ABSTRACT
Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing systemic oxygenation. To assess the role of leukotrienes (LTs) in the attenuation of HPV during endotoxemia, the increase in left lung pulmonary vascular resistance (LPVR) before and during left mainstem bronchus occlusion (LMBO) was measured in mice with and without a deletion of the gene encoding 5-lipoxygenase (5-LO). LMBO increased the LPVR equally in saline-challenged wild-type and 5-LO-deficient mice (96+/-20% and 94+/-19%, respectively). Twenty-two hours after challenge with Escherichia coli endotoxin, the ability of LMBO to increase LPVR was markedly impaired in wild-type mice (27+/-7%; P<0.05) but not in 5-LO-deficient mice (72+/-9%) or in wild-type mice pretreated with MK886, an inhibitor of 5-LO activity (76+/-10%). Compared with wild-type mice, endotoxin-induced disruption of lung structures and inflammatory cell influx in the lung were markedly attenuated in 5-LO-deficient mice. Administration of MK571, a selective cysteinyl LT(1) receptor antagonist, 1 hour before endotoxin challenge preserved HPV and attenuated pulmonary injury in wild-type mice but did not prevent the endotoxin-induced increase in pulmonary myeloperoxidase activity. Taken together, these findings demonstrate that a 5-LO product, most likely a cysteinyl LT, contributes to the attenuation of HPV and to pulmonary injury after challenge with endotoxin.
Subject(s)
Arachidonate 5-Lipoxygenase/metabolism , Endotoxemia/metabolism , Hypoxia/physiopathology , Membrane Proteins , Pulmonary Circulation , Receptors, Leukotriene , Vascular Resistance , Vasoconstriction , Administration, Inhalation , Animals , Arachidonate 5-Lipoxygenase/deficiency , Bronchoalveolar Lavage Fluid/chemistry , Disease Models, Animal , Endotoxemia/chemically induced , Endotoxemia/complications , Endotoxins/pharmacology , Enzyme Inhibitors/pharmacology , Hemodynamics/drug effects , Hypoxia/complications , Hypoxia/enzymology , Leukocyte Count , Leukotriene Antagonists/pharmacology , Leukotrienes/analysis , Lipoxygenase Inhibitors/pharmacology , Lung/blood supply , Lung/drug effects , Lung/pathology , Mice , Mice, Mutant Strains , Nitric Oxide/administration & dosage , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Peroxidase/metabolism , Pulmonary Alveoli/blood supply , Pulmonary Alveoli/metabolism , Pulmonary Circulation/drug effects , Pulmonary Circulation/physiology , Vascular Resistance/drug effects , Vascular Resistance/physiology , Vasoconstriction/drug effects , Vasoconstriction/physiologyABSTRACT
The importance of arachidonic acid metabolites (termed eicosanoids), particularly those derived from the COX-1 and COX-2 pathways (termed prostanoids), in platelet homeostasis has long been recognized. Thromboxane is a potent agonist, whereas prostacyclin is an inhibitor of platelet aggregation. In contrast, the effect of prostaglandin E2 (PGE2) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE2 enhance platelet aggregation, whereas high PGE2 levels inhibit aggregation. The mechanism for this dual action of PGE2 is not clear. This study shows that among the four PGE2 receptors (EP1-EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE2 concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE2 concentrations. Furthermore, the relative activation of these two receptors, EP3 and IP, regulates the intracellular level of cAMP and in this way conditions the response of the platelet to aggregating agents. Consistent with these findings, loss of the EP3 receptor in a model of venous inflammation protects against formation of intravascular clots. Our results suggest that local production of PGE2 during an inflammatory process can modulate ensuing platelet responses.
Subject(s)
Cyclic AMP/biosynthesis , Dinoprostone/pharmacology , Platelet Aggregation , Receptors, Prostaglandin E/metabolism , Animals , Calcium/metabolism , Female , Male , Mice , Mice, Knockout , Models, Biological , Platelet Aggregation/drug effects , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptors, Epoprostenol , Receptors, Prostaglandin/genetics , Receptors, Prostaglandin/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E, EP3 Subtype , Venous Thrombosis/pathologyABSTRACT
The aim of the study was to compare the accuracy of multiplane transesophageal echocardiography (TEE) with the more conventional biplane technique in the direct assessment of aortic valve area in patients with aortic stenosis. Short-axis images of the aortic valve adequate for measuring aortic valve area were obtained in all 81 patients studied by multiplane TEE but in only 56 of 64 patients (88%) using the biplane approach. The correlation coefficient for aortic valve area determined by multiplane TEE (r = 0.89; SEE = 0.04 cm2) was higher (p < 0.01) than biplane TEE (r = 0.74; SEE = 0.06 cm2). Correlations were higher for bicuspid valves (multiplane, r = 0.93; biplane, r = 0.75) than tricuspid valves (multiplane, r = 0.87; biplane, r = 0.75). Our study has demonstrated the superiority of multiplane TEE to both biplane TEE and transthoracic echocardiography (TTE) in the direct evaluation of aortic valve area in patients with aortic stenosis.
