Maintenance of normal intracellular/extracellular Na+ and K+ gradients is of vital importance to all mammalian cells. The Na+ gradient provides energy for Na+-coupled transport of nutrients and other substances into cells, including transport of glucose, amino acids, and serotonin. Gradients of Na+ and H+ govern the movement of other ions, such as Ca2+ across cell membranes. Osmotic balance and cell volume are dependent on normal ion gradients. The sodium-potassium-adenosine-triphosphate pump (Na/K pump, E.C. 3.6.1.3) is primarily responsible for maintenance of Na+ and K+ gradients. 1 Horisberger J-D Lemas V Kraehenbuhl J-P et al. Structurefunction relationship of Na/K ATPase. Ann Rev Physiol. 1991; 53: 565-584 Crossref PubMed Scopus (257) Google Scholar Thus, function of the Na/K pump is critically important in cell homeostasis in the face of injury. Maintenance of cell homeostasis is a crucial component of endogenous mechanisms of resistance to cell injury. Endothelial cell injury from inflammatory processes may be important in the development of some types of pulmonary hypertension.

Apoptosis may be important in the exacerbation of endothelial cell injury or limitation of endothelial cell proliferation. We have found that extracellular ATP (exATP) and adenosine cause endothelial apoptosis and that the development of apoptosis is linked to intracellular metabolism of adenosine [Dawicki, D. D., D. Chatterjee, J. Wyche, and S. Rounds. Am. J. Physiol. 273 (Lung Cell Mol. Physiol. 17): L485-L494, 1997]. In the present study, we investigated the mechanism of this effect. We found that exATP, adenosine, and the S-adenosyl-L-homocysteine (SAH) hydrolase inhibitor MDL-28842 caused apoptosis and decreased the ratio of S-adenosyl-L-methionine to SAH compared with untreated control cells. Using release of soluble [3H]thymidine as a measure of DNA fragmentation, we found that the effect of adenosine on soluble DNA release was potentiated by coincubation with homocysteine. These results suggest that the mechanism of exATP- and adenosine-induced endothelial cell apoptosis involves inhibition of SAH hydrolase. exATP-induced apoptosis was enhanced by an inhibitor of adenosine deaminase, whereas exogenous adenosine-induced apoptosis was partially inhibited by an adenosine deaminase inhibitor. These results suggest that adenosine deaminase may also be involved in the mechanism of adenosine-induced endothelial cell apoptosis. Adenosine and MDL-28842 caused intracellular acidosis as assessed with the fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. The cell-permeant base chloroquine prevented adenosine-induced acidosis but not apoptosis. Thus, although intracellular acidosis is associated with adenosine-induced apoptosis, it is not necessary for this effect. We speculate that exATP- and adenosine-induced endothelial cell apoptosis may be due to an inhibition of methyltransferase(s) activity. Purine-induced endothelial cell apoptosis may be important in limiting endothelial cell proliferation after vascular injury.

The Na/K pump is critically important in maintenance of cell homeostasis in the face of injury. Little is known about the regulation of endothelial cell Na/K-pump activity. We previously reported that short-term (30-minute) oxidant-induced endothelial cell perturbation increased Na/K-pump activity in intact monolayers of bovine pulmonary artery endothelial cells (BPAECs). In this study we investigated the mechanism of oxidant-induced increases in endothelial Na/K-pump activity, focusing on short-term modulation of alpha1-pump subunit. By using immunofluorescence microscopy and confocal scanning laser microscopy, we found alpha1 subunit on both apical and basal aspects of BPAECs without polarized distribution. Short-term (30-minute) incubation of PAEC monolayers with H2O2 (1 mmol/L) did not change the relative amounts of alpha1 subunit in membrane fractions, as assessed by immunoblotting. Phosphorylation of the alpha1 subunit also was not affected by H2O2 treatment. Because protein kinases have been reported to alter Na/K-pump activity in several tissues and because H2O2 has been reported to increase PKC activity of endothelial cells, we determined the effects of inhibition and activation of protein kinase C (PKC) on Na/K-pump activity quantitated as ouabain-inhibitable uptake of 86Rb. We also determined the effects of PKC activation and inhibition on H2O2-induced increases in Na/K-pump activity. Inhibitors of PKC increased Na/K-pump activity over a 30-minute period in intact monolayers. Inhibition or depletion of PKC did not prevent H2O2-induced increases in pump activity. These results indicate that PKC is an endogenous regulator of pulmonary artery endothelial cell Na/K-pump activity but that the effects of H2O2 are not mediated by activation of PKC or by changes in the expression or phosphorylation of alpha1 subunit.

