Effects Of PAF-acether Research Articles

Relaxation of the guinea-pig trachea induced by platelet-activating factor and by serotonin

Platelet-activating factor (PAF-acether), a known platelet stimulant and bronchoconstrictor (in vivo), is a potential mediator of inflammation and trombosis. However, all smooth muscle effects of PAF-acether described to date are indirect, relying upon intravascular platelet activation. Novel actions of PAF-acether and serotonin (5-HT) are presented here; these actions may lead to the development of a practical bioassay for PAF-acether and contribute to the understanding of the mechanism of action for both substances. PAF-acether, when added to a spiral cut guinea-pig trachea suspended in a tissue bath containing Krebs-Henseleit buffer, produced a dose-dependent loss of active tissue tension. The ED 50 for this effect of PAF-acether was 75 ng/ml. PAF-acether produced a maximal relaxation which was 68% of that produced by PGE 1 and the effect could not be modified by aspirin or propranolol pretreatment. 5-HT, alone, contracted the guinea-pig trachea strip in a dose-dependent manner, but caused relaxation instead when methysergide was present. Aspirin, phenoxybenzamine and propranolol did not alter this loss of active tissue tension. A similar observation was made in vivo using the guinea-pig bronchoconstriction model, in which PAF-acether as well as 5-HT given to methysergide-treated animals caused a decrease in intratracheal pressure. This action of PAF-acether may yield a suitable bioassay method which could facilitate routine measurements of the substance. Furthermore, the similarity in action of PAF-acether and of 5-HT on methysergide-treated animals leads one to speculate about the relationship between the two substances and their mechanism of action in smooth muscle.

Vascular actions of synthetic PAF-acether (a synthetic platelet-activating factor) in the rat: Evidence for a platelet independent mechanism

Since rat platelets fully responsive to thrombin and collagen did not respond by releasing 3H-serotonin with up to 10 μg/ml of synthetic PAF-acether, the rat, contrariwise to the rabbit, was considered to be an appropriate model to study the actions of PAF-acether not mediated through the activation of platelets and the subsequent release of their inflammatory mediators. We developed an experimental approach using 57Co and 113Sn radiolabeled microspheres to assess the effect of PAF-acether on cardiac output, peripheral vascular resistance, and regional flows and resistance. The effect on vascular permeability and blood volume was studied by measuring the clearance of 125I-HSA and the variations of the hematocrit. A significant fall in blood pressure and peripheral vascular resistance was found with doses of PAF-acether ranging from 0.05 to 5 μg. Moreover, the higher doses of PAF-acether also induced a marked depletion of blood volume. A significant fall in spleen, coronary, and kidney output, but not in cardiac output, was also found. Our data show that PAF-acether, by itself, induces a drop in peripheral vascular resistance and, at higher doses, also in circulating volume, accounting for both by the hypotensive effect. The redistribution of cardiac output seems to be the expression of a nonuniform action of the compound on the vascular resistance of the different organs.

Platelet-activating factor induces a platelet-dependent bronchoconstriction unrelated to the formation of prostaglandin derivatives

Platelet-activating factor (PAF-acether) is a phospholipid derivative released from stimulated basophils, macrophages and platelets. It induced the release of ATP from, and aggregated guinea-pig platelets. These effects were inhibited by neither aspirin nor eicosatetraynoic acid, ruling out the participation of platelet cyclooxygenase and lipoxygenase. Accordingly, no thromboxane A2 activity was found in incubates of guinea-pig platelet-rich plasma with PAF-acether. Prostacyclin suppressed in vitro platelet activation by PAF-acether, which therefore appears to be controled by platelet cyclic AMP levels. PAF-acether injected i.v. to guinea pigs induced hypotension and an increase of bronchial resistance to inflation accompanied by thrombocytopenia. The latter, as well as bronchoconstriction were inhibited by prostacyclin, whereas doses of aspirin which suppress the in vivo platelet and bronchial effects of the TxA2 precursor arachidonic acid were inactive against PAF-acether. Bronchoconstriction due to PAF-acether was platelet-dependent as it was suppressed by immune platelet depletion. The hypotensive effect of PAF-acether was not inhibited after platelet depletion. The pharmacological properties of PAF-acether are compatible with its proposed role in the bronchoconstriction of asthma which is probably caused by a still unidentified factor.