Experiments were undertaken to establish whether prazosin prevents isolated hearts from gaining excess Ca2+ during post-ischaemic reperfusion, to determine whether this effect is dose-dependent, if it is accompanied by a change in the energy-rich phosphate reserves, and whether prazosin is effective when added only upon reperfusion. Isolated, spontaneously beating rat hearts were used. The ischaemic episodes ranged from 15 to 60 min, and prazosin (0.01 to 10 micro mol/1) was added both before inducing ischaemia and upon reperfusion. When 0.01 to 1 micro mol/1 prazosin was present before and after the ischaemic episode the reperfusion-induced gain in Ca2+ was attenuated, but not abolished. Pretreatment with 0.01 to 1 micro mol/1 prazosin slowed the ischaemic-induced rise in resting tension, enhanced mechanical recovery after 30 but not 60 min ischaemia, and exerted a dose-dependent slowing effect on the ischaemia-induced depletion of ATP and CP, with 1 micro mol/1 being the optimal dose. Adding 0.01 to 1 micro mol/1 prazosin at the time of reperfusion neither prevented excess Ca2+ accumulation upon reperfusion nor did it exert an energy-sparing effect. 5 to 10 micro mol/1 prazosin did not attenuate the reperfusion-induced gain in Ca2+, irrespective of whether it was added before or only at the time of reperfusion. These results show that the dose-response curve for the inhibitory effect of prazosin on Ca2+ overload is complex, and that adding prazosin coincident with the reperfusion of isolated ischaemic hearts does not attenuate Ca2+ gain.