ATP acts as an intracellular energy source and an extracellular signaling molecule. We report that extracellular ATP causes apoptosis in pulmonary artery endothelial cells, as assessed by morphological changes and internucleosomal DNA degradation. We investigated the mechanism of this effect using release of tritiated soluble DNA as a marker for apoptosis. We conclude that the metabolite adenosine is responsible for the apoptotic effect of ATP, since nucleotides that can be degraded to adenosine, as well as adenosine itself, cause DNA damage, whereas nonmetabolizable ATP analogs and uridine 5'-triphosphate are inactive. Furthermore, the ecto-5'-nucleotidase inhibitor alpha, beta-methylene-ADP blocks ATP-induced DNA fragmentation. The adenosine receptor agonist 5'-N-ethylcarboxamide adenosine does not cause DNA fragmentation, and adenosine receptor antagonists do not block adenosine-induced apoptosis. However, the nucleoside transport inhibitor dipyridamole prevents extracellular ATP-induced DNA cleavage. These findings indicate that ATP- and adenosine-mediated apoptosis are mediated via intracellular events rather than through cell surface receptor(s). The adenosine metabolites inosine, hypoxanthine, and xanthine do not cause apoptosis. The adenosine analogs 3-deazaadenosine and MDL-28842, which are not metabolized and are S-adenosylhomocysteine hydrolase inhibitors, also cause DNA fragmentation. Therefore, we speculate that extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells by altering methylation reactions that require S-adenosylmethionine as the methyl donor. We speculate that ATP released from cells undergoing cytolysis or degranulation may cause endothelial cell death. Endothelial cell apoptosis may be important in acute vascular injury or in limiting angiogenesis.

Previously we have shown that ATP enhances the adherence of HL-60 cells and human neutrophils to bovine pulmonary artery endothelial cells. The current investigations extend earlier findings by showing that ATP and UTP dose-dependently stimulate human neutrophil adherence to human pulmonary artery endothelial cells. We have also explore the mechanisms of ATP- and UTP-stimulated adherence. We have found that fucose, a component of selectin receptors, inhibits ATP-stimulated HL-60 cell-bovine pulmonary artery endothelial cell adhesion. Additionally, pretreatment of HL-60 cells with neuraminidase abolishes ATP enhancement. However, fucose does not affect ATP- or thrombin-induced adhesion of freshly isolated human neutrophils to human endothelial cells. Antibodies to human P-selection intercellular adhesion molecule (ICAM)-1, and the beta-subunit of CD11/CD18 do not alter ATP-induced adherence of HL-60 cells to bovine endothelial cells. Similarly, antibodies to human P-selectin and ICAM-1 do not inhibit human neutrophil-human pulmonary artery endothelial cell adhesion. The platelet-activating factor receptor antagonists, WEB-2086 and L-659,989, are effective in attenuating ATP- and UTP-stimulated adherence. Preincubation of neutrophils or human pulmonary artery endothelial cells with ATP or UTP also enhances adherence, an effect that is blocked by L-659,989. Thus platelet activating factor, associated with both neutrophils and endothelial cells, mediates ATP- and UTP-induced neutrophil adherence. ATP, released during vascular injury, may exacerbate neutrophil-endothelial cell interaction and thereby contribute to neutrophil-induced injury.

