{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:47:54Z","timestamp":1790200074027,"version":"4.1.0"},"reference-count":47,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2009,5]]},"abstract":"<jats:p>Activation of the G protein G<jats:sub>s<\/jats:sub>results in increases in cAMP, a necessary step in the pathway for ATP release from rabbit and human erythrocytes. In all cells, the level of cAMP is the product of its synthesis by adenylyl cyclase and its hydrolysis by phosphodiesterases (PDEs). Both iloprost (Ilo), a PGI<jats:sub>2<\/jats:sub>analog, and isoproterenol (Iso), a \u03b2-agonist, stimulate receptor-mediated increases in cAMP in rabbit and human erythrocytes. However, the specific PDEs associated with each of these signaling pathways in the erythrocyte have not been fully characterized. Previously, we reported that PDE3B is present in rabbit and human erythrocyte membranes and that PDE3 inhibitors potentiate Ilo-induced increases in cAMP. Here we report that inhibitors of either PDE2 or PDE4, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and rolipram, respectively, potentiate Iso-induced increases in cAMP in rabbit and human erythrocytes. Importantly, these inhibitors had no effect on cAMP increases associated with the incubation of erythrocytes with Ilo. In addition, we establish, for the first time, the presence of PDE2A protein in rabbit and human erythrocyte membranes. Finally, we determined that preincubation of human erythrocytes with EHNA and rolipram together potentiate Iso-induced ATP release, whereas preincubation with cilostazol enhances Ilo-induced release of ATP. These results are consistent with the hypothesis that, in rabbit and human erythrocytes, Ilo-induced increases in cAMP and ATP release are regulated by PDE3, whereas those associated with Iso are regulated by the activities of both PDE2 and PDE4. These studies demonstrate that PDE activity in these cells is localized to specific signaling pathways.<\/jats:p>","DOI":"10.1152\/ajpheart.01226.2008","type":"journal-article","created":{"date-parts":[[2009,2,28]],"date-time":"2009-02-28T03:08:26Z","timestamp":1235790506000},"page":"H1617-H1624","source":"Crossref","is-referenced-by-count":24,"title":["Iloprost- and isoproterenol-induced increases in cAMP are regulated by different phosphodiesterases in erythrocytes of both rabbits and humans"],"prefix":"10.1152","volume":"296","author":[{"given":"Shaquria P.","family":"Adderley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen A.","family":"Dufaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meera","family":"Sridharan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Bowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelyn S.","family":"Hanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H.","family":"Stephenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary L.","family":"Ellsworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy S.","family":"Sprague","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","unstructured":"Babu CR, Azhar S, Krishna Murti CR.Loss of epinephrine stimulated synthesis of cyclic adenosine 3\u2032:5\u2032 monophosphate during maturation of rabbit and human reticulocytes.Med Biol53: 148\u2013155, 1975."},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.03.089"},{"key":"R3","unstructured":"Beltman J, Becker DE, Butt E, Jensen GS, Rybalkin SD, Jastorff B, Beavo JA.Characterization of cyclic nucleotide phosphodiesterases with cyclic GMP analogs: topology of the catalytic domains.Mol Pharmacol47: 330\u2013339, 1995."},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.5"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/26.1.40"},{"key":"R6","unstructured":"Butt E, Beltman J, Becker DE, Jensen GS, Rybalkin SD, Jastorff B, Beavo JA.Characterization of cyclic nucleotide phosphodiesterases with cyclic AMP analogs: topology of the catalytic sites and comparison with other cyclic AMP-binding proteins.Mol Pharmacol47: 340\u2013347, 1995."},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1038\/36362"},{"key":"R8","doi-asserted-by":"crossref","unstructured":"Devic E, Xiang Y, Gould D, Kobilka B.\u03b2-Adrenergic receptor subtype-specific signaling in cardiac myocytes from \u03b21and \u03b22adrenoceptor knockout mice.Mol Pharmacol60: 577\u2013583, 2001.","DOI":"10.1016\/S0026-895X(24)12621-1"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1042\/bj3230371"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1249\/01.MSS.0000106284.80300.B2"},{"key":"R11","doi-asserted-by":"crossref","unstructured":"Fimia GM, Sassone-Corsi P.Cyclic AMP signaling.J Cell Sci114: 1971\u20131972, 2001.","DOI":"10.1242\/jcs.114.11.1971"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Fujitani K, Kambayashi J, Murata K, Yano Y, Shinozaki K, Yukawa M, Sakon M, Murata T, Kawasaki T, Shiba E, Mori T.Clinical evaluation on combined administration of oral prostacyclin analogue beraprost and phosphodiesterase inhibitor cilostazol.Pharmacol Res31: 121\u2013125, 1995.","DOI":"10.1016\/1043-6618(95)80057-3"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00349.2008"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1042\/bj20021698"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1124\/mol.62.5.971"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20051368"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2005.07.003"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615860"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1613099"},{"key":"R20","unstructured":"Maurice DH, Haslam RJ.Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP.Mol Pharmacol37: 671\u2013681, 1990."},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1124\/mol.64.3.533"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000200178.34179.93"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1042\/BST0340510"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00677.2003"},{"key":"R25","unstructured":"Olearczyk JJ, Stephenson AH, Lonigro AJ, Sprague RS.Receptor-mediated activation of the heterotrimeric G-protein Gsresults in ATP release from erythrocytes.Med Sci Monit7: 669\u2013674, 2001."},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1074683"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1358\/mf.1998.20.5.485699"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00691.2004"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00121.2006"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1177\/002215549904700707"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(82)90243-X"},{"key":"R32","doi-asserted-by":"crossref","unstructured":"Schermuly RT, Roehl A, Weissmann N, Ghofrani HA, Schudt C, Tenor H, Grimminger F, Seeger W, Walmrath D.Subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange.J Pharmacol Exp Ther292: 512\u2013520, 2000.","DOI":"10.1016\/S0022-3565(24)35320-0"},{"key":"R33","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022186402442"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.3.1588"},{"key":"R35","unstructured":"Sprague R, Bowles E, Stumpf M, Ricketts G, Freidman A, Hou WH, Stephenson A, Lonigro A.Rabbit erythrocytes possess adenylyl cyclase type II that is activated by the heterotrimeric G proteins Gsand Gi.Pharmacol Rep57: 222\u2013228, 2005."},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1080\/10739680701833804"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.275.5.H1726"},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1996.271.6.H2717"},{"key":"R39","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2001.281.4.C1158"},{"key":"R40","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.41.1.751"},{"key":"R41","unstructured":"Strehler BL.Bioluminescence assay: principles and practice.Methods Biochem Anal16: 99\u2013181, 1968."},{"key":"R42","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg628"},{"key":"R43","doi-asserted-by":"publisher","DOI":"10.2174\/156802607779941224"},{"key":"R44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1983.tb02065.x"},{"key":"R45","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601113"},{"key":"R46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0405263102"},{"key":"R47","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.106.144501"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.01226.2008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T23:09:00Z","timestamp":1738969740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.01226.2008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2009,5]]}},"alternative-id":["10.1152\/ajpheart.01226.2008"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.01226.2008","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5]]}}}