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Effects of Aspirin and Dipyridamole on the Degradation of Adenosine Diphosphate by Cultured Cells Derived from Bovine Pulmonary Artery

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Effects of Aspirin and Dipyridamole on the Degradation of Adenosine Diphosphate by Cultured Cells Derived from Bovine Pulmonary Artery Effects of aspirin and dipyridamole on the degradation of adenosine diphosphate by cultured cells derived from bovine pulmonary artery. D J Crutchley, … , U S Ryan, J W Ryan J Clin Invest. 1980;66(1):29-35. https://doi.org/10.1172/JCI109831. Research Article To improve understanding of the mechanisms by which ADP is degraded during passage through the pulmonary vascular bed, we examined cultured endothelial and smooth muscle cells of bovine pulmonmary artery for their abilities to metabolize [8-14C]ADP. ADP is rapidly converted to AMP and then to adenosine, hypoxanthine, and inosine. Inosine is the major metabolite produced by endothelial cells. Radioactivity (5-10%) is accumulated intracellularly primarily as ATP. Medium containing 50 micro M ADP incubated with endothelial cells rapidly loses its ability to aggregate platelets and becomes antiaggregatory under conditions in which prostacyclin is absent. The antiaggregatory activity is probably the result of accumulated adenosine. 10 micro M dipyridamole inhibits cellular uptake of radioactivity by greater than 90%, and inosine in the medium is largely replaced by adenosine. This is accompanied by increased anti-aggregatory activity of conditioned medium, which can be matched by authentic adenosine at the same concentration. 1 mM aspirin had no effect on the metabolism of ADP by endothelial cells. Our results suggest: (a) Metabolism of ADP during passage through the lung is mainly the result of endothelial ADPase. (b) ADP released from aggregating platelets can be converted to the antiaggregatory substance, adenosine. Dipyridamole may exert some of its antithrombotic actions by preventing the intracellular uptake of adenosine, thereby increasing its concentration near the site of thrombus formation. (c) […] Find the latest version: https://jci.me/109831/pdf Effects of Aspirin and Dipyridamole on the Degradation of Adenosine Diphosphate by Cultured Cells Derived from Bovine Pulmonary Artery DAVID J. CRUTCHLEY, UNA S. RYAN, and JAMES W. RYAN, Research Division, Miami Heart Institute, Miami Beach, Florida 33140; Department of Medicine, University of Miami School of Medicine, Miami, Florida 33101 A B S T R A C T To improve understanding of the INTRODUCTION mechanisms by which ADP is degraded during pas- Although the lung can trap and remove large numbers sage through the pulmonary vascular bed, we ex- of thromboemboli presented to it via the systemic cir- amined cultured endothelial and smooth muscle cells culation (1), uncontrolled platelet aggregation in the of bovine pulmonary artery for their abilities to metab- lung would rapidly prove fatal. At least two protec- olize [8-"C]ADP. ADP is rapidly converted to AMP tive mechanisms appear to exist to prevent this. First, and then to adenosine, hypoxanthine, and inosine. the lung may continuously produce antiaggregatory Inosine is the major metabolite produced by endo- prostacyclin (PGI2)' (2-4); second, the pulmonary thelial cells. Radioactivity (5-10%) is accumulated vessels possess an active ADPase that rapidly degrades intracellularly primarily as ATP. Medium containing the important mediator of platelet aggregation, ADP 50,.M ADP incubated with endothelial cells rapidly (5, 6). An additional function of pulmonary ADPase loses its ability to aggregate platelets and becomes may be to prevent the entry of ADP into the systemic antiaggregatory under conditions in which prostacyclin circulation, thereby complementing the postulated is absent. The antiaggregatory activity is probably the systemic antithrombotic functions of PGI2. result of accumulated adenosine. 10 ,uM dipyridamole To determine more precisely the location of pul- inhibits cellular uptake of radioactivity by >90%, monary vascular ADPase, we have examined the and inosine in the medium is largely replaced by metabolism of ADP by cultured cells derived from adenosine. This is accompanied by increased anti- bovine pulmonary artery. Our results show that both aggregatory activity of conditioned medium, which can endothelial and smooth muscle cells rapidly metabo- be matched by authentic adenosine at the same con- lize ADP and produce antiaggregatory adenosine. We centration. 