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PubMed2005

Ascorbate uptake in pig coronary artery endothelial cells.

Although smooth muscle and endothelial cells in pig coronary artery are morphologically and functionally distinct, ascorbate uptake has been characterized only in smooth muscle cells. Ascorbate transporters in kidney and intestinal epithelial cells differ from those in smooth muscle. We examined ascorbate transport and mRNA expression of sodium-dependent vitamin C transporters (SVCT) by RT-PCR in the pig coronary artery endothelial cell cultures. When 14C-ascorbate uptake in endothelial cells was examined as 14C or by HPLC, the two values did not differ from each other. 14C-ascorbate uptake was Na(+)-dependent, stereoselective for L-ascorbate and inhibited by sulfinpyrazone. The kinetic characteristics of the uptake were: Km = 27 +/- 3 microM (Hill coefficient = 1) for ascorbate and Km = 73 +/- 14 mM (Hill coefficient = 2) for Na+. Surprisingly, endothelial cells had similar kinetic parameters as smooth muscle cells, except for a slightly lower uptake velocity in endothelial cells. Comparison with the smooth muscle showed that both tissue types expressed mRNA for SVCT2. Endothelial cells differ from epithelial cells which express mainly SVCT1 but resemble smooth muscle cells in this respect.

Animals↗

PubMed1989

Influence of cardioprotective cyclooxygenase and lipoxygenase inhibitors on peroxidative injury to myocardial-membrane phospholipid.

Oxygenase-catalyzed and non-enzymatic polyunsaturated fatty acid peroxidations have potential pathogenic roles in ischemic-reperfusion damage to the myocardium. Certain oxygenase inhibitors protect heart muscle from irreversible ischemic injury, and some antiperoxidants can inhibit oxygenase enzymes. We investigated the antiperoxidative abilities of eight anti-ischemic, cardioprotective oxygenase inhibitors to prevent myocardial-membrane phospholipid peroxidation through superoxide-driven, iron-promoted reactions with xanthine oxidase as the source of superoxide. Flurbiprofen, ibuprofen, and REV-5901-5 did not affect peroxidation at concentrations up to 1000 microM. BW755C, AA-861, nafazatrom, dipyridamole, and propyl gallate did protect and cardiac lipids against oxidative injury in a concentration-dependent manner with respective and antiperoxidant IC50 values (concentrations at which peroxidation was inhibited by 50%) of 0.22, 1.25, 3.0, 3.6 and 50 microM. Catechin and phenidone, known oxygenase inhibitors not yet evaluated as anti-ischemic agents, were also found to be antiperoxidants at low micromolar concentrations. Four cyclooxygenase inhibitors ineffective against myocardial infarction (aspirin, indomethacin, naproxen, and sulfinpyrazone) evidenced no antiperoxidant properties at concentrations up to 500 microM. The oxygenase inhibitor-antiperoxidants identified could neither quench superoxide radical nor inhibit xanthine oxidase. However, they were able to interrupt the propagation of an on-going peroxidation reaction. Their antiperoxidant profiles resembled those of known antioxidants, such as alpha-tocopherol, which inhibit peroxidation by intercepting lipid free-radical intermediates. These data raise the possibility that at least some oxygenase inhibitors could exert cardioprotective effects by directly influencing the sensitivity of myocardial-membrane phospholipid to peroxidative injury. Consequently, recognition of the antiperoxidant properties of these agents may aid dissection of their physiological and pharmacological actions.

Aspirin↗

PubMed1981

Effect of non-steroid anti-inflammatory drugs in experimental myocardial infarction in rats.

Four non-steroid anti-inflammatory drugs, sulfinpyrazone, acetylsalicylic acid, sodium salicylate and indomethacin were tested in the acute phase of experimental myocardial infarction in conscious rats. A single oral dose was administered, then 1 h later the occlusion of the left anterior descending coronary artery was made by using a previously implanted silk loop. It was found that each drug markedly increased the survival rate, reduced the occurrence of ventricular fibrillation and tachycardia, and delayed the appearance and shortened the duration of arrhythmias.

Animals↗

PubMedDate not supplied

Inhibition of Fura-2 sequestration and secretion with organic anion transport blockers.

Fura-2 is widely used to measure the concentration of cytosolic free calcium, but in many cells the dye does not remain localized within the cytoplasmic matrix. In these cells, Fura-2 is sequestered within intracellular organelles, secreted into the extracellular medium, or both. We have found that, in mouse peritoneal macrophages, J774 cells, PC12 cells, and N2A cells, Fura-2 sequestration and secretion are mediated by organic anion transport systems and are blocked by the inhibitors probenecid and sulfinpyrazone. Under appropriate conditions these agents have little affect on calcium transients, and may facilitate the use of Fura-2 in a variety of cell types.

