Effects of tumour necrosis factor-α 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 mu M (increase in CPP after 10 min: 13+/-4 mmHg vs TNF-alpha alone, P<0.05). 4 The thromboxane receptor antagonist GR32191, 10 mu M, attenuated the TNF-alpha induced coronary constriction (12+/-2 mmHg vs TNF-alpha alone, P<0.05), as did the joint thromboxane A(2) synthesis inhibitor and receptor antagonist ZD1542, 10 mu M (8+/-1 mmHg vs TNF-alpha alone, P<0.05). 5 The ceramidase inhibitor N-oleoylethanolamine (NOE), 1 mu M, 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 endothelin(A/B) receptor antagonist bosentan, 3 mu M (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 A(2) and sphingosine, suggesting an interaction between both the sphingomyelinase and phospholipase A(2) metabolic pathways.