Mannitol has been shown to exert a dose-dependent, antiarrhythmic effect in the rat heart during reperfusion following a brief period of regional myocardial ischemia. Isolated perfused rat hearts were used to determine whether this protective effect is direct (ie, operative during reperfusion) or indirect (ie, due to an action during ischemia). Hearts (12 in each group) were subjected to 5, 10, 20, 30 or 40 mins of regional ischemia which was induced by ligation of the left anterior descending coronary artery. Upon reperfusion 25%, 100%, 83%, 33% and 17%, respectively, of the hearts fibrillated and 8%, 92%, 58%, 17% and 17% remained in irreversible fibrillation for the duration of the reperfusion period. Addition of mannitol (50 mM, the optimal antiarrhythmic dose) to the perfusion fluid throughout the experiment (early administration) caused a shift of this 'bell-shaped' time-vulnerability curve to the right such that the highest incidence of arrhythmias occurred after 20 mins rather than 10 mins of ischemia. Similar shifts were seen in other indices of electrical instability. Regional ischemia caused a 40 to 45% reduction in coronary flow in all groups of hearts, with no significant difference between the control and the mannitol-treated series. Heart rate fell by a mean of 10 to 15% in all control hearts and by a similar extent in mannitol-treated hearts. In additional studies, mannitol (50 mM) was administered 2 mins before reperfusion and throughout the reperfusion period (late administration studies). In the mannitol-free control group 100% of the hearts exhibited fibrillation and 92% remained in fibrillation for the duration of the reperfusion period.(ABSTRACT TRUNCATED AT 250 WORDS)