PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats.
Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
Ono
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Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Westcott
J Y
JY
Voelkel
N F
NF
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D001381:Azepines; D016232:Endothelins; D010972:Platelet Activating Factor; D014230:Triazoles; C064509:BN 50739; D009240:N-Formylmethionine Leucyl-Phenylalanine; C063964:bepafant