Animals↗

PubMed1990

Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy.

The perioperative consequences of preoperative aspirin administration were assessed in a large prospective cooperative study of 772 patients undergoing coronary artery bypass grafting. The 772 patients were randomized to receive either aspirin (325 mg once a day), aspirin (325 mg three times a day), aspirin plus dipyridamole (325 and 75 mg together three times a day) (aspirin group), sulfinpyrazone (267 mg three times a day) or placebo (nonaspirin group). The therapy, except in the aspirin group, was started 48 h before the operation. In all aspirin subgroups, one 325 mg aspirin dose was given 12 h before surgery and maintained thereafter according to the assigned regimen. Patients in the aspirin group had significantly more postoperative bleeding and received more packed blood cells and blood products than did patients in the nonaspirin group. Although total operative duration and cardiopulmonary bypass duration were not different, the interval between completion of cardiopulmonary bypass and wound closure was significantly longer (p = 0.035) in the aspirin group. Thirty-one (6.6%) of 471 patients in the aspirin group and 5 (1.7%) of 301 patients in the nonaspirin group also required reoperation for control of postoperative bleeding (p = 0.002). The site of bleeding found at reoperation was not different between the two groups. There was no difference in operative mortality rates, incidence of other bleeding complications or occurrence of other post-operative complications between the two groups. Thus, antiplatelet regimens involving preoperative initiation of aspirin therapy, which has been shown to improve graft patency, increase the risk of abnormal postoperative bleeding and the need for reoperation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗

PubMed2005

Chondrocyte transport and concentration of ascorbic acid is mediated by SVCT2.

Collagen II is the major protein component of articular cartilage and forms the collagen fibril network, which provides the tensile strength of cartilage. Collagen II synthesis is enhanced by ascorbic acid (vitamin C) at both a transcriptional and post-transcriptional level. While the importance of ascorbic acid in the synthesis of collagen has been established, the mechanism by which this essential nutrient is transported into chondrocytes has not been investigated previously. We have characterized the transport of the reduced form of ascorbic acid in passaged primary human chondrocytes to discern the physiologically relevant pathways of ascorbic acid transport in cartilage. We have found that chondrocytes are robust concentrators of ascorbic acid, capable of transporting the reduced form, and concentrating total ascorbic acid, in the reduced form and its metabolites, 960-fold over the concentration in the extracellular milieu. Chondrocyte transport of ascorbic acid was sodium and temperature dependent, stereoselective for the L-forms, and inhibited by the anion transport inhibitor, sulfinpyrazone. Chondrocytes preferentially expressed the full-length and functional isoform of sodium-dependent vitamin C transporter 2 (SVCT2). When this transcript was suppressed with sequence-specific siRNAs, the active transport component of ascorbic acid was abolished. Thus, we provide the first evidence that SVCT2 mediates the secondary active and concentrative transport of ascorbic acid in human chondrocytes.

Amino Acids↗

PubMed1998

Nuclear and cytosolic calcium changes in osteoclasts stimulated with ATP and integrin-binding peptide.

Cytosolic calcium modulates the activity of osteoclasts, large multinucleate cells that resorb bone. Nuclear events, such as gene transcription, are also calcium-regulated in these cells, and fluorescence imaging has suggested that calcium signals produced by some stimuli are specifically targeted to, or amplified within, osteoclast nuclei. We used two alternative techniques of dye loading to examine the changes of intracellular calcium induced in rat osteoclasts by three stimuli. Osteoclasts loaded with the calcium indicator Fura-2 by the acetoxymethyl (AM) ester technique appeared to display marked nuclear calcium amplification. During stimulation with integrin-binding peptides, ATP, or high extracellular calcium, fluorescence ratios recorded from the nuclei rose higher than did ratios recorded from extranuclear regions. In contrast, nuclear calcium amplification was not observed after AM loading in the presence of the anion transport inhibitor sulfinpyrazone, nor in osteoclasts injected with Fura-2 conjugated to a high MW dextran. In these cells, nuclear fluorescence ratios were equal to the extranuclear values at all times: upon stimulation by an agonist, the nuclear and cytosolic calcium concentrations increased by the same amount. The calcium changes seen in stimulated osteoclasts can no longer be taken as evidence for the general validity of the phenomenon of nuclear calcium amplification.