1 mM aspirin had no effect on the metabo- have also studied the effects of dipyridamole and lism of ADP by endothelial cells. Our results suggest: aspirin, both of which are currently undergoing clini- (a) Metabolism of ADP during passage through the cal trials as antithrombotic drugs (i.e., the Persantine- lung is mainly the result of endothelial ADPase. (b) aspirin reinfarction study). Dipyridamole was of par- ADP released from aggregating platelets can be con- ticular interest because it inhibits the intracellular verted to the antiaggregatory substance, adenosine. uptake of adenosine in several systems, including cul- Dipyridamole may exert some of its antithrombotic tured endothelial cells (7, 8) and lung (9, 10). Our actions by preventing the intracellular uptake of adeno- results provide additional information on the anti- sine, thereby increasing its concentration near the site thrombotic actions of dipyridamole and also suggest ofthrombus formation. (c) The ability of the vessel wall that the ability of the vessel wall to degrade ADP will to degrade ADP should not be compromised by the use not be compromised by the use of aspirin as an anti- of aspirin as an antithrombotic drug. (d) Endothelium thrombotic drug. may retain some of its antithrombogenicity when prostacyclin generation is impaired. METHODS Materials for the preparation of cell culture medium were ob- tained from Gibco Laboratories, Grand Island Biological Co., Received for publication 24 September 1979 and in revised form 18 February 1980. IAbbreviation used in this paper: PGI2, prostacyclin. J. Clin. Invest. X3 The American Society for Clinical Investigation, Inc. - 0021-9738/80/07/0029/07 $1.00 29 Volume 66 July 1980 29-35 Grand Island, N. Y. Collagenase was obtained from Worthing- studies, the drug was dissolved according to the manu- ton Biochemical Corp., Freehold, N. J. [8-'4C]ADP, sp act facturer's instructions and added to cells simultaneously 39 mCi/mmol, [8-14C]adenosine, sp act 54 mCi/mmol, and with ADP. Riafluor scintillator were obtained from New England Thin-layer chromatography. Aliquots of conditioned Nuclear, Boston, Mass. Unlabelled purines, aspirin, and tryp- medium or cell extracts were applied to silica gel plates sin were obtained from Sigma Chemical Co., St. Louis, Mo. containing a fluorescent indicator. Authentic ATP, ADP, Aluminum-backed plates for thin-layer chromatography, AMP, adenosine, inosine, hypoxanthine, and adenine were coated with 0.2 mm silica gel containing fluorescent indi- applied to the plates as standards. The plates were developed cator, were manufactured by Merck AG, Darmstadt, West in the system isobutyl alcohol/amyl alcohol/ethylene glycol Germany. Rabbit antiserum to human Factor VIII-associated monoethyl ether/ammonia/water, 45:30:90:45:60 (17). Typical protein, and rabbit antiserum to human a2-macroglobulin Rf values obtained with a solvent front height of 18 cm were: were obtained from Behring Diagnostics, Inc., Woodbury, ATP 0.18, ADP 0.29, AMP 0.43, inosine 0.63, hypoxanthine N. Y. Fluorochrome-conjugated goat antiserum to rabbit 0.72, adenosine 0.74, adenine 0.84. Better separation of immunoglobulin (Ig)G was obtained from Miles-Yeda, Miles nucleosides and bases was obtained by chromatography of Laboratories Inc., Elkhart, Ind. [3H]Benzoyl-Phe-Ala-Pro- samples in the solvent system n-butanol/ethyl acetate/metha- OH was used as the substrate for angiotensin-converting nol/ammonia, 7:4:3:4 (18). TypicalRfvalues obtained with this enzyme assay and was synthesized as described (11). system were: inosine 0.23, hypoxanthine 0.49, adenosine 0.56, Cell culture. Endothelial cells were obtained by treat- adenine 0.69, whereas ATP, ADP,, and AMP remained at or ment of bovine pulmonary arteries with 0.2% collagenase near the origin. Standards were visualized under ultraviolet (12). Smooth muscle cells were obtained from the same vessels light, and appropriate zones were cut out and transferred to (13). Cells were growth in Eagle's minimal essential medium scintillation vials. The purines were eluted with 1 ml water, containing 2 mM L-glutamine and supplemented with 20% Riafluor was added, and radioactivity was determined in a heat-inactivated (56°C for 30 min) fetal calf serum, 50 ug/ml liquid scintillation counter. Recovery of radioactivity from the streptomycin, 50 U/ml penicillin, 100 ,ug/ml fungizone, and plates was routinely >90% of that applied. 100,ug/ml kanomycin. Platelet aggregation. Venous blood from human volun- Criteria for the morphological and biochemical characteri- teers was anticoagulated with one ninth vol 110 mM tri- zation of our endothelial cell cultures have been described sodium citrate, centrifuged at 200 g for 10 min to obtain plate- in detail previously (12). Endothelial cells grew as contact- let-rich plasma (PRP), and then further centrifuged at 1000 g inhibited monolayers with a "cobblestone" morphology. for 20 min to obtain platelet-poor plasma. Platelet aggrega- Electron microscopic examination of thin sections indicated tion was determined turbidometrically (19) using a Bio/Data large numbers of caveolae, occasional Weibel-Palade bodies, aggregometer (Bio/Data Corp., Willow Grove, Pa.). For cal- and the full complement of organelles characteristic of culation of apparent ADP concentration in conditioned endothelial cells in situ. The cells were reactive
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