Effects of tumour necrosis factor-alpha on the coronary circulation of the rat isolated perfused heart: a potential role for thromboxane A2 and sphingosine.

1. The actions of tumour necrosis factor-alpha (TNF-alpha) on the coronary circulation were investigated in the rat isolated heart, perfused under constant flow, recirculating conditions. 2. An early increase in coronary perfusion pressure (CPP) was observed upon treatment with TNF-alpha (increase in CPP 10 min after TNF-alpha treatment: 45+/-12 mmHg vs control: 15+/-4 mmHg, P<0.05). The role of sphingosine, prostanoids and endothelins, in this coronary constrictor action, was investigated with the use of pharmacological inhibitors and antagonists. 3. The TNF-alpha induced increase in coronary tone was blocked by indomethacin, 10 microM (increase in CPP after 10 min: 13+/-4 mmHg vs TNF-alpha alone, P<0.05). 4. The thromboxane receptor antagonist GR32191, 10 microM, attenuated the TNF-alpha induced coronary constriction (12+/-2 mmHg vs TNF-alpha alone, P<0.05), as did the joint thromboxane A2 synthesis inhibitor and receptor antagonist ZD1542, 10 microM (8+/-1 mmHg vs TNF-alpha alone, P<0.05). 5. The ceramidase inhibitor N-oleoylethanolamine (NOE), 1 microM, also blocked the TNF-alpha induced response (8+/-4 mmHg vs TNF-alpha alone, P<0.05). 6. In contrast, the coronary constrictor action of TNF-alpha was not inhibited by the endothelinA/B receptor antagonist bosentan, 3 microM (38+/-9 mmHg vs TNF-alpha, P=NS). 7. These data indicated that the early coronary vasoconstriction induced by TNF-alpha was mediated by both thromboxane A2 and sphingosine, suggesting an interaction between both the sphingomyelinase and phospholipase A2 metabolic pathways.