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PubMed1980

Pulmonary leukostasis and its relationship to pulmonary dysfunction in sheep and rabbits.

Pulmonary leukostasis, as a result of complement activation, has been invoked as a cause of pulmonary dysfunction. To investigate this phenomenon, we studied the pulmonary response to infusion of autologous complement-activated plasma in sheep and rabbits. Complement activation was produced by plasma incubation with zymosan. Leukopenia, with selective loss of polymorphonuclear leukocytes into the lungs, occurred in all animals immediately after the onset of plasma infusion. Complement-activated plasma infusion in sheep produced a significant fall in the arterial PO2 and a marked rise in pulmonary vascular resistance, whereas no such effects were observed in rabbits. Pretreatment of the sheep with sulfinpyrazone eliminated the pulmonary response to complement-activated plasma without altering the leukopenic response. Pulmonary histology in rabbits and sheep confirmed the presence of intracapillary leukostasis after the plasma infusions, whether or not sulfinpyrazone had been administered previously. The pulmonary response to complement activation is associated with pulmonary capillary leukostasis, but leukostasis alone is not an adequate explanation of the phenomenon.

Animals↗

PubMed1988

Antiplatelet agents in the secondary prevention of stroke: meta-analysis of the randomized control trials.

Randomized control trials of antiplatelet agents in the prevention of stroke following transient ischemic attacks have had conflicting results. The decision to employ aspirin instead of placebo as the control regimen in trials testing newer antiplatelet agents emphasizes the need for an accurate estimate of the efficacy of older drugs. A meta-analysis of seven randomized control trials comparing aspirin and/or sulfinpyrazone or dipyridamole with placebo was performed. For aspirin compared with placebo, a nonsignificant reduction in stroke of 15% (odds ratio 0.85, 95% confidence interval 0.60-1.19; chi 2 = 0.78, p greater than 0.30) was found. For aspirin combined with sulfinpyrazone or dipyridamole compared with placebo, a 39% reduction in stroke was observed (odds ratio 0.61, 95% confidence interval 0.39-0.95; chi 2 = 4.22, p less than 0.05); at the same time a 350% increase in gastrointestinal hemorrhage or peptic ulcer was noted (odds ratio 3.5, 95% confidence interval 1.26-9.75; chi 2 = 4.61, p less than 0.05). A trend in reduction of strokes for men was observed (odds ratio 0.58, 95% confidence interval 0.32-1.07; chi 2 = 2.52, p less than 0.15) for any regimen containing aspirin. The significant benefit of aspirin-combination therapy on stroke must be interpreted cautiously because of a number of possible biases. It is still conceivable that aspirin alone may decrease the incidence of stroke by as much as 40%, but a sample of greater than 13,000 patients would be needed to confirm the benefit observed in our analysis.

Aspirin↗

PubMedDate not supplied

Increased platelet aggregates in patients with transient ischemic attacks.

In order to evaluate the pathogenetic importance of platelet aggregates in cerebrovascular disease, a platelet count ratio method was used to study 66 patients with transient ischemic attacks (TIAs). Thirty normal subjects and 22 patients without thromboembolic disorders were also included as controls. The mean platelet aggregate ratio of the TIA group was 0.75 +/- 0.03 SEM which was significantly lower than that of normal subjects (0.90 +/- 0.02) or patients controls (0.88 +/- 0.01) (P less than 0.01). Seventeen patients with TIA were then treated with aspirin (1,200 mg) and dipyridamole (200 mg) daily. The platelet aggregate ratios were normalized in 13 patients. Of four patients who did not respond to this regimen, one did respond to sulfinpyrazone. When sulfinpyrazone was discontinued, recurrence of symptoms was preceded by an increase in platelet aggregates. These findings suggest that platelet aggregates may play an important role in the pathogenesis of cerebrovascular insufficiency. The determination of platelet aggregates appears useful in selecting patients for antiplatelet therapy.

