DIFFERENTIAL SENSITIZATION OF CARDIAC ACTIONS OF ADENOSINE IN RATS AFTER CHRONIC THEOPHYLLINE TREATMENT

To determine the effect of chronic adenosine receptor blockade on atri al responsiveness, we administered theophylline to rats in their drink ing water (0.6 mg/ml) for 2 wk. Inotropic and chronotropic responses t o the adenosine receptor agonists N6-cyclopentyladenosine (CPA) and 5' -(N-ethylcarboxamido)adenosine (NECA) were then measured in isolated a tria from treated and control animals. The indirect (antiadrenergic) a ctions of CPA and NECA on force and rate, measured during beta-adrener gic receptor stimulation by isoproterenol, were markedly sensitized (2 - to 10-fold reductions in the agonist concentration needed to obtain a half-maximal response) after theophylline. The sensitization was hom ologous because inotropic and chronotropic responses to carbachol were not affected by theophylline. The direct negative inotropic and chron otropic actions of CPA and NECA, measured without concomitant beta-adr energic stimulation, were not sensitized after theophylline. The numbe r of atrial A1-receptors, measured by antagonist radioligand binding ( maximum specific binding at saturation), was increased by 22% in theop hylline-treated rats [66.2 +/- 3.4 vs. 54.3 +/- 1.9 (control) fmol/mg protein, P < 0.05]. Competition binding indicated that the fraction of coupled (high-affinity) receptors was unchanged. The number of ventri cular A1-receptors was increased to a similar extent without any chang e in coupling. Thus chronic dietary theophylline upregulated cardiac A 1-adenosine receptors without changing coupling state or affinity and sensitized rat atria to the indirect, antiadrenergic, inhibitory inotr opic and chronotropic actions of adenosine receptor agonists.