Effects of Theophylline and Dibutyryl-camp on Adenosine Receptors and Heart Rate in Cultured Cardiocytes

The effects of chronic exposure to the adenosine antagonist theophylline (Theo) and dibutyryl cyclic-AMP, a membrane-permeant derivative of the second messenger 3′,5′-cyclic-AMP (cAMP), on contractions and adenosine receptor levels in cultured cardiocytes were studied. Binding of the Ai-adenosine receptor antagonist [³H]8- cyclopentyl-1,3-dipropylxanthine ([³H]CPX) was used to monitor the level of the receptors in intact cardiocytes. Both Theo and cAMP stimulated the rate of contraction and also increased the density of adenosine receptors. The B_maxvalue for [³H]CPX binding to intact cardiocytes was increased by 45-47% following 4 days of exposure to either 50 μM Theo or 100 μ cAMP. Scatchard analysis indicated that the affinity of the Ai receptors for [³H]CPX remained unchanged (K_d0.1-0.2 nM). No significant differences were observed in protein content or in cell number. A linear correlation was achieved between the level of A₁-adenosine receptors and heart rate at various Theo and dibutyryl-cAMP concentrations, although Theo was more efficient in elevation of the receptor density. Increases of 82, 78, 138 and 235% in A₁receptor density and increases of 63, 59, 66 and 150% in heart rate were obtained following 5 days of treatment with 1,10, and 1000 μM of Theo, respectively. It is concluded that there is a linkage between the rate of cardiac contractions and the level of adenosine receptors. Thus, changes in the density of adenosine receptors may compensate for chronic drug-induced changes in cardiac contractile activity so as to restore conditions to the normal state.