Mechanism of action of platelet activating factor in the pulmonary circulation: an investigation using a novel isotopic system in rabbit isolated lung.
1. Rabbit isolated lungs were perfused via the pulmonary artery with Tyrode solution containing 4.5% Ficoll and 0.1% bovine serum albumin at a constant rate of 20 ml min-1. Lung perfusate was drawn for alternating 5 min periods from two reservoirs, one containing 125I-albumin and the other unlabelled albumin to wash out the intravascular label. Microvascular 125I-albumin leakage was determined from the count remaining at the end of the washout phase with an external gamma scintillation probe. In addition, perfusion pressure was monitored continuously. Each experiment comprised 6 cycles over a total period of 60 min. 2. Infusion of platelet activating factor (PAF, 3 nmol min-1 for 10 min) resulted in microvascular 125I-albumin leakage, whereas lyso-PAF was without effect. During PAF infusions there was also an increase in perfusion pressure. Both the permeability and pressor effects of PAF were inhibited by the PAF antagonist L-652731. 3. Infusion of the thromboxane analogue U-46619 (0.6 nmol min-1 for 10 min) caused an increase in perfusion pressure but protein accumulation was not significantly different from that observed with control infusions. 4. Bolus injections of PAF (1 nmol) caused increases in perfusion pressure which were reduced by indomethacin, dazmegrel and BW 755C. Bolus injections of PAF, repeated at 30 min intervals caused reproducible pressor responses; however, repeated injections at 60 min intervals resulted in augmented responses. This augmentation did not occur in the presence of indomethacin. 5. Retrograde perfusion of PAF via the pulmonary vein induced increased perfusion pressure and microvascular 125I-albumin leakage. The observed increase in leakage when compared with forward perfusion suggests that PAF produces predominantly arteriolar constriction i.e. proximal to the site of leakage during forward perfusion. 6. These results indicate that PAF is a vasoconstrictor in the rabbit pulmonary circulation and augmented responses occur with repeated injections at 60 min intervals. Cyclo-oxygenase inhibition abolished this vascular hyperresponsiveness induced by PAF. PAF also caused protein accumulation in the lungs. Both these actions of PAF appear to be receptor-mediated because they were inhibited by PAF antagonists. Another pulmonary vasoconstrictor, U-46619 did not cause protein accumulation suggesting that the extravasation of protein with PAF is not merely secondary to changes in vascular tone.
Seale
J P
JP
Department of Applied Pharmacology, National Heart and Lung Institute, London.
Nourshargh
S
S
Hellewell
P G
PG
Williams
T J
TJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D005663:Furans / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010477:Perfusion; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011654:Pulmonary Edema / Q000503:physiopathology; D011817:Rabbits; D012711:Serum Albumin, Radio-Iodinated / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D001798:Blood Proteins; D005663:Furans; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D012711:Serum Albumin, Radio-Iodinated; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran