A1- and A2-selective adenosine antagonists: in vivo characterization of cardiovascular effects.

Caffeine, a nonselective adenosine receptor antagonist, 7-methyl-1,3-dipropylxanthine, a purported A2 selective antagonist and a 1,3-dipropyl-8-phenylxanthine amine congener (XAC), an A1 selective antagonist, were evaluated for their in vivo selectivity at A1 vs. A2 adenosine receptors. Blockade of the negative chronotropic effect of bolus i.v. injections of 2-chloroadenosine, R-phenylisopropyladenosine and N-ethylcarboxamidoadenosine was utilized as an index of antagonism at A1 receptors; blockade of the hypotensive effect of the same series of adenosine agonists was used as an index of activity at A2 receptors. In addition, blockade of the potentiating effect of adenosine on the hypertensive and chronotropic effects of nicotine was studied to assess further the role of A1 and A2 adenosine receptors in this response. The potent antagonist XAC displayed considerable A1 selectivity as demonstrated by blockade of adenosine receptor-mediated bradycardia at doses 5- to 10-fold lower than those antagonizing adenosine receptor-mediated hypotension. XAC also selectively blocked potentiation by adenosine of the positive chronotropic effect of nicotine, at doses which had minimal effects on the enhancement of the hypertensive effect of nicotine. The caffeine homolog 7-methyl-1,3-dipropylxanthine exhibited A2 selectivity as demonstrated by prevention of adenosine receptor-mediated hypotension at doses which only minimally attenuated the bradycardiac effect of adenosine analogs. Caffeine displayed no selectivity for A1 vs. A2 adenosine receptors. The results indicate that selective analogs such as XAC and F-methyl-1,3-dipropylxanthine will be useful probes for investigation of receptors involved in the physiological functions of adenosine.