sq-29548 and Sepsis

Cyclooxygenase (COX) products play an important role in modulating sepsis and subsequent endothelial injury. We hypothesized that COX inhibitors may attenuate endothelial dysfunction during sepsis, as measured by receptor-mediated bradykinin (BK)-induced vasoconstriction and/or receptor-independent hypoxic pulmonary vasoconstriction (HPV). Rats were administered intraperitoneally a nonselective COX inhibitor (indomethacin, 5 or 10 mg/kg) or a selective COX-2 inhibitor (NS-398, 4 or 8 mg/kg) 1 h before lipopolysaccharide (LPS, 15 mg/kg), or saline (control). Three hours later, the rats were anesthetized, the lungs were isolated, and pulmonary vasoreactivity was assessed with BK (0.3, 1.0, and 3.0 microg) and HPV (3% O(2)). Perfusion pressure was monitored as an index of vasoconstriction. To investigate what receptor-subtype is mediating BK responses, the BK(1)-receptor antagonist des-Arg(9)-[Leu(8)]-BK, the BK(2)-receptor antagonist HOE-140, or the thromboxane A(2)-receptor antagonist SQ 29548 (all at 1 microM) were added to the perfusate. BK-induced vasoconstriction was significantly increased in LPS lungs (1.4-5.2 mm Hg) compared with control (0.1-1.1 mm Hg). In LPS lungs, indomethacin 10 mg/kg significantly decreased BK vasoconstriction by 78% +/- 9%, whereas 5 mg/kg did not. NS-398, 4 mg/kg, significantly attenuated BK vasoconstriction at 0.3 microg (71% +/- 7%) and 1.0 microg (56% +/- 12%), whereas 8 mg/kg attenuated 0.3 microg BK (57% +/- 14%), compared with LPS lungs. HPV was increased in LPS lungs (21.5 +/- 2 mm Hg) compared with control lungs (9.8 +/- 0.6 mm Hg). Indomethacin 5 mg/kg increased HPV in LPS lungs; otherwise, HPV was not altered by COX inhibition. BK-induced vasoconstriction was prevented by BK(2), but not BK(1) or thromboxane A(2)-receptor antagonism. This study suggests that nonselective COX inhibition, and possibly inhibition of the inducible isoform COX-2, may attenuate sepsis-induced, receptor-mediated vasoconstriction in rats.. This study demonstrated that, in an isolated rat lung model, nonselective inhibition of the cyclooxygenase pathway, and possibly selective inhibition of the inducible cyclooxygenase-2 isoform, may attenuate sepsis-induced endothelial dysfunction.

Topics: Animals; Bradykinin; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Hypoxia; Lipopolysaccharides; Lung; Male; Nitric Oxide; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Sepsis; Vasoconstriction

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Output; Eicosanoic Acids; Endotoxins; Fatty Acids, Unsaturated; Female; Gas Chromatography-Mass Spectrometry; Hemodynamics; Hydrazines; Lymph; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Receptors, Prostaglandin; Receptors, Thromboxane; Respiratory Distress Syndrome; Sepsis; Sheep; Vascular Resistance

The purpose of this study was to determine whether or not thromboxane A2 (TXA2) was necessary or sufficient for the development of end-organ pathology during graded bacteremia. Pulmonary artery catheters were placed in 21 adult male pigs under pentobarbital anesthesia and breathing room air. After a control period, animals were studied in four groups: Group 1, anesthesia only; Group 2, infusion of 1 X 10(9) ml Aeromonas hydrophila which was gradually increased from 0.2 ml/kg/hr to 4.0 ml/kg/hr over 4 hours; Group 3, pretreatment with SQ 29,548 (TXA2 antagonist) then Aeromonas h. infusion; Group 4, infusion of U46619 (TXA2 agonist) to pulmonary artery pressures measured in Group 2. Animals were sacrificed after 4 hours and the lungs, liver, spleen, kidneys, and heart were examined under light microscopy by a pathologist unaware of study groups. The results indicated that physiologic thromboxane A2 agonist (Group 4) was sufficient alone to cause pulmonary inflammation. Thromboxane A2 was neither necessary nor sufficient for significant renal, hepatic, pulmonary, or splenic pathology to occur in graded bacteremia, manifested in similar microanatomic abnormalities in these organs in Groups 2 and 3 and in Groups 1 and 4. Pulmonary leukocyte infiltration was significantly increased in Group 3 compared to all other groups, suggesting that TXA2 impairs inflammatory responses.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Kidney; Liver; Lung; Male; Myocardium; Prostaglandin Endoperoxides, Synthetic; Radioimmunoassay; Sepsis; Spleen; Swine; Thromboxane A2; Thromboxane B2

Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aeromonas; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Capillary Permeability; Cardiac Output; Epoprostenol; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Hypertension, Pulmonary; Hypoxia; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Gas Exchange; Sepsis; Shock, Septic; Swine; Thromboxane A2; Thromboxane B2