Vasoactive eicosanoids in the rat heart: Clues to a contributory role of cardiac throm☐ane to post-ischaemic hyperaemia

Abstract

To assess the potential role of vasoactive cardiac eicosanoids in the modulation of coronary flow, we measure throm☐ane(TX)B 2, 6-keto-prostaglandin(PG)F 1α, PGE 2 and sulphido-peptide leukotrienes (LTC 4, D 4, E 4) in the coronary effluent of isolated perfused rat heart in both baseline and post-ischaemic conditions. Leukotrienes were undetectable. The order of production rate for the other eicosanoids was 6-keto-PGF 1α > TXB 2 > PGE 2. Production of such substances was increased about seven-fold over control after 5 min. global ischaemia; experiments with hypoxia showed that this was due to an actual increase in synthesis and not to a washout effect. A platelet source for TXB 2 was excluded by 111In platelet labelling experiments. We assessed relative sensitivity to inhibition of cardiac TX synthesis relative to production of 6-keto-PGF 1α to inhibition by aspirin, ibuprofen, diclofenac and the specific throm☐ane synthase inhibitor OKY-046. Aspirin, ibuprofen and diclofenac decreased 6-keto-PGF 1α production at a concentration always greater than required for a similar extent of TX inhibition. On the other hand a selective inhibition (> 90%) of TX was observed in the presence of OKY-046. Regression analysis of various 6-keto-PGF 1α/TXB 2 ratios, as obtained in these different conditions, vs coronary flow, showed no cor relation in baseline conditions, but a significant positive correlation ( r = 0.59, P < 0.01) for post-ischaemic values. These data suggest a role for cardiac eicosanoids, including a non-platelet, cardiac-derived TX, in modulating the hyperaemic response in the isolated rat heart.