15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and 2-5-bis(3-4-5-trimethoxyphenyl)tetrahydrofuran

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Proteins; Capillary Permeability; Furans; In Vitro Techniques; Male; Microcirculation; Perfusion; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pulmonary Edema; Rabbits; Serum Albumin, Radio-Iodinated; Vascular Resistance; Vasoconstriction

Platelet-activating factor (PAF) may be involved in the pathophysiology of gastrointestinal damage and motility changes. The effects of PAF in inducing gastric contractions in vivo have now been determined in pentobarbital sodium-anesthetized rats. Local intra-arterial infusion of PAF (5-50 ng.kg-1.min-1 for 10 min) induced a maintained rise in intragastric pressure followed by a further postinfusion increase. Inhibitors of eicosanoid biosynthesis had no effect on these gastric motility changes. However, pretreatment with cimetidine or methysergide decreased by 50% the initial increase in intragastric pressure, whereas mepyramine, adrenergic alpha- and beta-receptor blockade, atropine, hexamethonium, or vagotomy had no effect. During the local infusion of tetrodotoxin, the initial increase in intragastric pressure was not maintained, and the postinfusion increase was abolished. With these inhibitors and antagonists, there was no consistent correlation between the extent of PAF-induced mucosal damage and increase in intragastric pressure. Tetrodotoxin had no effect on the changes in intragastric pressure induced by the thromboxane mimetic U-46619. Administration of Escherichia coli and Salmonella typhosa endotoxin (50 mg/kg iv) also increased intragastric pressure, which peaked after 10 min and slowly declined thereafter. These effects were inhibited by the specific PAF-receptor antagonist L652,731, suggesting that the endogenous release of PAF may contribute to the endotoxin-induced increases in gastric motility. The present study suggests that PAF initially acts directly on smooth muscle and through histamine and serotonin release with a secondary motility response due to activation of nonadrenergic noncholinergic, neuronal activity.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Furans; Gastrointestinal Motility; Male; Platelet Activating Factor; Pressure; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Tetrodotoxin

The ability of three platelet activating factor (PAF) antagonists, BN52021, L652,731 and 48740RP, and the leukotriene antagonist FPL55712 to block iv PAF-induced death was tested in mice. PAF-induced sudden death has been previously characterized as a model of systemic anaphylaxis and circulatory shock related its hypotensive actions. Of the drugs, BN5201 and L652,731 provided dose-dependent protection against PAF toxicity, whereas the others had no effect. 48740RP was, however active against PAF-induced rabbit platelet aggregation. BN52021 was inactive in three other mouse sudden death models in which arachidonic acid, U46619 or collagen combined with epinephrine is injected iv to provoke a thrombotic/ischemic sudden death. In contrast, the TXA2 antagonist SQ29548 inhibited the acute toxicity of two of these latter challenges (arachidonic acid and thromboxane agonist U46619), but was inactive against PAF lethality. These results suggest that PAF toxicity in mice is a specific model for PAF agonism, and is not mediated by TXA2 or peptido-leukotrienes. Further, PAF-induced mortality should be a simple and useful technique for testing potential PAF antagonists for in vivo activity by various routes of administration.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Bridged Bicyclo Compounds, Heterocyclic; Collagen; Diterpenes; Epinephrine; Fatty Acids, Unsaturated; Furans; Ginkgolides; Hydrazines; Lactones; Male; Mice; Platelet Activating Factor; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Pyridines; Thiazoles; Thromboxane A2