Pneumotoxicity of lipopolysaccharide in nitric oxide-deficient rats is limited by a thromboxane synthase inhibitor.
Both nitric oxide and arachidonic acid metabolites have been implicated in pathogenesis of septic shock. We have recently described a model of endotoxin-induced acute lung injury in rats in which nitric oxide synthase is inhibited. The possible interplay between nitric oxide and eicosanoids (thromboxane A2, prostacyclin) in this model have been presently studied. Animals were randomly assigned to four experimental groups which received the following treatment. 1. Lipopolysaccharide (LPS) infusion only, 2 mg.kg-1min-1 during 10 min (LPS group). 2. N omega-Nitro-L-Arginine 10 mg.kg-1 (L-NNA, nitric oxide synthase inhibitor) pretreatment followed by LPS infusion (L-NNA + LPS group). 3. L-NNA and camonagrel 25 mg.kg-1 (CAM, thromboxane synthase inhibitor) pretreatment followed by LPS infusion (L-NNA + CAM + LPS group). 4. L-NNA and iloprost 0.3 microgram.kg-1.min-1(ILO, stable analog of prostacyclin) pretreatment followed by LPS infusion (L-NNA + ILO + LPS group). LPS infusion resulted in a biphasic response in mean arterial blood pressure. A transient but deep fall in arterial blood pressure was followed by a long-lasting hypotension that led to death after 278 +/- 49 min. L-NNA + LPS rats died within 22 +/- 5 min among the symptoms of systemic hypotension and acute lung injury. In L-NNA + CAM + LPS group a significant attenuation of early phase of hypotension occurred and survival time was comparable with that of the LPS group (298 +/- 68 min). In rats of the L-NNA + ILO + LPS group survival time increased insignificantly to 48 +/- 41 min. It is concluded that immediate deleterious effects of lipopolysaccharide in NO-deficient rats are at least partially mediated by thromboxane A2 while prostacyclin cannot replace NO in its pneumoprotective action.
Wołkow
P P
PP
Department of Pharmacology, Jagiellonian University, Medical College, Cracow, Poland.
Bartuś
J B
JB
Gryglewski
R J
RJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D011464:Epoprostenol / Q000502:physiology; D004926:Escherichia coli; D007189:Indans / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008171:Lung Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013928:Thromboxane A2 / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D007189:Indans; D008070:Lipopolysaccharides; D019335:Nitroarginine; D009569:Nitric Oxide; D013928:Thromboxane A2; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D013930:Thromboxane-A Synthase; C103583:camonagrel