Adult↗

PubMed1973

Pyrazinoate excretion in the chimpanzee. Relation to urate disposition and the actions of uricosuric drugs.

These experiments were designed to define the renal disposition of pyrazinoic acid in a nonhuman primate that is phylogenetically close to man and to relate this to the effects of pyrazinoate on urate excretion. The renal clearance of pyrazinoate was almost always greater than the simultaneous glomerular filtration rate at plasma concentrations ranging from 1.9 to 960 mug/ml. Some inhibitors of tubular secretion, probenecid, MK-282 (an experimental, potent uricosuric drug), p-aminohippurate, iodopyracet, sulfinpyrazone, and mersalyl, reduced clearances of pyrazinoate to values far below filtration rate. Chlorothiazide, allopurinol, and salicylate did not. The clearance of pyrazinoate was not influenced by changes in urine flow. It is concluded that pyrazinoate is actively secreted and actively reabsorbed. Pyrazinoate had a dual effect on urate excretion. At concentrations in plasma less than 10 mug/ml there was a concentration related fall in urate/inulin clearance ratio, reaching values of 10-20% of control. Over the range of 10-100 mug/ml in plasma, the clearance of urate remained maximally depressed. At higher concentrations of pyrazinoate there was a concentration related increase in urate/inulin clearance ratio such that at pyrazinoate levels above 600 mug/ml a definite uricosuric response was obtained. Prior administration of pyrazinoate to give plasma levels of 20-140 mug/ml completely or almost completely prevented uricosuric responses to probenecid, PAH, chlorothiazide, and sulfinpyrazone. Iodopyracet, mersalyl, salicylate and N-acetyl-4-dibutylsulfamoyl-3-trifluoromethylbenzenesulfonamide (MK-282) retained significant uricosuric action, but the activities were probably less than normal. The results are consistent with a model of urate transport involving high rates of bidirectional transtubular flux.

Allopurinol↗

PubMed1978

Platelet-mediated pulmonary hypertension and hypoxia during pulmonary microembolism: reduction by platelet inhibition.

The literature indicates that vasoactive substances released from platelets contribute to the pulmonary pressor response and hypoxemia during pulmonary microembolism. Hence, removal of the platelets or inhibition of their function should reduce these effects. The purpose of this study was, therefore, to investigate the pulmonary effects of experimental embolism with glass beads in dogs rendered thrombocytopenic with platelet antiserum and to compare these effects to the effects in dogs pretreated with sulfinpyrazone (Anturane) or heparin, both substances that affect the function of platelets, probably by inhibiting the release of platelets. In all three groups the pulmonary hypertension was reduced by more than half, and hypoxemia was lessened or abolished. The results of this study indicate the platelets contribute to the effects of pulmonary microembolism and that administration of sulfinpyrazone or heparin reduces the embolism-induced pulmonary hypertension to the same extent as the depletion of platelets. Platelet-inhibiting drugs might therefore be useful prophylactically in human pulmonary microembolism.

Animals↗

PubMed1989

Search for drugs that may reduce the load of neutrophil azurophilic granule enzymes in the lungs of patients with emphysema.

Neutrophil elastase and myeloperoxidase probably play an important role in the development of pulmonary emphysema. We have analyzed drugs from the major classes of agents that alter neutrophil function to determine if there are drugs in use today that can reduce the load of neutrophil elastase or myeloperoxidase in the lungs of smokers. Eleven representative drugs were tested for their ability to inhibit chemotaxis and degranulation. None of the drugs inhibited chemotaxis in a dose-response fashion at concentrations achievable in human plasma. Sulfinpyrazone, phenylbutazone, and auranofin completely inhibited the release of azurophilic granules (myeloperoxidase) and tertiary granules (beta-D-glucuronidase) when formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) was used as the stimulant, and inhibited azurophilic granule release by 69%, 19%, and 64% respectively, but not tertiary granule release when macrophage-conditioned media was used as the stimulus. In conclusion, none of the drugs tested are inhibitors of chemotaxis; however, three are excellent inhibitors of azurophilic granule enzyme release. Of these three, sulfinpyrazone, a drug that is not currently used clinically for its antiinflammatory effects, is the least toxic and should be considered as a potential drug to reduce the elastase and myeloperoxidase load in the lungs of smokers who are developing emphysema.

