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(Hypertension. 2000;36:337.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Cardiac Fibroblasts Express the cAMP-Adenosine Pathway

Raghvendra K. Dubey; Delbert G. Gillespie; Zaichuan Mi; Edwin K. Jackson

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.).

Correspondence to Dr Raghvendra K. Dubey, Center for Clinical Pharmacology, 623 Scaife Hall, 200 Lothrop St, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582. E-mail dubey{at}novell2.dept-med.pitt.edu

Abstract—The extracellular "cAMP-adenosine pathway" 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'-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-p-sulfophenylxanthine), or ecto-5'-nucleotidase (, ß-methylene-adenosine-5'-diphosphate). Treatment with exogenous cAMP inhibited cell growth as assessed by DNA synthesis (³H-thymidine incorporation), cell proliferation (cell counts), and protein synthesis (³H-leucine incorporation). Antagonism of A₂ (KF17837) or A₁/A₂ (low concentration of 1,3-dipropyl-8-p-sulfophenylxanthine), but not A₁ (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.

Key Words: adenosine • cyclic AMP • cardiac fibroblast • myocardial infarction • cardiac remodeling

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