Chlorpromazine modulates the morphological macro- and microstructure of endothelial cells (original) (raw)
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The influence of chlorpromazine on the potential-induced shape change of human erythrocyte
Bioscience Reports, 1991
The effect of chlorpromazine (CPZ) on the shape of human erythrocytes with different values of transmembrane potential (TMP) was investigated. The shape of red blood cells with negative values of the TMP remained unchanged after the formation of stomatocytes by chlorpromazine, while cells with positive TMP showed a characteristic time course of shape change during the incubation with CPZ. Experiments with vanadate show that this might be due to a difference in the activity of the phospholipid-translocase at different values of TMP.
Chemico-Biological Interactions, 2000
In recent studies, we showed that flunitrazepam (FNTZ) and other benzodiazepines interact with artificial phospholipid membranes locating at the polar head group region, inducing a membrane expansion, reducing the molecular packing and reorganising molecular dipoles. In the present paper we investigated the possibility that those phenomena could be transduced into changes in the curvature of membranes from natural origin. Hence we studied the effect of FNTZ on cellular morphology using human erythrocyte as a natural assay system. Shape changes of erythrocytes were evaluated by light microscopy and expressed as a morphological index (MI). FNTZ induced echinocytosis in a time-dependent manner with MI values significantly higher than those of control (without drug) or DMSO (vehicle) samples. Lidocaine, a local anesthetic known to induce stomatocytosis by incorporating in the inner monolayer, counterbalanced the concentration-dependent FNTZ crenating effects. FNTZ induced protective effects, compared with control and DMSO, against time-dependent hemolysis. Hypotonic-induced hemolysis, was also lowered by FNTZ in a concentration-dependent manner. Both antihemolytic effects suggested a drug-induced membrane expansion allowing a greater increase in cell volume before lysis. In such a complex system like a cell, curvature changes triggered by drug partitioning towards the plasma : S 0 0 0 9 -2 7 9 7 ( 0 0 ) 0 0 2 5 4 -4 D. A. García et al. / Chemico-Biological Interactions 129 (2000) 263-277 264 membrane, might be an indirect effect exerted through modifications of ionic-gradients or by affecting cytoskeleton-membrane linkage. In spite of that, the curvature changes can be interpreted as a mechanism suitable to relieve the tension generated initially by drug incorporation into the bilayer and may be the resultant of the dynamic interactions of many molecular fluxes leading to satisfy the spontaneous membrane curvature.
Biochemical Pharmacology, 1985
The influence of the anionic drugs indomethacin, barbitone, salicylate and the cationic drugs chlorpromazine and tetracaine on the morphology of human erythrocytes suspended in solutions of different chloride concentration (thus altering cell membrane potential) and constant osmolality, has been examined. As expected, the anionic and cationic drugs produced echinocytes and stomatocytes respectively in 145 mM NaCl. The cationic drugs induced fewer stomatocytes in 60 mM chloride than in 145 mM chloride at 37". Tetracaine induced echinocytes in 60 mM chloride at 20". Indomethacin and barbitone produced echinocytes in 145 mM chloride and stomatocytes in 60 mM chloride. Salicylate no longer produced echinocytes when the chloride concentration was reduced. Cells exposed to salicylate in 60mM chloride were less cupped than the control cells. We suggest that the distribution of the charged form of the drug across the membrane is in equilibrium with the distribution of chloride ions. Changes in the intracellular drug concentration when the extracellular chloride is varied could then account for the observed shape changes in a manner which is consistent with the bilayer couple hypothesis for drug-membrane interactions.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 1982
Chemically induced shape changes of the human erythrocyte may result from cell membrane bending by surface tension changes at the lipid bilayer Biophys. J. 14, 923-931) implicating differential expansion of the monolayers coupled to form the red cell membrane (Sheetz, M.P. and Singer, S.J. (1974) Proc. Natl. Acad. Sci. U.S. A. 71, 4457-4461). Interacting with calcium, the antibiotic chiorotetracycline (CTC) transforms crenated cells (echinocytes) into cup-shaped ones (stomatocytes), presumably expanding thereby the red cell membrane inner leaflet relative to the outer one (Behn, C., Ltibbemeier, A. and Weskamp, P. (1977) Pfltigers Arch. 372, 259-268). Whether the Ca-CTC interaction with lipid monolayers may in fact expand the latter, has now been examined by surface tension measurements at the air/water interface. CTC and lipids appeared to compete for the available sites at the air/water interface, contributing additively to its surface pressure. Ca increased both the adsorption rate of the antibiotic to the interface and the CTC-induced surface pressure increment. The latter was not influenced by the subphase pH and ionic strength, or by the type of phospholipid polar head. Correspondingly, CTC-induced cell shape changes should be determined by the pCa values facing either monolayer of the erythrocyte membrane. Both stomatocytes and echinocytes could indeed be obtained with 0.5 mmol. !-t CTC, the cell shape depending on whether the external medium was adjusted respectively to pCa 9 or to pCa 3. Fluorescence microscopy revealed the Ca-CTC complex to be mostly restricted to the cell in stomatocytes and to the external medium in echinocytes. The possibility of inducing alternative cell shapes by varying the transmembrane Ca-CTC distribution, and the demonstration of a Ca-dependent expansion of even relatively compressed lipid monolayers by CTC, together suggest that the Ca-CTC complex may also differentially expand either leaflet of the red cell membrane.