Anti-Inflammatory Agents↗

PubMed1996

Ascorbate uptake by microvascular endothelial cells of rat skeletal muscle.

OBJECTIVE: In several systems, exogenous ascorbate (reduced vitamin C) has been shown to protect against microvascular injury induced by reactive oxygen species. Since skeletal muscle is relatively resistant to oxidative injury, it is possible that under physiological conditions endogenous ascorbate in the muscle microvasculature affords such protection. To examine the ability of microvascular endothelium to accumulate ascorbate, we aimed (1) to develop an in vitro model of microvascular endothelial cells derived from rat hindlimb skeletal muscles and (2) to investigate the uptake and steady-state concentration of ascorbate in these cells. METHODS: Microvascular cells were enzymatically dissociated, isolated on a density gradient, and grown in serum-supplemented medium. After passaging, they were tested for formation of tube-like structures, coagulation factor VIII antigen expression, Griffonia simplicifolia lectin I-isolectin B4 binding, and acetylated low-density lipoprotein (LDL) uptake. Concentrations of reduced ascorbate were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. Transport activity was assessed on the basis of the initial rate [14C]ascorbate uptake. RESULTS: The cultured cells tested positively for factor VIII antigen expression, lectin binding, LDL uptake, and tube formation. Although these cells did not synthesize ascorbate de novo, they accumulated reduced vitamin C when it was added to the culture medium. The initial rate of [14C]ascorbate uptake was 0.9 mumol/g cell protein 10 min when cells were incubated with 10 microM of the radiolabeled vitamin. This uptake was Na+-dependent and was blocked by the organic anion transport inhibitor sulfinpyrazone, but was not acutely affected by glucose. Following incubation with a physiological concentration of vitamin C (100 microM L-ascorbate), cells accumulated a high concentration of ascorbate within 6 h (approximately 16 mM at steady-state). Steady-state cellular ascorbate concentration was also dependent on extracellular Na+ and sensitive to sulfinpyrazone. CONCLUSIONS: Microvascular cells derived from rat hindlimb muscles demonstrated endothelial characteristics. These cells accumulated reduced vitamin C by means of Na+-dependent ascorbate transporters, which are distinct from hexose carriers. The high endothelial ascorbate concentration at steady-state is consistent with the role of ascorbate as a major antioxidant in the skeletal muscle microvasculature.

Animals↗

PubMed1985

The influence of antiplatelet drugs on injury-stimulated migration of cultured smooth muscle cells.

Smooth muscle cell (SMC) migration, one of the early events in arteriosclerotic lesion formation in vivo, can be triggered by balloon catheter injury. This accelerated migration persists when aortic explants are grown in tissue culture. Under low serum conditions (0.1% fetal bovine serum) virtually no smooth muscle cell migration occurs out of explants from sham operated control animals, while over 70% of explants from balloon injured rats show SMC migration. Since platelets are thought to contribute to SMC proliferation and migration, we tested the effect of different antiplatelet drugs (sulfinpyrazone, aspirin, dipyridamole, and a combination of the last two) on balloon injury stimulated SMC migration. One week after onset of drug treatment balloon catheterization was performed and SMC migration from aortic explants was assessed 4 days later in vitro. The time and number of explants showing SMC migration was recorded daily over 8 days. Sulfinpyrazone reduced stimulated SMC migration most effectively, followed by the combination of aspirin and dipyridamole, while aspirin or dipyridamole alone had no significant effect on stimulated SMC migration. Using this technique we were able to single out SMC migration and analyze the effect of antiplatelet drugs on this early step in arteriosclerotic lesion formation.