Adenosine, ATP, and various nucleotides were examined for their effects on the adherence of leukocytes to bovine pulmonary artery endothelial cells. Extracellular ATP enhanced adherence of HL-60 cells and human neutrophils to endothelial cells in a dose-dependent fashion. Maximal adherence occurred after 15 min coincubation of ATP and HL-60 cells or neutrophils with endothelial cells. ATP stimulation was mediated by direct effects on both HL-60 cells and endothelial cells. The potency profile of various nucleotides was ATP = 2-MeSATP > beta,gamma-CH2ATP, indicative of a P2y receptor. Interestingly, UTP was as potent as ATP in stimulating HL-60 cell adherence, suggesting the presence of a pyrimidine nucleotide receptor. Photoaffinity labeling of endothelial cells with 8-Az-[alpha-32P]ATP showed the presence of two ATP binding proteins of 48 and 87 kDa. ATP and 2-MeSATP inhibited binding by both proteins. Labeling of the 87-kDa protein was inhibited by beta,gamma-CH2ATP, whereas UTP blocked binding by the 48-kDa protein. Thus photoaffinity labeling experiments support the proposal that endothelial cells possess two ATP receptors, one of which is a P2u nucleotide receptor. These findings show that extracellular nucleotides enhance leukocyte adherence to endothelial cells. Nucleotide release into the extracellular space may be one mechanism of exacerbating vascular cell injury relevant to conditions such as adult respiratory distress syndrome and septic shock.

The biochemical, ultrastructural and functional aspects of digitonin-permeabilized platelets were investigated. Human platelets were permeabilized by exposure to the steroid glycoside digitonin. A 60 microM concentration of this permeabilizer produced a very substantial release of cytosolic enzymes from the platelets. Release from subcellular granules was relatively low and did not inhibit the response of platelets to a series of agonists. Although digitonin-permeabilized platelets required higher threshold concentrations of the usual stimulants, both primary and secondary aggregation as well as the release of nucleotides and enzymes from their respective granules remained intact. Transmission electron micrographs revealed discontinuities in the plasma membrane of digitonin-treated platelets, but scanning electron microscopy showed no difference between control and permeabilized platelets. No substantial loss of structural or membrane proteins could be detected by one- and two-dimensional gel electrophoresis. The pore size produced by digitonin treatment was sufficient to allow entry of 125I-labeled IgG into the platelet cytosolic space.

The role of microtubules in platelet aggregation and secretion has been analyzed using platelets permeabilized with digitonin and monoclonal antibodies to alpha (DM1A) and beta (DM1B) subunits of tubulin. Permeabilized platelets were able to undergo aggregation and secretory release. However, threshold doses of agonists capable of eliciting a second wave of aggregation and the platelet release reaction were higher than in control platelets exposed to dimethyl sulfoxide, the solvent for digitonin. Both antibodies to alpha and beta tubulin caused a further increase in the threshold concentration of agonists and inhibited the secretory release of permeabilized platelets, but were ineffective using intact platelets. Neither monoclonal antibody inhibited polymerization or depolymerization of platelet tubulin in vitro. Antibodies to platelet actin and myosin also exhibited an inhibitory activity on platelet aggregation albeit less severe than that observed with the antibodies to alpha and beta tubulin. There was evidence of an interaction between DM1A and DM1B and the antibodies to actin and myosin. The interaction of platelet tubulin and myosin was investigated by two different methods. (1) Coprecipitation of the proteins at low ionic strength at which tubulin by itself did not precipitate and (2) affinity chromatography on columns of immobilized myosin. Tubulin freed of its associated proteins (MAPs) by phosphocellulose chromatography bound to myosin in a molar ratio which approached 2. Platelet actin competed with tubulin for 1 binding site on the myosin molecule. MAPs also reduced the binding stoichiometry of tubulin/myosin. Treatment of microtubule protein with p-chloromercuribenzoate or colchicine did not influence its binding to myosin. DM1A and DM1B inhibited the interaction of tubulin and myosin. This effect could also be demonstrated by reaction of electrophoretic transblots of extracted platelet tubulin with the respective proteins. We interpret these results as evidence for an interference of the two monoclonal antibodies to the tubulin subunits (DM1A and DM1B) with the translocation of microtubule protein from its submembranous site to a more central one during the activation process.