Interaction of chlorpromazine with phospholipid membranes
European Biophysics Journal, 1995
Chlorpromazine penetration into the lipid core of the membrane was demonstrated through measurements on lipid monolayers (surface pressure and surface potential). The surface pressure measurements allow us to calculate the intrinsic binding constant (partition coefficient) for the lipid-Chlorpromazine interaction. This latter value is in correct agreement with the obtained results by electrophoretic mobilities measurements on liposomes.
Mechanism of endothelial cell shape change in oxidant injury
Journal of Surgical Research, 1989
Changes in endothelial cell morphology induced by neutrophil-generated hydrogen peroxide (I&02) may account for the capillary leak of the adult respiratory distress syndrome (ARDS). The relationship of Hz02 effects on the concentration of intracellular Ca2'([Caa'],) and ATP to changes in microfllaments and microtubules, important determinants of cell shape, was examined. Bovine pulmonary artery endothelial cells were injured over a 2-hr time course with a range of HzOz doses (O-20 mM). The higher concentrations of HzOz consistently produced contraction and rounding of >60-76% of cells by l-2 hr. The range of l-20 mM HzOz produced rapid, significant reductions in endothelial ATP levels over the time course of injury. Although there were significant increases in mean endothelial [Ca2+11 in response to 5,10, and 20 m&f HzOz , 1 mAfHzOz did not affect the [Ca2'],. Fluorescence microscopy revealed that microfilament disruption occurred as ATP levels fell and preceded depolymerization of microtubules which developed after [Ca2'], approached 1 X lo-' M. HzOz at 1 n&f injury caused microfilament disruption but did not depolymerize microtubules. Microfilament disruption occurred without oxidant exposure, when ATP levels were reduced by glucose depletion and mitochondrial inhibition with oligomycin (650 n&Z). If a Ca2+ ionophore, ionomycin (6 a), was then added, [Caz'], rose to >l X 10m6 M, microtubules fragmented and depolymerized, and cell contraction and rounding very similar to that induced by HzOz occurred. These results suggest that endothelial cell dysfunction and capillary leak in ARDS may be due to HzOz-mediated changes in cellular ATP and [Ca2'],.
Chemistry and Physics of Lipids, 2001
The interactions of three neuroleptic drugs, clozapine (CLZ), chlorpromazine (CPZ), and haloperidol (HPD) with phospholipids were compared using DSC and Langmuir balance. Main emphasis was on the drug-induced effects on the lateral organization of lipid mixtures of the saturated zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and the unsaturated acidic phosphatidylserine, brainPS. In multilamellar vesicles (MLV) phase separation was observed by DSC at X PS E0.05. All three drugs bound to these MLVs, abolishing the pretransition at X drug E0.03. The main transition temperature (T m ) decreased almost linearly with increasing contents of the drugs, CLZ having the smallest effect. In distinction from the other two drugs, CLZ abolished the phase separation evident in the endotherms for DPPC/brainPS (X PS =0.05) MLVs. Compression isotherms of DPPC/brainPS/drug (X PS = X drug =0.05) monolayers revealed the neuroleptics to increase the average area/molecule, CLZ being the most effective. Penetration into brainPS monolayers showed strong interactions between the three drugs and this acidic phospholipid (in decreasing order CPZ \ HPD\CLZ). Hydrophobic interactions demonstrated using neutral eggPC monolayers decreased in a different order, CLZ \CPZ\HPD. Fluorescence microscopy revealed domain morphology of DPPC/brainPS monolayers to be modulated by these drugs, increasing the gel-fluid domain boundary length in the phase coexistence region. To conclude, our data support the view that membrane-partitioning drugs could exert part of their effects by changing the lateral organization and thus also the functions of biomembranes.
Toxicology, 1999
Tricyclic antidepressants can, when taken in overdose, cause serious pulmonary failure such as the adult respiratory distress syndrome (ARDS). In this study we have examined the effects of some tricyclic antidepressants (amitriptyline, imipramine, nortriptyline and desipramine) on the viability and morphology of human endothelial and smooth muscle cells derived from umbilical cord. Effects of amitriptyline on endothelial cell fluidity, as well as permeability changes to an endothelial-smooth muscle cell bi-layer, were also studied. The tricyclic antidepressants induced acute, sub-lethal toxicity in both cell types above 100 mM as assessed by the MTT reduction assay. Morphological changes were also observed at these concentrations. Such changes were, however, absent at 33 mM and below. Amitriptyline did, however, cause a concentration-dependent fall in the electrical resistance of an endothelial -smooth muscle cell bi-layer, with significant effects already evident at 33 mM. All of these observed effects were fairly rapid and appeared within 5-15 min of exposure. The rapidity of these permeabilisation effects suggests potential membrane perturbations, since tricyclic antidepressants are lipophilic molecules with affinity for cell membranes. However, fluorescence anisotropy measurements showed no significant difference in membrane fluidity between amitriptyline-treated and control endothelial cells. Collectively, these data point to specific mechanisms of action of amitriptyline, and probably also the other tricyclic antidepressants studied, on endothelial permeability, which is a hallmark of ARDS. The data suggest that increased endothelial permeability could be due to impaired tight junction function. : S 0 3 0 0 -4 8 3 X ( 9 9 ) 0 0 0 3 5 -9 K.L. Dahlin et al. / Toxicology 136 (1999) 1-13
Biophysical Journal, 1990
When human erythrocytes are treated with exogenous monopalmitoyl phosphatidylcholine (MPPC), the normal biconcave disk shape red blood cells (RBC) become spiculate echinocytes. The present study examines the quantitative aspect of the relationship between effective bilayer expansion and erythrocyte shape change by a newly developed method. This method is based on the combination of direct surface area measurement of micropipette and relative bilayer expansion measurement of 13C crosspolarization/magic angle spinning nuclear magnetic resonance (NMR). Assuming that 13C NMR chemical shift of fatty acyl chain can be used as an indicator of lateral packing of membrane bilayers, it is possible for us to estimate the surface area expansion of red cell membrane induced by MPPC from that induced by ethanol. Partitions of lipid molecules into cell membrane were determined by studies of shape change potency as a function of MPPC and red cell concentration. It is found that 8(±0.5) x 106 molecules of MPPC per cell will effectively induce stage three echinocytes and yield 3.2(±0.2)% expansion of outer monolayer surface area. Surface area of normal cells determined by direct measurements from fixed geometry of red cells aspirated by micropipette was 118.7 + 8.5 AMm2. The effective crosssectional area of MPPC molecules in the cell membrane therefore was determined to be 48(±4) A2, which is in agreement with those determined by x-ray from model membranes and crystals of lysophospholipids. We concluded that surface area expansion of RBC can be explained by a simple consideration of cross-sectional area of added molecules and that erythrocyte shape changes correspond quantitatively to the incorporated lipid molecules.
Chlorpromazine-induced Erythrocyte Shape Change in Ratswith Obstructive Cholestasis
Pharmacy and Pharmacology Communications, 1999
Cholestasis is associated with an accumulation of endogenous opioids in plasma which are known to reduce erythrocyte deformability in-vitro. We compared chlorpromazine-induced erythrocyte shape change in bile duct ligated (cholestatic), sham-operated and control rats to evaluate the effect of cholestasis on erythrocyte deformability.