Thromboxane receptor-mediated bronchial and hemodynamic responses in ovine endotoxemia.
The role of thromboxane A2 in sheep endotoxemia, an animal model of the adult respiratory distress syndrome, was investigated by a combined biochemical and pharmacological approach. Endogenous thromboxane biosynthesis was assessed by gas chromatographic-mass spectrometric analysis of urinary (thromboxane B2, 2,3-dinor-thromboxane B2) and plasma (11-dehydrothromboxane B2) metabolites that demonstrated a significant stimulation by endotoxin. The functional relevance of thromboxane A2 was probed with a specific thromboxane-prostaglandin endoperoxide receptor antagonist, SQ 29548. The antagonist significantly blunted the increase in pulmonary arterial pressure, pulmonary vascular resistance, lung lymph flow, and lymph protein clearance induced by endotoxin. Whereas the reduction in lung compliance caused by endotoxin was abolished, the augmented airway resistance was unaffected. From the simultaneous increase in thromboxane biosynthesis and effects of receptor blockade, it was concluded that thromboxane A2 mediates the early pathophysiological changes of sheep endotoxemia. Thromboxane receptor antagonism may offer a potential therapeutic approach to patients at risk of the adult respiratory distress syndrome.
Kühl
P G
PG
Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
Bolds
J M
JM
Loyd
J E
JE
Snapper
J R
JR
FitzGerald
G A
GA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000403:Airway Resistance; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002302:Cardiac Output; D004537:Eicosanoic Acids / Q000096:biosynthesis; D004731:Endotoxins / Q000097:blood; D005231:Fatty Acids, Unsaturated; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006439:Hemodynamics; D006834:Hydrazines / Q000494:pharmacology; D008196:Lymph / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism; D011652:Pulmonary Circulation; D011982:Receptors, Prostaglandin / Q000502:physiology*; D017482:Receptors, Thromboxane; D012128:Respiratory Distress Syndrome / Q000503:physiopathology; D018805:Sepsis / Q000503:physiopathology*; D012756:Sheep; D014655:Vascular Resistance
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004537:Eicosanoic Acids; D004731:Endotoxins; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548