Adenosine Triphosphate↗

PubMed1998

Analysis of the uptake of the fluorescent marker 2',7'-bis-(2-carboxyethyl)-5(and-6)-carboxyfluorescein (BCECF) by hydrogenosomes in Trichomonas vaginalis.

The fluorescent dye 2',7'-bis-(2-carboxyethyl)-5(and-6)-carboxyfluorescein (BCECF) has been widely used as an indicator of cytosolic pH. Here we report that BCECF localizes to hydrogenosomes (hydrogen-generating organelles found in several phylogenetically separate groups of anaerobic protists) in Trichomonas vaginalis, where it was observable by fluorescence microscopy. Its cellular location was confirmed by treatment of BCECF-loaded cells with diaminobenzidine and hydrogen peroxide together with UV illumination. This produced an osmiophilic precipitate in the matrix of hydrogenosomes, observable by electron microscopy. Use of a short (7.5 min) loading period, loading on ice, use of concentrations of BCECF (acetoxymethyl ester) down to 10 nM, and inclusion of the anion channel blockers probenicid or sulfinpyrazone, or the K+/H+ ionophore nigericin in the loading buffer all failed to prevent hydrogenosomal accumulation of BCECF. This uptake was best observed when intact cells were loaded with the ester form of BCECF, but could also be seen using free BCECF following either incubation with ruptured cells or electroporation of intact cells. Hydrogenosomal BCECF loading was also obtained with washed cell lysates, without cytoplasm or metabolic substrates. We tested a range of other fluorogenic dyes designed for cytosolic labeling, and found that the calcium indicator fura-2 (acetoxymethyl ester) and the cell viability marker fluorescein diacetate also labeled hydrogenosomes. The results illustrate a novel use for BCECF as a fluorescent marker for hydrogenosomes (the first such marker), but present a warning against the indiscriminate use of fluorogenic ester dyes to measure properties of the cytosol in hydrogenosome-containing organisms - the dyes may also be indicating the properties of the hydrogenosome.

Animals↗

PubMed1987

The consent form as a possible cause of side effects.

In a multicenter trial of aspirin or sulfinpyrazone in the treatment of unstable angina, we examined the possible importance to the outcome of mentioning potential side effects in the consent form. Inclusion, in two of the three centers, of a statement outlining possible gastrointestinal side effects resulted in a sixfold increase (P less than 0.001) in the number of subjects in these centers withdrawing from the study because of subjective, minor gastrointestinal symptoms. Major gastrointestinal complications such as peptic ulcer or bleeding as diagnosed by study physicians were similar in the three centers. Furthermore, no patient discontinued therapy because of subjective, nongastrointestinal side effects. Post hoc analysis suggests that the inclusion of gastrointestinal side effects in the consent form may have increased the likelihood of patients attributing gastrointestinal symptoms to drug therapy, leading to subsequent withdrawal from the study.

Angina Pectoris↗

PubMed1998

Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1 (MRP1) in antineoplastic drug detoxification. Mechanism of GST A1-1- and MRP1-associated resistance to chlorambucil in MCF7 breast carcinoma cells.

To examine the role of multidrug resistance protein 1 (MRP1) and glutathione S-transferases (GSTs) in cellular resistance to antineoplastic drugs, derivatives of MCF7 breast carcinoma cells were developed that express MRP1 in combination with one of three human cytosolic isozymes of GST. Expression of MRP1 alone confers resistance to several drugs representing the multidrug resistance phenotype, drugs including doxorubicin, vincristine, etoposide, and mitoxantrone. However, co-expression with MRP1 of any of the human GST isozymes A1-1, M1-1, or P1-1 failed to augment MRP1-associated resistance to these drugs. In contrast, combined expression of MRP1 and GST A1-1 conferred approximately 4-fold resistance to the anticancer drug chlorambucil. Expression of MRP1 alone failed to confer resistance to chlorambucil, showing that the observed protection from chlorambucil cytotoxicity was absolutely dependent upon GST A1-1 protein. Moreover, using inhibitors of GST (dicumarol) or MRP1 (sulfinpyrazone), it was shown that in MCF7 cells resistance to chlorambucil requires both intact MRP1-dependent efflux pump activity and, for full protection, GST A1-1 catalytic activity. These results are the first demonstration that GST A1-1 and MRP1 can act in synergy to protect cells from the cytotoxicity of a nitrogen mustard, chlorambucil.

Antineoplastic Agents↗

PubMed1979

Antiplatelet drugs in thromboembolism.

