We investigated the temporal and spatial development of infarcts in porcine hearts to evaluate the time-dependent beneficial effect of reperfusion on infarct size. The left anterior descending coronary artery (LAD) was occluded in 17 pigs for different periods of time followed by 4 hours of reperfusion. Transmural needle biopsies subdivided into subendocardial and subepicardial halves were taken from the ischemic apex after 60 min of ischemia to determine the tissue concentrations of ATP and NAD. The myocardium-at-risk was assessed with a fluorescent dye injected into the right atrium at the end of the experiments, just after the LAD had been reoccluded. The excised hearts were cut into slices parallel to the heart basis. The ischemic myocardium was measured by planimetry of the non-fluorescent areas whereas the infarcted tissue was determined with the NBT stain and related to the area-at-risk. Ischemic cell death started in the jeopardized left ventricular subendocardial septum after about 30 min of ischemia. The further progress involved the right subendocardial septum and the subendocardium of the left anterior free wall. Already after 75 min of ischemia most of the myocytes-at-risk were irreversibly injured. Infarctions reached their final extent after 90-120 min of ischemia. These results indicate that in hearts without a significant collateral blood flow reperfusion can only reduce infarct size if its initiated within 60-75 min of ischemia. Like in canine hearts infarctions progress from the ischemic subendocardium towards the outer layers.

IT IS well accepted that the speed at which ischemic myocytes die depends on the extent of the imbalance between oxygen supply and demand. 2Accordingly, a number of agents have been found that delay the development of infarcts by reducing myocardial oxygen consumption during ischemia.3 Among them are calcium antagonists, a heterogeneous group of compounds that can improve the myocardial oxygen supply-demand balance by depressing myocardial contractility, decreasing heart rate, and inducing coronary vasodilation. A beneficial effect of calcium antagonists on ischemic cellular injury has been demonstrated in a variety of different preparations,5-1 although in some studies this favorable influence has not been observed.'2'13 Since the basic action of calcium antagonists is not only an inhibition of the slow channel in myocytes and pacemaker cells but also in all types of smooth muscle cells (which results in a systemic and coronary vasodilation'4), it is difficult to distinguish in intact animals the beneficial effect that is due to an obviously improved oxygen supply-demand ratio (e.g.,

Urethane-anesthetized thoracotomized rats were used to ascertain whether the density of plasma-perfused capillaries increases in the heart during pharmacologically induced vasodilation. Carbocromene, in a dose of 3.0 mg/(kg x min) i.v., infused for 5 min, raised coronary blood flow from 6.2 +/- 0.6 to 15.6 +/- 0.1 ml/(min x g); heart rate and blood pressure were only slightly changed. Capillary density was determined by timed infusions of a plasma label (FITC or RB 200 coupled with gamma-globulin), infused for different periods of time in the same animal. No significant difference could be observed in the number of capillaries marked for 10 min in the carbocromene-treated rats as compared to the controls (carbocromene-treated rats: 3,630 +/- 90 cap/mm2 subepicardium, 3,360 +/- 70 cap/mm2 subendocardium; controls: 3,750 +/- 140 cap/mm2 subepicardium, 3,210 +/- 90 cap/mm2 subendocardium). In those rats treated with the vasodilator the filling of the microcirculatory system was nearly complete within a labelling period of 1 sec (3,500 +/- 170 cap/mm2 subepicardium, 3,070 +/- 110 cap/mm2 subendocardium), whereas significantly lower values were found when the dye was infused for 1 sec in the controls (2,560 +/- 460 cap/mm2 subepicardium, 1,960 +/- 400 cap/mm2 subendocardium). The results indicate that the filling of the cardiac microcirculatory system is accelerated by a pharmacologically induced vasodilation, the maximal density of plasma-perfused capillaries is not raised, however.

We investigated the effect of reperfusion with hyperosmotic mannitol on the infarct size in porcine hearts. The distal half of the left anterior descending coronary artery was occluded in each of 21 anesthetized pigs for 75 min and was reperfused for 2 h. During reperfusion mannitol (1075 mosmol/kg) was intracoronarily infused at a dose of 0.5 ml/min in 6 pigs ("low" mannitol group), at a dose of 1.5 ml/min in another 6 pigs ("high" mannitol group), and at a dose of 5 ml/min in 3 pigs for the first 8 min of reperfusion ("very high" mannitol group). 6 pigs served as controls. Although mannitol infusion increased plasma osmolality in the ischemic, reperfused myocardium in all experiments, the infarct size expressed as the ratio of the infarcted tissue over the area at risk of necrosis was not significantly influenced. Infarct size amounted to 72 +/- 25% in the control group, to 75 +/- 14% in the "low" mannitol group, to 78 +/- 18% in the "high" mannitol group, and to 93 +/- 8% in the "very high" mannitol group. These results clearly indicate that reperfusion with hyperosmotic mannitol after 75 min of ischemia does not exert any beneficial effect on the infarct size.

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