title: Lipoxygenase and cyclooxygenase blockade by BW755C does not prevent the secondary phase of septic pulmonary hypertension.
abstract: The infusion of Group B beta hemolytic streptococci (GBS) in newborn animals generates a dual phase pulmonary hypertensive response. The initial, acute phase responds to cyclooxygenase or thromboxane inhibition, and appears to be thromboxane mediated. The second phase is characterized by a more moderate rise in pulmonary vascular resistance, accompanied by an increase in microvascular permeability. It has been speculated that this phase may be leukotriene mediated. In an attempt to clarify this, we have studied and compared the effects of the thromboxane synthetase inhibitor, Dazmegrel (DAZ), and the combined cyclooxygenase/lipoxygenase inhibitor, BW755C, on the cardiopulmonary hemodynamics of the secondary phase of GBS induced pulmonary hypertension in newborn piglets. Ten piglets were infused with GBS, and all animals developed a significant increase in pulmonary artery pressure (to 39 +/- 5 and 36 +/- 5 mmHg for DAZ and BW755C animals respectively). After one hour of GBS, either DAZ or BW755C was administered. Data were collected for another two hours following drug administration. GBS infusion was continued throughout. Both DAZ and BW755C were associated with transient, acute reductions in pulmonary artery pressure (to 22 +/- 5 and 22 +/- 8 mmHg, respectively). However, after 60 minutes, PAP again began to rise in both groups (PAP 30 +/- 5 and 30 +/- 11 mmHg respectively by 240 minutes). There were no differences between the groups at any time. These data do not support a significant role for lipoxygenase products in mediating the secondary phase of septic pulmonary hypertension.
authors.affiliation: Dept. Pediatrics, University of Chicago Medical Center, Illinois 60637.
authors.forename: C
authors.initials: C
authors.lastname: Hammerman
authors.forename: M J
authors.initials: MJ
authors.lastname: Aramburo
authors.forename: V
authors.initials: V
authors.lastname: Hill
mesh_terms: D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001794:Blood Pressure; D016861:Cyclooxygenase Inhibitors; D006339:Heart Rate; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D013552:Swine; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; C039242:dazmegrel; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D013930:Thromboxane-A Synthase