The stimulatory effects of cationic amphiphilic drugs on human platelets treated with thrombin
Section snippets
Platelet isolation
Blood was obtained from regular donors at the blood bank (Haukeland Hospital, Bergen, Norway), who claimed to have taken no medication for the previous ten days. Thirty-six milliliters of blood was mixed with 6 mL “acid citrate dextrose” (86.7 mM trisodium citrate, 73.3 mM citric acid, 100 mM dextrose) as anticoagulant, and then centrifuged at 535 g for 6 min at ambient temperature. Platelet-rich plasma was collected and centrifuged again at 1200 × g for 10 min (ambient temperature) to pellet
Results
The effects of cationic amphiphilic drugs on the parameters determined in the present study varied considerably among platelets from different blood donors. However, the parameters measured always varied with the concentration of a given drug in the same pattern among the donors. The results are therefore presented as single experiments, each of which has been performed with platelets from at least 3 donors.
Effects on cell permeabilization and secretion
The effects of varying concentrations of several psychoactive cationic amphiphilic drugs on membrane integrity, secretion, and phosphoinositide metabolism in resting and thrombin-activated platelets are described in this study. We found that our earlier observations showing that CPZ and TFZ caused permeabilization and loss of small molecular weight cell components at concentrations over 50 μM in both resting and thrombin-activated platelets 7, 18 were also true for all of the other psychoactive
Conclusions
The major finding we report here is that several psychoactive drugs, both neuroleptics and antidepressants, all exhibited a stimulatory effect at low drug concentrations (<30 μM) and an inhibitory effect at higher concentrations (>50 μM). The most obvious, common feature of these agents is that they are amphipathic enough to cross the blood–brain barrier. Such small molecular weight, lipid-soluble substances would easily distribute into the plasma membrane and intracellular membranes and not be
Acknowledgements
This work was supported by the Norwegian Research Council for Science, the Blix Fund, the EU Biomed 2 program contract no. BMH4-CT-97 2609, and the L. F. Saugstad Foundation.
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2010, Biophysical ChemistryCitation Excerpt :The functional blockade of these receptors may contribute to its broad efficacy in the treatment of schizophrenia and related psychoses [9–12]. However, it has been shown that CPZ interferes with polyphosphoinositide metabolism in stimulated platelets [13–16]. These cells do not contain D2 receptors [17], which are assumed to be the main target for the phenothiazines [18,19].
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2008, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :Above 30–40 μM trifluoperazine (TFP) [21], CPZ [22], and other phenothiazines or tricyclic antidepressants [23] cause leakage of low molecular weight cytoplasmic substances, such as adenine nucleotides and glycolytic intermediates from human platelets, but not of lactate dehydrogenase, a large, high molecular weight enzyme [22]. Loss of essential cytoplasmic components could be responsible for the inhibitory effects reported in numerous studies in which drug concentrations ranging from 50–2000 μM have been used (see Refs. [3–15] in Ref. [23]). Below 30–40 μM CPZ exerts two effects: 1) below 10–15 μM it stimulates thrombin-induced dense granule secretion and PA production in human platelets and 2) at 15–30 μM it inhibits these effects [23].
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2007, Progress in Neuro-Psychopharmacology and Biological PsychiatryResveratrol inhibits polyphosphoinositide metabolism in activated platelets
2005, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :Many of the pleiotropic effects of resveratrol in nucleated cells in vitro may be attributed to its antioxidant effects [5] and its amphipathic structure. Studies on phospholipid monolayer films using the Langmuir technique showed that resveratrol interacts strongly with negatively charged phospholipids (unpublished observations); control studies with 3H-adenine labelling of cytoplasmic ATP showed that this interaction of resveratrol with membrane lipids did not compromise membrane integrity by causing leakage of radioactive, cytoplasmic ATP in both resting and thrombin-stimulated platelets (not shown), as is the case with a number of amphipathic compounds [33,42]. Its solubility properties due to its aromatic rings and phenolic functional groups undoubtedly enable it to penetrate into diverse cellular compartments and then adsorb to various proteins as well as form DNA adducts, resulting in various degrees of enzyme activation or inhibition or interference with transcription.
Role of liquid membrane phenomenon in the biological actions of thioridazine
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