Effect of ischaemia and role of eicosanoids in release of atrial natriuretic factor from rat heart

Objective: The aim was to investigate (1) the relationship between atrial natriuretic factor (ANF) release and the extent of ischaemia-hypoxia, and (2) the potential role of eicosanoids in ANF release during global ischaemia, particularly the cyclo-oxygenase derivatives (prostaglandins) and the lipoxygenase derivatives (leukotrienes). Methods: Using an isolated perfused, spontaneously beating rat heart, global ischaemia was achieved by the reduction of perfusion flow rate relative to basal flow rate. ANF was measured by radioimmunoassay. Results: A decrease in perfusion flow rate by 75-80% to a final value of 2-2.5 ml·min−1·g−1 heart (n=6) caused a gradual but sustained increase of ANF release which reached a plateau after 12 min, attaining a peak value of 89.9(SEM 26.6)% over baseline. A decrease in perfusion flow rate by 55-60% (n=5) also resulted in an increased ANF secretion, with a peak of 125.6(23.2)% over baseline at 14 min. A decrease in perfusion flow rate by 25-30% to a final value of 5-6.75 ml·min−1·g−1 heart (n=4) showed no change in ANF release. The mean basal value of ANF release was 8.23(2.39) ng·min−1·g−1 heart (n=26). In a separate series of experiments using a reduction of 55-60% in perfusion flow rate but with the addition to the perfusion medium of the specific cyclo-oxygenase inhibitor meclofenamate 10 μM (n=5) or the lipoxygenase inhibitor nordihydroguaiaretic acid 10 μM (n=5), no increase in ANF release occurred during the period of global ischaemia. Neither inhibitor affected ANF release during basal perfusion rates (7-9 ml·min−1·g−1 heart). Conclusions: ANF released in response to global ischaemia is likely to be mediated by prostanoids generated via the cyclo-oxygenase pathway and leukotrienes generated via the lipoxygenase pathway. Both pathways may provide important paracrine/autacoid regulatory roles for the protection of the heart during ischaemia by stimulating ANF release, with the subsequent beneficial effects of the peptide on peripheral tissues, ultimately leading to a reduction in load on the heart. Cardiovascular Research 1993;27:000-000