Evidence is mounting that three drugs that inhibit platelet function--aspirin, dipyridamole, and sulfinpyrazine--have an antithrombotic effect in humans. Particularly in men, aspirin is beneficial in controlling transient ischemic attacks and stroke, and there is evidence that it may be effective in preventing thrombotic and embolic complication of hip surgery. It abolishes symptoms in peripheral ischemia associated with thrombocytosis and spontaneous platelet aggregation and may prove effective in coronary artery disease. When combined with oral anticoagulants, aspirin is more effective than oral anticoagulants alone in preventing systemic embolism in patients with prosthetic heart valves. Dipyridamole in combination with oral anticoagulants reduces the incidence of systemic embolism after prosthetic heart valve replacement. Sulfinpyrazone reduces the incidence of sudden death in the first year after myocardial infarction, decreases the incidence of arteriovenous shunt thrombosis in patients undergoing chronic hemodialysis, and when combined with anticoagulants, may be effective in reducing the frequency of episodes in recurrent venous thrombosis.

Anticoagulants↗

PubMed1967

Alteration of the response of platelets to surface stimuli by pyrazole compounds.

Sulfinpyrazone and phenylbutazone block the aggregating action of collagen, antigen-antibody complexes, and gamma globulin-coated surfaces on blood platelets. These drugs do not block the action of ADP or thrombin. Inhibition of surface-induced aggregation appears to be the result of a decreased response of the platelets to surface stimuli, giving rise to diminished release of platelet constituents, such as ADP and serotonin. The intravenous infusion of these drugs produced results similar to those found in the in vitro experiments. Administration of phenylbutazone in doses sufficient to produce marked suppression of the platelet-collagen reaction impaired hemostatic plug formation at the ends of transected mesenteric vessels in rabbits. Since platelet function is considered a factor influencing platelet survival, the effect of phenylbutazone on platelet survival was examined. It was found that phenylbutazone prolonged platelet survival to more than twice the normal time and reduced platelet turnover by nearly 50%. These studies show that drugs which suppress platelet response to surface stimuli alter platelet function in vivo.

Adenine Nucleotides↗

PubMed1981

Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model.

Accelerated graft arteriosclerosis is a major cause of death in human heart transplantation. Despite many investigations, the pathogenesis of this disease remains undetermined and its control inadequate. In this study using a rat heart transplant model and cyclosporin A, a new immunosuppressant, acute rejection was prevented but arteriosclerotic-like vessel disease still developed consistently as early as 20 days postoperatively. The combination of cyclosporin A and dipyridamole prevented the development of this vessel disease in transplanted hearts at 20 and 50 days postoperatively. Sulfinpyrazone and cyclosporin A reduced but did not prevent the disease. These findings suggest that immunologically induced graft arteriosclerosis can be prevented in transplanted rat hearts by the combination of cyclosporin A and dipyridamole.

Animals↗

PubMed2004

Contribution of multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter.

p-Aminohippurate (PAH) is the classical substrate used in the characterization of organic anion transport in renal proximal tubular cells. Although basolateral transporters for PAH uptake from blood into the cell have been well characterized, there is still little knowledge on the apical urinary efflux transporters. The multidrug resistance protein 2 (MRP2/ABCC2) is localized to the apical membrane and mediates ATP-dependent PAH transport, but its contribution to urinary PAH excretion is not known. In this report, we show that renal excretion of PAH in isolated perfused kidneys from wild-type and Mrp2-deficient (TR(-)) rats is not significantly different. Uptake of [(14)C]PAH in membrane vesicles expressing two different MRP2 clones isolated from Sf9 and MDCKII cells exhibited a low affinity for PAH (Sf9, 5 +/- 2 mM; MDCKII, 2.1 +/- 0.6 mM). Human MRP4 (ABCC4), which has recently been localized to the apical membrane, expressed in Sf9 cells had a much higher affinity for PAH (K(m) = 160 +/- 50 microM). Various inhibitors of MRP2-mediated PAH transport also inhibited MRP4. Probenecid stimulated MRP2 at low concentrations but had no effect on MRP4; but at high probenecid concentrations, both MRP2 and MRP4 were inhibited. Sulfinpyrazone only stimulated MRP2, but inhibited MRP4. Real-time PCR and Western blot analysis showed that renal cortical expression of MRP4 is approximately fivefold higher as compared with MRP2. MRP4 is a novel PAH transporter that has higher affinity for PAH and is expressed more highly in kidney than MRP2, and may therefore be more important in renal PAH excretion.

Animals↗

PubMed1984

Sudden death related to advanced coronary atherosclerosis in mini-pigs: influence of some drugs.

