1 Adenosine and the adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) produced a small positive and negative inotropic effect, respectively, in isolated electrically driven papillary muscles of guinea-pigs. 2 Adenosine (100 mumol l-1) had no effect on cyclic AMP or cyclic GMP content. PIA (100 mumol l-1) slightly increased cyclic AMP. 3 In the presence of 3-isobutyl-1-methylxanthine (IBMX; 60 mumol l-1), which increased force of contraction 2 fold, adenosine and PIA exerted strong negative inotropic effects. PIA was more potent than adenosine (mean IC25 2.1 and 168 mumol -1, respectively). 4 In contrast, the nucleosides did not affect the increase in force of contraction produced by elevating extracellular Ca2+ concentration. 5 The IBMX-antagonistic effects of adenosine and PIA were not accompanied by modification of the IBMX-induced increase in cyclic AMP and cyclic GMP. 6 The effects of adenosine and PIA on force of contraction were accompanied by a partial reversal of the IBMX-induced increase in the maximal rate of depolarization of slow action potentials. 7 It is concluded that adenosine and PIA are able to attenuate the positive inotropic effect of a phosphodiesterase inhibitor. This effect is unlikely to be due to a reduction of the IBMX-induced increase in cyclic AMP content. It is conceivably due to an inhibition of the stimulant action of cyclic AMP on slow Ca2+ channels leading to the reduction of the slow inward current which in turn reduces force of contraction.