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(Hypertension. 1998;31:943-948.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Adenosine Inhibits Collagen and Protein Synthesis in Cardiac Fibroblasts

Role of A_2B Receptors

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

From the Center for Clinical Pharmacology, Departments of Medicine (R.K.D., D.G.G.) and Pharmacology (E.K.J.), University of Pittsburgh Medical Center (Pa).

Correspondence to Dr Raghvendra K. Dubey, Center for Clinical Pharmacology, Department of Medicine, 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 objective of this study was to characterize the effects of exogenous and endogenous (cardiac fibroblast-derived) adenosine on [³H]proline and [³H]leucine incorporation, which are reliable markers of collagen and total protein synthesis, respectively, in rat left ventricular cardiac fibroblasts. Growth-arrested confluent cardiac fibroblast monolayers were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), or modulators of adenosine levels including (1) erythro-9-(2-hydroxy-3-nonyl) adenine (adenosine deaminase inhibitor), (2) dipyridamole (adenosine transport blocker), and (3) iodotubericidin (adenosine kinase inhibitor). All agents inhibited in a concentration-dependent fashion FCS-induced [³H]proline and [³H]leucine incorporation. These effects were blocked by KF17837 (selective A₂ antagonist) and 1,3-dipropyl-8-(p-sulfophenyl)xanthine (A₁/A₂ receptor antagonist) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A₁ antagonist), thus excluding the participation of A₁ receptors. The lack of effect of CGS21680 (selective A_2A agonist) excluded involvement of A_2A receptors, thus suggesting a major role for A_2B receptors. Comparisons of the inhibitory potencies of N⁶-cyclopentyladenosine (selective A₁ agonist), 5'-N-ethylcarboxamidoadenosine (A₁/A₂ agonist), and 5'-N-methylcarboxamidoadenosine (A₁/A₂ agonist) were consistent with that of an A_2B receptor subtype mediating the inhibitory effects. We conclude that adenosine inhibits FCS-induced collagen and total protein synthesis in cardiac fibroblasts via activation of A_2B receptors. These studies suggest, but do not prove, that endogenous adenosine may protect against cardiac fibrosis.

Key Words: adenosine • fibroblasts • myocardial infarction • extracellular matrix • collagen • hypertrophy

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