Animals↗

PubMed1983

[Pharmacology of anti-platelet agents].

A new class of drugs has appeared alongside classical anti-thrombotic agents such as heparin and oral anticoagulants, characterised by their ability to modify the behaviour of platelets: "anti-platelet" agents. This article reviews the platelet actions, pharmacokinetics, conditions of use and side effects of the four chief agents available: acetylsalicylic acid (ASA), sulfinpyrazone, dipyridamole and ticlopidine. The mode of action of the first of them is that best studied. ASA opposes the conversion of arachidonic acid to prostaglandins and thromboxane, by the irreversible acetylation of cyclo-oxygenase. Nevertheless, major therapeutic trials involving ASA have yielded only poor results. There are at least two possible explanations for this state of affairs: --aggregation may occur even when thromboxane is blocked, in particular in response to thrombin; --ASA has been used at doses also capable of inhibiting the formation by the vascular wall of an anti-aggregant prostaglandin, PGI2. Current efforts by pharmacologists which should result in better adapted and hence more effective anti-thrombotic methods, are essentially concerned with the following points: --to understand why sulfinpyrazone, which in principle has the same mode of action as ASA, seems sometimes more active and sometimes less active than the latter according to whether coronary or cerebrovascular accidents are involved; --to propose a rational prescription programme for ASA, in such a way that it inhibits only little, and for as short a time as possible, the production of PGI2 (e.g. 200 mg every three days): --to perfect more active combinations; --synthesis of new substances, e.g. thromboxane synthetase inhibitors, or stable analogues of PGI2. The reasons which suggest that such substances could be used more beneficially in man are expanded.

Animals↗

PubMed1983

Gastrointestinal blood loss in patients undergoing maintenance dialysis.

Gastrointestinal blood loss was measured for 14 days in 19 patients treated by hemodialysis and in 2 patients treated by chronic ambulatory peritoneal dialysis. 51Cr was used as a marker for erythrocytes. Fecal blood loss was 5.0 +/- 3.3 ml/day in hemodialysis patients who were not taking drugs affecting thrombocyte aggregation and 4.6 +/- 4.3 ml/day in those receiving sulfinpyrazone. There was no relationship between the severity of anemia, duration of dialysis, dose of heparin, grade of uremic intoxication, or dose of aluminum hydroxide and amount of fecal blood loss. It is concluded that gastrointestinal blood loss is not a major determinant of anemia in chronic renal failure. However, sulfinpyrazone is preferable to acetylsalicylic acid for prevention of shunt thrombosis in uremic patients because of their propensity for gastrointestinal bleeding.

Adult↗

PubMed1976

Clinical trials in thrombosis: secondary prevention of myocardial infarction.

Numerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin, and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that anti-platelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.

Aspirin↗

PubMed1997

Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles.

Inhibition of [14C]-urate uptake by uricosuric and antiuricosuric agents was investigated in human brush-border membrane vesicles, urate being transported either by anion exchange mechanisms or by voltage sensitive pathway. The IC50 for drugs on [14C]-urate uptake in vesicles loaded with 1 mM cold urate or with 5 mM lactate was, respectively: 0.7 and 0.3 microM for benzbromarone; 6 and 4 microM for salicylate; 133 and 13 microM for losartan; 520 and 190 microM for sulfinpyrazone and 807 and 150 microM, for probenecid. The IC50 ratio for [14C]-urate uptake in exchange for cold urate or for lactate varied from about 1 for salicylate to 10 for losartan, supporting the hypothesis that two distinct anion exchangers are involved in urate transport. Application of Hill equation revealed that urate/anion exchangers have more than one binding site, possibly two binding sites with high cooperativity, for benzbromarone and sulfinpyrazone, but only one for probenecid, salicylate and losartan. The uricosuric diuretic, tienilic acid was 10 to 50 times more potent than hydrochlorothiazide, chlorothiazide and furosemide, for inhibiting [14C]-urate uptake in exchange for cold urate. This higher potency is the reason of its uricosuric properties. All uricosuric agents, as well as the antiuricosuric agents, pyrazinoate and ethambutol, had a much lower potency for inhibiting [14C]-urate uptake through the voltage sensitive pathway (apical secretory step) than through the urate/anion exchangers. This suggests that antiuricosuria, induced by pyrazinoate and ethambutol, as well as by low concentrations of uricosuric agents, does not result from an inhibition of the apical voltage sensitive pathway.

