The postischemic response of control, acute diabetic (48 h) and chronic diabetic (60 days) hearts was studied in isovolumically-perfused rat hearts. Isolated hearts were subjected to 20 min of total global ischemia with reperfusion at preischemic flow rates in the presence or absence of the thromboxane analogue, U-46619. A low concentration (30 nM) of U-46619 which did not produce significant hemodynamic responses prior to ischemia caused significant decreases in isovolumic left ventricular developed pressure and increases in coronary vascular resistance during reperfusion of control but not acute or chronic diabetic hearts. Simultaneously, U-46619 stimulated an additional increment of prostacyclin release during reperfusion of control but not diabetic hearts. Thus, while diabetic hearts may be resistant to certain stimuli of postischemic injury, a caveat results in that the diabetic heart may be jeopardized by a failure to counter other potentially thrombotic or vasospastic factors in vivo by an inadequate compensatory increase in prostacyclin.