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Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 \u03bcmol\/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol\/L; an inhibitor of both extracellular and intracellular phosphodiesterase), \u03b1,\u03b2-methyleneadenosine 5\u2032-diphosphate (AMP-CP, 100 \u03bcmol\/L; an ecto-5\u2032-nucleotidase inhibitor), and 1,3-dipropyl-8-<jats:italic>p<\/jats:italic>-sulfophenylxanthine (DPSPX, 100 \u03bcmol\/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5\u2032-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10<jats:sup>\u22124<\/jats:sup>mol\/L) and 8-bromo-cAMP (10<jats:sup>\u22124<\/jats:sup>mol\/L) on fetal calf serum\u2013induced DNA synthesis ([<jats:sup>3<\/jats:sup>H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A<jats:sub>2<\/jats:sub>adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5\u2032-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.<\/jats:p>","DOI":"10.1161\/01.hyp.28.5.765","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:53:46Z","timestamp":1339462426000},"page":"765-771","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":63,"title":["Cyclic AMP\u2013Adenosine Pathway Inhibits Vascular Smooth Muscle Cell Growth"],"prefix":"10.1161","volume":"28","author":[{"given":"Raghvendra K.","family":"Dubey","sequence":"first","affiliation":[{"name":"the Center for Clinical Pharmacology, Laboratory of Cell Biology and Physiology, Departments of Medicine and Pharmacology (E.K.J.), University of Pittsburgh (Pa) Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaichuan","family":"Mi","sequence":"additional","affiliation":[{"name":"the Center for Clinical Pharmacology, Laboratory of Cell Biology and Physiology, Departments of Medicine and Pharmacology (E.K.J.), University of Pittsburgh (Pa) Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delbert G.","family":"Gillespie","sequence":"additional","affiliation":[{"name":"the Center for Clinical Pharmacology, Laboratory of Cell Biology and Physiology, Departments of Medicine and Pharmacology (E.K.J.), University of Pittsburgh (Pa) Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin K.","family":"Jackson","sequence":"additional","affiliation":[{"name":"the Center for Clinical Pharmacology, Laboratory of Cell Biology and Physiology, Departments of Medicine and Pharmacology (E.K.J.), University of Pittsburgh (Pa) Medical Center."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(79)90115-8"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(81)90100-X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S0022-3565(25)20893-X","volume":"232","year":"1985","unstructured":"Churchill PC, Churchill MC. 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