Aged↗

PubMed1978

Drug effects on platelet adherence to collagen and damaged vessel walls.

The interaction of platelets with damaged vessel walls leads to the formation of platelet-fibrin thrombi and may also contribute to the development of atherosclerotic lesions because platelets adherent to exposed collagen release a mitogen that stimulates smooth muscle cell proliferation. The first step in thrombus formation, platelet adherence to an injured vessel wall, can be studied quantitatively by the use of platelets labeled with 51chromium. In these investigations, rabbit aortas were damaged by passage of a balloon catheter and segments of the aortas were everted on probes that were rotated in platelet suspensions. Collagen-coated glass cylinders were also used. Adherence was measured in a medium containing approximately physiologic concentrations of calcium, magnesium, protein and red blood cells. Conditions of testing influence the effect of non-steroidal anti-inflammatory drugs, sulfinpyrazone, and dipyridamole on platelet adherence. Aspirin and sulfinpyrazone were not inhibitory when tested in a medium with a 40% hematocrit; this indicates that products formed by platelets from arachidonate probably do not play a major part in the adherence of the first layer of platelets to the surface, although they may be involved in thrombus formation. Indomethacin, dipyridamole, prostaglandin E1, methylprednisolone and penicillin G and related antibiotics did inhibit platelet adherence although the concentrations required were higher than would likely be achieved in vivo upon administration to human patients. None of the non-steroidal anti-inflammatory drugs inhibited the release of granule contents from adherent platelets. Pretreatment of the damaged vessel wall with aspirin increased platelet adherence, presumably because it prevented the formation of PGI2 by the vessel wall. Platelet adherence to undamaged or damaged vessel walls was enhanced by prior exposure of the wall to thrombin. Platelet reactions with aggregating agents and platelet survival can be modified by changes in dietary lipids but there is very little evidence concerning the effects of lipids on platelet adherence. If some forms of dietary fat damage the endothelium, platelet interaction with the damaged area and release of the mitogen for smooth muscle cells would contribute to the development of atherosclerotic lesions.

Animals↗

PubMed1976

Are agents affecting platelet functions clinically useful?

