Text Box: CYCLOOXYGENASE (COX) INHIBITOR CAN ENHANCE THE RESPONSE TO INHALED NTRIC OXIDE AND PREVENT THE REBOUND RESPONSE AFTER ITS DISCONTINUATION
Chen Luni, Mondejar Enrique Fernandez, He Hao, Hedenstierna Göran
Department of Medical Science, University Hospital, Uppsala, Sweden

Inhaled nitric oxide (INO) may be an efficient therapy in the patients with pulmonary hypertension, but around 1/3 of the patients are hypo- or non-responders to INO. In addition, life-threatening hemody-namic instability and reduction in oxygenation, have been observed during attempts to withdraw INO (“rebound response’’). This study investigated the possible role of cyclo-oxgenase (COX) and its products in the ‘‘hypo-response and rebound’’ to INO and INO withdrawal. 
Materials and Methods: 34 anesthetized, mechanically ventilated piglets were given endotoxin infusion. 12 animals then received INO (30 ppm) for two 30-min periods, another 12 received both INO and COX inhibitor Diclofenac 3 mg/kg/iv. Ten controls were not given NO and Diclofenac. Measurements were made of blood gases and hemodynamic parameters, lung tissue COX expression and plasma prostanoids (PGs) concentration.
Result: Endotoxin induced pulmonary hypertension and hypoximia. INO decreased MPAP and increased PaO2, but INO withdrawal caused a short rebound reaction. Up-regulation of lung tissue expression of inducible COX by expose to endotoxin, and of constitute COX by INO was recorded. Plasma concentration of TXA2, PGF2a and PGI2 also time dependently increased during endotoxin infusion, and plasma TXA2 increased further after INO withdrawal. The administration of Diclofenac fully absorbed the rebound reaction to INO withdrawal and enhanced the response to INO; and down-regulated the expression of COX, absorbed the further increase of plasma PGs by endotoxin and INO. 
Conclusion: we consider that both hypo-response and rebound response to INO and INO discontinuation are related to COX products, TXA2, PGF2a and may other PGs. Combination of INO with COX inhibitor has important clinical implications.

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