Tubulin phophorylation was analyzed during the different phases of platelet activation. Platelets preloaded with [32P]-phosphate were stimulated with collagen. Tubulin was immunoprecipitated from serial samples obtained during the activation process. The immunoprecipitates were resolved by SDS-polyacrylamide gel electrophoresis and autoradiographs analyzed by laser densitometry. Agonist induced dephosphorylation of platelets occurred after the onset of shape change at the time of initiation of the secretory release. The dephosphorylation was selective affecting specific peptides.

Changes in the phosphorylation of platelet tubulin were analyzed as a function of platelet activation. Non-activated platelets incubated with [32P]-phosphate showed multiple peaks of radioactivity when solubilized platelet proteins were analyzed by SDS-polyacrylamide gradient gel electrophoresis. Both tubulin monomers were found to be phosphorylated. Agonistic stimulation (thrombin or 1,2-diacylglycerol) resulted in a lowering of the phosphate incorporation into alpha- and beta-tubulin. Such changes we believe are important in the modulation of the reversible polymerization-depolymerization of platelet tubulin that occurs in the course of the agonistic stimulation of platelets.

Adenosine (Ado, 10 - 50 μM), a potent inhibitor of ADP-induced human platelet aggregation in platelet-rich plasma (PRP), does not inhibit aggregation in whole blood. However, the Ado analogs, 2-fluoroadenosine, 2-chloroadenosine and 5′-N-ethylcarboxamidoadenosine (NECA) which are resistant to deamination (2-fluoroadenosine) or deamination and phosphorylation (2-chloroadenosine and NECA), inhibit aggregation in whole blood with IC50 values of 12 μM, 2.3 μM and 0.26 μM, respectively. The inhibitory effect of NECA (200 nM) is potentiated by the platelet cAMP phosphodiesterase (PDE) inhibitor RA 233 (5 μM). Inhibition of the erythrocytic nucleoside transport system by dilazep (1 μM) or dipyridamole (10 pM), or blockade of Ado metabolism by 2'-deoxycoformycin (5 μM) plus 5-iodotubercidin (10 μM), evokes the antiaggregatory action of Ado in whole blood (IC50 = 2 μM). RA 233 (5 μM) potentiates Ado-mediated inhibition about 10-fold when nucleoside transport or Ado metabolism is blocked. Ado (10 μM or 200 nM) is rapidly metabolized within 1 min in whole blood. When nucleoside transport is inhibited by dilazep or dipyridamole, or when Ado metabolism is blocked by 2′-deoxycoformycin and 5-iodotubercidin, 50 - 60 % of the Ado remains in the plasma after 5 min. These results show that the failure of Ado to inhibit platelet aggregation in whole blood results from its rapid uptake and metabolism by erythrocytes. More importantly, these data emphasize the key role of nucleoside transport inhibition in the antiplatelet actions of dipyridamole and dilazep. In addition, superior therapeutic results may be obtained from the combination of blockade of the nucleoside transport system with inhibition of platelet cAMP PDE.