Notwithstanding the large number of clinical trials, most of them designed and performed according to the requirements of modern clinical pharmacology, only a few firm clinical recommendations on drugs affecting platelet function in the prevention of arterial or venous thrombosis can be made at present. There is no good evidence for the clinical effectiveness of aspirin or any other drug affecting platelet function in patients with peripheral arterial occlusion or after vascular grafting. In cerebrovascular disease there is reasonable evidence that the administration of sulfinpyrazone can significantly reduce cerebral ischemia or mortality, but similar trials performed with aspirin, dipyridamole or clofibrate failed to reveal a significant difference in favor of the experimental treatment. Patients with angina only were shown to benefit from treatment with clofibrate, but prospective trials with dipyridamole or aspirin in the primary or secondary prevention of myocardial infarction did not reveal a significant reduction in morbidity or mortality in the experimental group. Use of a combination of the latter two drugs did, however, reveal a reduction in morbidity and mortality. In patients with prosthetic heart valves, there is firm evidence that dipyridamole and sulfinpyrazone therapy can normalize decreased platelet survival, an effect which has been shown to correlate well with the incidence of thromboembolism. Provided further trials lead to confirmatory conclusions, drugs inhibiting platelet function associated or not with oral anticoagulants may constitute an ideal prophylaxis in patients with a substitute valve. There is still much uncertainty as to whether dipyridamole, given in addition to conventional treatment, benefits patients with membranous or mesangiocapillary glomerulonephritis. The same holds for drugs inhibiting platelet function after kidney or heart transplantation in man. Only scanty reports are available on the usefulness of drugs affecting platelet function in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Three different types of antiplatelet drugs are available for the prevention of postoperative deep vein thrombosis: dextran, oral drugs also affecting platelet function and heparin administered subcutaneously in small doses. In orthopedic surgery dextran 70 administered before and every second day after surgery was the drug showing the most convincing reduction in the incidence of phlebographically proved deep vein thrombosis. Major orthopedic surgery is precisely the type of surgery in which the effectiveness of small dose heparin is much in doubt and in which the effectiveness of aspirin and dipyridamole is still to be confirmed. In general surgery, use of a combination of 1 g aspirin and 0.225 g dipyridamole daily was shown to offer approximately the same level of protection as small doses of heparin, land these two forms of prevention seem to offer a greater degree of protection than dextran...

Aged↗

PubMed2001

A human lymphocyte based ex vivo assay to study the effect of drugs on P-glycoprotein (P-gp) function.

PURPOSE: The effect of drugs on P-glycoprotein (P-gp) is normally studied in transfected or overexpressing cell lines derived from tumor cells or animal tissue. We wanted to develop an assay using normal healthy human tissue to study and characterize the drug-transporter interaction. METHODS: Lymphocytes were isolated from healthy human blood. The effect of inhibitors of P-gp (cyclosporine, tacrolimus, verapamil, quinidine, vinblastine) and of other transporters (indomethacin, probenecid, sulfinpyrazone) on intracellular accumulation of rhodamine 123 was evaluated by flow cytometry. RESULTS: The efflux of rhodamine 123 was inhibited by P-gp inhibitors in a saturable, concentration-dependent manner. The potency of inhibition of P-gp was cyclosporine > tacrolimus > quinidine > verapamil > vinblastine. Vinblastine inhibited P-gp at lower concentrations, whereas at high concentrations, there was an activation of rhodamine 123 efflux from lymphocytes. The multidrug resistance associated protein (MRP) inhibitors, sulfinpyrazone and probenecid, did not have any significant effect on intracellular accumulation of rhodamine 123, but indomethacin caused a concentration-dependent increase in retention of rhodamine 123, indicating the involvement of other uncharacterized transporters. CONCLUSIONS: Lymphocytes can serve as a model tissue for studying modulation of P-gp activity by drugs. Both inhibitors and inducers of P-gp activity can be evaluated.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Cellular retention of liposome-delivered anionic compounds modulated by a probenecid-sensitive anion transporter.

