{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:20:15Z","timestamp":1789579215874,"version":"build-2803163510"},"reference-count":14,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Hypertension"],"published-print":{"date-parts":[[2000,9]]},"abstract":"<jats:p><jats:italic>Abstract<\/jats:italic>\u2014The extracellular \u201ccAMP-adenosine pathway\u201d refers to the local production of adenosine mediated by cAMP egress into the extracellular space, conversion of cAMP to AMP by ectophosphodiesterase, and the metabolism of AMP to adenosine by ecto-5\u2032-nucleotidase. The goal of this study was to assess whether the cAMP-adenosine pathway limits cardiac fibroblast growth. Studies were conducted in ventricular cardiac fibroblasts maintained in 3-dimensional cultures. Addition of exogenous cAMP to cardiac fibroblasts increased extracellular levels of AMP, adenosine, and inosine in a concentration-dependent and time-dependent manner. This effect was attenuated by blockade of total phosphodiesterase activity (3-isobutyl-1-methylxanthine), ectophosphodiesterase activity (high concentration of 1,3-dipropyl-8-<jats:italic>p<\/jats:italic>-sulfophenylxanthine), or ecto-5\u2032-nucleotidase (\u03b1, \u03b2-methylene-adenosine-5\u2032-diphosphate). Treatment with exogenous cAMP inhibited cell growth as assessed by DNA synthesis (<jats:sup>3<\/jats:sup>H-thymidine incorporation), cell proliferation (cell counts), and protein synthesis (<jats:sup>3<\/jats:sup>H-leucine incorporation). Antagonism of A<jats:sub>2<\/jats:sub>(KF17837) or A<jats:sub>1<\/jats:sub>\/A<jats:sub>2<\/jats:sub>(low concentration of 1,3-dipropyl-8-<jats:italic>p<\/jats:italic>-sulfophenylxanthine), but not A<jats:sub>1<\/jats:sub>(8-cyclopentyl-1,3-dipropylxanthine), adenosine receptors blocked the growth-inhibitory effects of exogenous cAMP, but not the growth inhibitory effects of 8-bromo-cAMP (stable cAMP analogue). The growth-inhibitory effects of exogenous cAMP were enhanced by the combined inhibition of adenosine deaminase [erythro-9-(2-hydroxy-3-nonyl) adenine] and adenosine kinase (iodotubercidin). In conclusion, the extracellular cAMP-adenosine pathway exists in cardiac fibroblasts and attenuates cell growth. Pharmacological augmentation of this pathway could abate pathological cardiac remodeling in heart disease.<\/jats:p>","DOI":"10.1161\/01.hyp.36.3.337","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:25:31Z","timestamp":1339460731000},"page":"337-342","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["Cardiac Fibroblasts Express the cAMP-Adenosine Pathway"],"prefix":"10.1161","volume":"36","author":[{"given":"Raghvendra K.","family":"Dubey","sequence":"first","affiliation":[{"name":"From the Departments of Medicine (R.K.D., D.G.G., Z.M., E.K.J.) and Pharmacology (E.K.J.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pa; and Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, Switzerland (R.K.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delbert G.","family":"Gillespie","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (R.K.D., D.G.G., Z.M., E.K.J.) and Pharmacology (E.K.J.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pa; and Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, Switzerland (R.K.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaichuan","family":"Mi","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (R.K.D., D.G.G., Z.M., E.K.J.) and Pharmacology (E.K.J.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pa; and Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, Switzerland (R.K.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin K.","family":"Jackson","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (R.K.D., D.G.G., Z.M., E.K.J.) and Pharmacology (E.K.J.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pa; and Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich, Switzerland (R.K.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.31.040191.000245"},{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/S0022-3565(25)09492-3","volume":"273","year":"1995","unstructured":"Mi Z, Jackson EK. Metabolism of exogenous cyclic AMP to adenosine in the rat kidney. J Pharmacol Exp Ther. 1995;273:728\u2013733.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.28.5.765"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.31.1.296"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1016\/S0022-3565(24)37882-6","volume":"287","year":"1998","unstructured":"Mi Z, Jackson EK. Evidence for an endogenous cAMP-adenosine pathway in the rat kidney. J Pharmacol Exp Ther. 1998;287:926\u2013930.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(96)88507-5"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02723005"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/S0022-3565(25)21284-8","volume":"279","year":"1996","unstructured":"Jackson EK, Mi Z, Koehler MT, Carcillo JA Jr, Herzer WA. Injured erythrocytes release adenosine deaminase into the circulation. J Pharmacol Exp Ther.. 1996;279:1250\u20131260.","journal-title":"J Pharmacol Exp Ther."},{"key":"e_1_3_2_9_2","first-page":"850","volume":"256","year":"1991","unstructured":"Tofovic SP, Branch KR, Oliver RD, Magee WD, Jackson EK. Caffeine potentiates vasodilator-induced renin release. J Pharmacol Exp Ther. 1991;256:850\u2013860.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_2_10_2","first-page":"19","volume":"14","year":"1996","unstructured":"Jackson EK, Koehler M, Mi Z, Dubey RK, Tofovic SP, Carcillo JA, Jones GS. Possible role of adenosine deaminase in vaso-occlusive diseases. J Hypertens. 1996;14:19\u201329.","journal-title":"J Hypertens"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2850345"},{"key":"e_1_3_2_12_2","first-page":"119","volume":"15","year":"1983","unstructured":"Barber R, Butcher RW. The egress of cyclic AMP from metazoan cells. Adv Cyclic Nucleotide Res. 1983;15:119\u2013138.","journal-title":"Adv Cyclic Nucleotide Res"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.27.3.786"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.96.8.2656"}],"container-title":["Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.HYP.36.3.337","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T19:40:05Z","timestamp":1743363605000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.HYP.36.3.337"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,9]]},"references-count":14,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2000,9]]}},"alternative-id":["10.1161\/01.HYP.36.3.337"],"URL":"https:\/\/doi.org\/10.1161\/01.hyp.36.3.337","relation":{},"ISSN":["0194-911X","1524-4563"],"issn-type":[{"value":"0194-911X","type":"print"},{"value":"1524-4563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,9]]},"assertion":[{"value":"1999-09-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-03-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-09-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}