Platelet-activating factor: evidence against a role in hypoxic pulmonary vasoconstriction.
The mechanism of hypoxic pulmonary vasoconstriction (HPV) remains unknown. The platelet-activating factor (PAF) antagonist WEB 2086 attenuated HPV in the isolated lung model of the rat. We evaluated the effect of WEB 2086 on HPV in an intact animal. Pigs were anesthetized, mechanically ventilated, and had their hemodynamic variables monitored with a pulmonary artery catheter and arterial line. Cardiac output was measured by thermodilution. Initial studies determined that PAF (0.03 to 1.0 micrograms) injected iv dose-dependently increased pulmonary vascular resistance (PVR) with a 262 +/- 58% increase in PVR 5 min after a dose of 1.0 microgram. WEB 2086 (25 mg/kg iv) completely blocked the increase in PVR caused by iv PAF. Additionally, indomethacin (2 mg/kg followed by 2 mg/kg.h iv) treatment of the animals attenuated the PAF-induced increase in PVR. To evaluate the effect of WEB 2086 on HPV, animals were alternately ventilated with 21% oxygen and 10-min periods of 10% oxygen to induce HPV. After three initial control episodes of hypoxic ventilation, WEB 2086 (25 mg/kg) was injected iv and two more episodes of ventilation with 10% oxygen were given. During the three control HPV episodes the increases in PVR were 80 +/- 10%, 108 +/- 10%, and 107 +/- 22% (n = 5). After WEB 2086, the increase in PVR during two episodes of hypoxia were 96 +/- 28% and 99 +/- 19%, respectively, which was not significantly different from the control response to hypoxia. We conclude that iv PAF dose dependently increases PVR in pigs, and can be blocked by WEB 2086, that its effect is partially mediated through cyclooxygenase products, and that PAF does not appear to mediate HPV in this species.
McCormack
D G
DG
Department of Thoracic Medicine, National Heart and Lung Institute, London, ON, Canada.
Barnes
P J
PJ
Evans
T W
TW
D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D007275:Injections, Intravenous; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D011652:Pulmonary Circulation / Q000187:drug effects*; D013552:Swine; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086