PURPOSE: Drug carriers such as liposomes may enhance the intracellular delivery of therapeutic agents for infectious or neoplastic diseases. However, the mechanisms affecting cellular retention of liposome contents are understood poorly. We tested the hypothesis that retention of anionic compounds may be modulated by a nonspecific probenecid-sensitive anion transport mechanism, and that liposome composition may determine the impact of such transporters on drug retention by cells. METHODS: The fluorescent anionic dye hydroxy-pyrene-[1,3,6]-trisulfonate (HPTS) was transferred to the cytoplasm of cultured CV-1 or J774 cells by direct needle-microinjection or by ATP-induced permeabilization of the-plasma membrane, respectively, to investigate whether the cells have anion transport mechanisms capable of extruding HPTS from the cytoplasm. Cellular retention of dye was monitored in the presence and absence of the anion transport inhibitors probenecid or sulfinpyrazone. Liposomes containing HPTS were co-labeled with tetramethylrhodamine-labeled phosphatidylethanolamine (Rho-PE) as a marker of liposome membrane fate, and uptake was investigated using J774 cells. RESULTS: Needle-injected HPTS underwent both sequestration in early endocytic vesicles and rapid extrusion into the extracellular medium. Probenecid or sulfinpyrazone reduced the extrusion of HPTS. Thus HPTS is a substrate for a probenecid-sensitive anion transporter in J774 and CV1 cells. After delivery via fluid liposomes composed of phosphatidylglycerol:phosphatidylcholine:cholesterol (3:7:5 mole ratio) and co-labeled with Rho-PE, cell-associated HPTS declined more rapidly than did Rho-PE. Exposure of cells to 5 mM probenecid doubled the quantity of HPTS retained by cells, without changing the retention of the Rho-PE membrane marker. In contrast, the effect of probenecid was negligible when gel-phase liposomes of distearoylphosphatidylglycerol:cholesterol (10:5 mole ratio) were used. CONCLUSIONS: Probenecid-sensitive nonspecific anion transporters can mediate the extrusion of model anions delivered via liposomes. However, liposome composition modulates the amount of material subject to extrusion from cells, possibly by altering the endocytic compartment in which liposomes release their contents.

Animals↗

PubMed1995

Ascorbate transport and intracellular concentration in cerebral astrocytes.

Regulation of the initial rate of uptake and steady-state concentration of ascorbate (reduced vitamin C) was investigated in rat cerebral astrocytes. Although these cells did not synthesize vitamin C, they accumulated millimolar concentrations of ascorbate when incubated with medium containing the vitamin at a level (200 microM) typical of brain extracellular fluid. Initial rate of [14C]-ascorbate uptake and intracellular ascorbate concentration were dependent on extracellular Na+ and sensitive to the anion transport inhibitor sulfinpyrazone. Comparison of the efflux profiles of ascorbate and 2',7'-bis(carboxyethyl)-5 (or -6)-carboxyfluorescein from astrocytes permeabilized with digitonin localized most intracellular ascorbate to the cytosol. Pretreatment of astrocytes with dibutyryl cyclic AMP (dBcAMP) doubled their initial rate of sulfinpyrazone-sensitive [14C]ascorbate uptake compared with cells treated with either n-butyric acid or vehicle. dBcAMP also increased steady-state intracellular ascorbate concentration by 39%. The relatively small size of the change in astrocytic ascorbate concentration was explained by the finding that dBcAMP increased the rate of efflux of the vitamin from ascorbate-loaded cells. These results indicate that uptake and efflux pathways are stimulated by cyclic AMP-dependent mechanisms and that they regulate the cytosolic concentration of ascorbate in astrocytes.

Animals↗

PubMed2002

Glial cells express multiple ATP binding cassette proteins which are involved in ATP release.

Rat brain astrocyte and microglia cultures express different members of ATP-binding-cassette (ABC) proteins. RT-PCR analysis showed that astrocytes are equipped with P-glycoprotein (mdr1a, mdr1b), multidrug resistance-associated-protein (mrp1, mrp4, mrp5) and cystic fibrosis transmembrane conductance regulator (CFTR). No transcripts for mrp5 and CFTR were detected in microglia. The ABC protein functional activities are shown by the following results: (i) cyclosporin A (50 microM), verapamil (50 microM), probenecid (1 mM) or sulfinpyrazone (2 mM) enhanced [3H]vincristine accumulation; (ii) cyclosporin A or verapamil but not probenecid or sulfinpyrazone enhanced [3H]digoxin accumulation; (iii) glibenclamide (100 microM) inhibited 36Cl efflux from astrocytes. ATP release from glial cells was inhibited by the pretreatment with ABC protein inhibitors indicating that ABC proteins are involved in nucleotide efflux from glial cells which represent the main source of cerebral extracellular purines.

ATP Binding Cassette Transporter, Subfamily B↗