Three groups of rabbit hearts (n = 5 in each) were perfused with blood and were subjected to 45 minutes of global normothermic (37 degrees C)
ischemia, followed by 1 hour of reperfusion. Group 1 was the control group (vehicle only); in group 2,
HOE 694 (1 mumol/L) was administered before
ischemia (pretreatment group); and in group 3,
HOE 694 was given only during reperfusion to separate actions exerted during
ischemia from those specifically obtained during reperfusion. End-diastolic pressure rise at 1 hour of reperfusion was reduced by administration of
HOE 694 starting before
ischemia (from 52.2 +/- 8.5 mm Hg in group 1 to 17.6 +/- 4.5 mm Hg in group 2, P < .01) or starting on reperfusion (28.8 +/- 5.4 mm Hg in group 3, P < .05 versus group 1). Left ventricular developed pressure (LVDP) and its derivative (dP/dt) recovered better in HOE 694-pretreated hearts (LVDP, 79 +/- 9.9 mm Hg in group 2 versus 24.8 +/- 10 mm Hg in group 1; dP/dt, 1580 +/- 198 mm Hg/s versus 340 +/- 221 mm Hg/s, P < .01). In hearts treated only on reperfusion, some improvement was observed, which, however, did not reach statistical significance. Coronary flow on reperfusion was higher in groups 2 and 3 compared with controls, and no "no-reflow" was observed. Two additional groups of hearts were perfused with
phosphate-free
Krebs-Henseleit solution to enable studies with 31P nuclear magnetic resonance (NMR).
ATP was better preserved in HOE 694-pretreated (62 +/- 4.9% of preischemic value) than in control hearts (44 +/- 3.3%) at the end of 30 minutes of reperfusion, and
phosphocreatine resynthesis was higher (109 +/- 3.7% versus 86 +/- 5.4%).
HOE 694 did not affect the time course of intracellular
acidosis during
ischemia but suppressed a small alkaline overshoot occurring early in reperfusion (pH 6.96 +/- 0.02 in
HOE 694-pretreated hearts versus 7.14 +/- 0.05 in control hearts). Electron microscopy with Ca2+ staining of the blood-perfused hearts showed that clumping of Ca2+ aggregates in mitochondria was prevented by
HOE 694.
CONCLUSIONS: Postischemic dysfunction was associated with a rise in end-diastolic pressure. This rise was effectively blocked by
HOE 694. The
drug was most effective when hearts were treated before
ischemia, although partial protection was observed when administration was started on reperfusion. The action of
HOE 694 strengthens the idea that Na(+)-H+ exchange during both
ischemia and reperfusion contributes to contractile dysfunction.