0001-0.01%, v/v), but become haemolytic at higher concentrations. This biphasic behaviour was demonstrated with Triton X-114, Triton X-100 and Triton X-102. However, a critical chain length is a prerequisite for the haemolytic effect, because Triton X-45, which differs from the other Tritons only by the shorter chain of the polyoxyethylene residue, does not exhibit this biphasic behaviour, but goes on protecting against osmotic rupture up to saturating concentrations. Even a 1 % solution of Triton X-45 does not cause haemolysis. This structural specificity of Triton X-45, namely the lack of haemolysis and efficient stabilization against osmolysis even at higher concentrations of the detergent, is exhibited at 0°and 37°C as well as at room temperature. Three conclusions are reached: (i) a critical chain length of the octylphenoxy polyoxyethylene ethers is required for the haemolytic effect; (ii) the different structural requirements would suggest that different mechanisms are responsible for the haemolytic and the stabilizing effect of amphiphilic substances; (iii) the results suggest that haemolysis is not caused simply by dissolution of the membrane by the detergent but is a rather more specific process.

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The membrane concentraton of a local anesthetic (Chlorpromazine)

Cited by 129 publications

References 47 publications

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

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

Effects of modification of the membranes of intact erythrocytes on the anti‐haemolytic action of chlorpromazine

Biphasic interaction of Triton detergents with the erythrocyte membrane

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