Annals of the New York Academy of SciencesVolume 451, Issue 1 p. 188-203 Role of Nucleoside Transport in Drug Action The Adenosine Deaminase Inhibitor, Deoxycoformycin, and the Antiplatelet Drugs, Dipyridamole and Dilazepa ROBERT E. PARKS JR., ROBERT E. PARKS JR. Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorDOLORETTA D. DAWICKI, DOLORETTA D. DAWICKI Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorKAILASH C. AGARWAL, KAILASH C. AGARWAL Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorSHIH-FONG CHEN, SHIH-FONG CHEN Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorJOHANNA D. STOECKLER, JOHANNA D. STOECKLER Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this author ROBERT E. PARKS JR., ROBERT E. PARKS JR. Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorDOLORETTA D. DAWICKI, DOLORETTA D. DAWICKI Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorKAILASH C. AGARWAL, KAILASH C. AGARWAL Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorSHIH-FONG CHEN, SHIH-FONG CHEN Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this authorJOHANNA D. STOECKLER, JOHANNA D. STOECKLER Section of Biochemical Pharmacology Division of Biology and Medicine Brown University Providence, Rhode Island 02912Search for more papers by this author First published: October 1985 https://doi.org/10.1111/j.1749-6632.1985.tb27110.xCitations: 14 † These investigations were supported by PHS grant nos. CA 07340, CA 13943, CA 09204, CA 37901, and HD 11343. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Rogler-Brown, T., R. P. Agarwal & R. E. Parks, Jr 1978. Tight-binding inhibitors-VI Interactions of deoxycoformycin and adenosine deaminase in intact human erythrocytes and Sarcoma 180 cells.. Biochem. Pharmacol. 27: 2289–2296. 2 Rogler-Brown, T. & R. E. Parks, Jr 1980. Tight-binding inhibitors-VIII Studies of the interaction of 2′-deoxycoformycin and transport inhibitors with the erythrocytic nucleoside transport system. Biochem. Pharmacol. 29: 2491–2497. 3 Chen, S. F., J. D. Stoeckler & R. E. Parks, Jr 1984. Transport of deoxycoformycin in human erythrocytes: Measurement by adenosine deaminase titration and radioisotope assays. Biochem. Pharmacol. 33: 4069–4079. 4 Londos, C., J. Wolff & D. M. F. Cooper. 1983. Adenosine receptors and adenylate cyclase interactions. In Regulatory Functions of Adenosine. R. M. Berne, T. W. Rall & R. Rubio, Eds.: 17–32. Martinus Nijhoff. The Hague . 5 Nees, S. & E. Gerlach. 1983. 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Pharmacol. 24: 547–550. 22 Agarwal, R. P., T. Spector & R. E. Parks, Jr 1977. Tight-binding inhibitors-IV Inhibition of adenosine deaminases by various inhibitors. Biochem. Pharamacol. 26: 359–367. 23 Cha, S., R. P. Agarwal & R. E. Parks, Jr 1975. Tight-binding inhibitors–I. Kinetic behavior. Biochem. Pharmacol. 24: 2177–2185. 24 Mahony, C., K. M. Wolfram, D. M. Cochetto & T. D. Bjornsson. 1982. Dipyridamole kinetics. Clin. Pharmacol. Ther. 31: 330–338. 25 Kistler, J. P., A. H. Ropper & R. C. Heros. 1984. Therapy of ischemic cerebral vascular disease due to atherothrombosis. N. Engl. J. Med. 311: 100–105. 26 McElroy, F. A. & R. B. Philp. 1975. Relative potencies of dipyridamole and related agents as inhibitors of cyclic nucleotide phosphodiesterases: Possible explanation of mechanism of inhibition of platelet function. Life Sci. 17: 1479–1494. 27 Asano, T., Y. Ochiai & H. Hiroyoski. 1977. 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Biochemistry 12: 3294–3302. 33 Parks, R. E., Jr, G. W. Crabtree, C. M. Kong, R. P. Agarwal, K. C. Agarwal & E. M. Scholar. 1975. Incorporation of analog purine nucleosides into the formed elements of human blood: Erythrocytes, platelets, and lymphocytes. Ann. N.Y. Acad. Sci. 255: 412–434. 34 Klabunde, R. E. 1983. Dipyridamole inhibition of adenosine metabolism in human blood. Eur. J. Pharmacol. 93: 21–26. 35 Moncada, S. & R. Korbut. 1978. Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin. Lancet 1: 1286–1291. Citing Literature Volume451, Issue1Adenosine Deaminase in Disorders of Purine Metabolism and in Immune DeficiencyOctober 1985Pages 188-203 ReferencesRelatedInformation