title: Differential effects of 5,6-EET on segmental pulmonary vasoactivity in the rabbit.
abstract: In the rabbit, 5,6-epoxyeicosatrienoic acid (EET) was reported both to dilate and to constrict pulmonary blood vessels. We propose that these seemingly contradictory results could be explained by differences in responses to 5,6-EET in large-conductance pulmonary arteries (PA) compared with smaller PA and resistance vessels. Thus we found that in rings of extralobar PA [>2-mm outside diameter (OD)], in which active tension had been increased with PGF(2alpha), 5,6-EET produced relaxation in a concentration- and cyclooxygenase (COX)-dependent manner. In contrast, 5,6-EET increased tension in intralobar (1- to 2-mm OD) PA. Small extralobar PA (2- to 2.5-mm OD) exhibited intermediate responses. In the intact lung, the net effect of 5,6-EET (1 x 10(-8)-1 x 10(-5) M) was an increase in pulmonary vascular resistance (PVR) from 13.0 +/- 0.5 to 47.8 +/- 4.6 mmHg. 100 ml(-1) x min(-1) (EC(50) 5.9 +/- 1.7 x 10(-7) M). The increase in PVR was accompanied by a 10-fold increase in perfusate thromboxane (TX)B(2) concentration. The 5,6-EET-induced increase in PVR was prevented with indomethacin (100 microM), a cyclooxygenase inhibitor, or ONO-3708 (20 microM), a TX/PGH(2) (TP) receptor antagonist, but not with OKY-046 (700 microM), a TX synthase inhibitor. These results demonstrate that although 5,6-EET dilates large extralobar PA segments in a COX-dependent manner, in the intact rabbit lung 5,6-EET produces constriction that requires synthesis of a COX-dependent agonist of the TP receptor other than TX.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Missouri 63104, USA. stephens@slu.edu
authors.forename: Alan H
authors.initials: AH
authors.lastname: Stephenson
authors.forename: Randy S
authors.initials: RS
authors.lastname: Sprague
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Losapio
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lonigro
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008689:Methacrylates / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000187:drug effects; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis; D013931:Thromboxanes / Q000096:biosynthesis; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D008689:Methacrylates; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013931:Thromboxanes; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C049855:ONO 3708; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D015126:8,11,14-Eicosatrienoic Acid; C034364:ozagrel; D007213:Indomethacin