5,6-Epoxyeicosatrienoic acid reduces increases in pulmonary vascular resistance in the dog.
We recently reported that canine pulmonary microsomes metabolize arachidonic acid to all four regioisomeric epoxyeicosatrienoic acids (EET). 5,6-EET dilates blood vessels in several nonpulmonary vascular beds, often in a cyclooxygenase-dependent manner. The present study was designed to determine whether 5,6-EET can decrease pulmonary vascular resistance (PVR) in the intact pulmonary circulation. In isolated canine lungs perfused with physiological salt solution, a constant infusion of U-46619 (3.28 +/- 0.99 nmol/min) increased PVR 62.1 +/- 4.5%. Administration of 5,6-EET (10(-5) M) into the perfusate reduced the U-46619-mediated increase in PVR by 23.6 +/- 6.1%. These effects of U-46619 and 5,6-EET were limited to changes in resistance solely in the pulmonary venous segment. In contrast, venous as well as arterial segmental resistances were increased in 5-hydroxytryptamine (5-HT)-treated lungs. However, in the latter instance, 5,6-EET reduced arterial but not venous segmental resistance. 5,6-EET increased pulmonary PGI2 synthesis from 70.5 +/- 18.4 to 675.9 +/- 125.4 ng/min. In the presence of indomethacin (10(-4) M), 5,6-EET did not increase PGI2 synthesis nor did it decrease U-46619- or 5-HT-mediated increases in PVR. In canine intrapulmonary vessels, 5,6-EET decreased active tension in veins contracted with U-46619. 5,6-EET decreased active tension in arteries but not veins contracted with 5-HT, consistent with results in the perfused lungs. These results demonstrate that 5, 6-EET is a vasodilator in the intact pulmonary circulation. Its dilator activity depends on the constrictor agent present, the segmental resistance, and cyclooxygenase activity.
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA.
A H
AH
Stephenson
R S
RS
Sprague
A J
AJ
Lonigro
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects*
D012701:Serotonin; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid; D007213:Indomethacin