Advanced coronary atherosclerosis was produced in 30 mini-pigs by a combination of a hypercholesterolaemic diet and X-irradiation to the precordial region. Within 11-25 weeks after the irradiation, 13 of the 30 animals died a sudden death probably caused by coronary atherosclerosis. The contents of free and ester-bound cholesterol in the right coronary artery were significantly higher in the animals which died spontaneously than in surviving animals. In an untreated group of 12 animals 7 died whereas in a group treated with beta-pyridylcarbinol only 1 out of 5 died. In the coronary arteries, the contents of both free and ester-bound cholesterol were significantly lower in the beta-pyridylcarbinol-treated animals. In a sulfinpyrazone-treated group 3 out of 8, and in a metoprolol-treated group 2 out of 5 animals died. None of these drugs reduced the accumulation of cholesterol in the coronary arteries. The rate of sudden death was 26 +/- 6% (P less than 0.05) lower in the combined group of treated animals than in the untreated ones. By regular ECG recordings, signs which could predict the fatal outcome of the experiment were looked for. Although depressed ST segments were present before death in a few animals, this was not a regular phenomenon. It is concluded that advanced coronary atherosclerosis in mini-pigs often leads to sudden death and that this animal model seems suitable for testing the potential therapeutic effects of drugs.

Animals↗

PubMed1975

Factors responsible for ADP-induced release reaction of human platelets.

Extensive aggregation of human platelets can be induced by ADP without secondaryaggregation or release of granule contents. This occurs with washed platelets in Tyrode solution containing 0.35% albumin, human fibrinogen, and apyrase, and in platelet-rich, heparin- or hirudin-plasma. Conditions that caused release during ADP-inducedaggregation were-citrate as the anticoagulant in platelet-rich plasma; addition of citrate (11-15 mM) to a suspension of washed platelets, or to hirudin-plasma or heparin-plasma; suspension of platelets in a medium containing magnesium but no calcium;and the presence of trace amounts of thrombin or aggregated gamma globulin in the platelet suspensions. Acetylsalicylic acid, phenylbutazone, or sulfinpyrazone inhibited secondary aggregation and release in all these circumstances. Heparin or hirudin inhibited ADP-INDUCED SECONDARY AGGREGATION AND RELEASE PROMOTED BY TRACES OF THROMBIN. Although fibrinogen is required for ADP-induced primary aggregation, it does not support secondary aggregation and release, provided that it has no clot-promoting activity. The main agent responsible for ADP-induced secondary aggregation and release in human, citrated, platelet-rich plasma appears to be sodium citrate. Suspending washed human platelets in a medium without calcium mimics the effect of citrate.

Adenosine Diphosphate↗

PubMed2002

Comparison of furosemide and vinblastine secretion from cell lines overexpressing multidrug resistance protein (P-glycoprotein) and multidrug resistance-associated proteins (MRP1 and MRP2).

Recent studies in our laboratory have shown that the loop diuretic, furosemide, is actively secreted by Caco-2 cells and rat jejunal tissue. This active secretion could be the result of efflux transporters such as P-gp, MRP1 or MRP2 (cMOAT). To determine if any of these transporters is responsible for the secretion of furosemide, we compared directional permeability in the wild-type cell lines, MDCK strains I and II, and LLC-PK1, vs. cell lines that overexpress a single transporter, in both the presence and absence of various inhibitors, for furosemide as compared to vinblastine. Sulfinpyrazone significantly inhibited the transport of vinblastine in MRP2 expressing cells, but not the wild-type controls. Vinblastine could not be confirmed as a substrate of MRP1. We were also unable to demonstrate that any particular transporter affected furosemide in excess of the background effects of endogenous transporters in the parental cell lines. Furosemide secretion from these kidney-derived cell lines is probably not the primary result of any of the well characterized efflux transporters (P-gp, MRP1 or MRP2), although they may still play a role in the observed Caco-2 secretion. This equivocal result acknowledges the difficulty in trying to determine the effect of a single protein in a complicated expression system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1985

Antiplatelet aggregators inhibit development of stress ulcers in Sprague-Dawley rats.

Antiplatelet aggregators such as sulfinpyrazone (10 mg/kg), ticlopidine (200 mg/kg), and pyridine (0.1 mg/kg) significantly inhibited the degree of gastric ulceration in Sprague-Dawley rats subjected to cold restraint stress. The inhibition of platelet aggregation and that of microthrombus formation were evident in rats given antiplatelet aggregating drugs and exposed to cold stress. Therefore, platelet aggregation does play an important role in stress ulcer formation, and drugs which inhibit this aggregation should be given greater attention as to possible clinical application for treatment of stress ulcers.

Animals↗