Evidence that a novel 8-phenyl-substituted xanthine derivative is a cardioselective adenosine receptor antagonist in vivo.

The ability of caffeine, enprofylline (3-propylxanthine), 8-phenyltheophylline, 8-p-sulphophenyl-theophylline, 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine, and 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine-2-aminoethyl amide (XAC) to antagonize the effects of an adenosine analogue, N-5'-ethylcarboxamidoadenosine, on heart rate and blood pressure in anesthetized rats was examined. The first five xanthine derivatives were equally active in antagonizing the two responses. By contrast, XAC was approximately 20 times more potent in antagonizing the heart rate response than the blood pressure response. Measurements of the concentration of XAC in plasma and brain indicate that it penetrates the central nervous system poorly. It is concluded that XAC is a cardioselective adenosine antagonist, and since adenosine is supposed to reduce heart rate via an effect on A1-receptors, and the blood pressure via A2-receptors, XAC may be a selective A1-adenosine receptor antagonist in vivo.