Platelet-activating factor: a potential mediator of shock.
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Animals↗
Biomedical subjects
P Bessin
Publications and source records attributed to P Bessin.
PAF-acether and leukotriene participation in acute circulatory shock.
The fact that PAF-acether elicites acute circulatory collapse in anesthetized dogs supports the hypothesis that its endogenous double is involved in shock state events. The fact that cysteinyl containing leukotrienes has been shown to be released in various shock states, themselves producing noxious effects related to such circulatory disturbances, suggests a possible role of these arachidonic acid metabolites in shock syndrome. The present report summarizes the part played by these mediators in shock developments. More precisely, nanograms PAF-acether IV in anesthetized dogs produced biphasic effects on mesenteric blood flow and inhibited, in dogs and rats, histamine induced gastric acid secretion. These results confirm the distributive component of the PAF-acether circulatory collapse. On the other hand, as leukotrienes, nanograms PAF-acether elicited both plasma extravasation and vasoconstriction in guinea pig skin. Lastly, in conscious mice, lipoxygenase antagonists, but not cyclooxygenase antagonists, inhibited lethal effects of PAF-acether, suggesting a mutual and synergistic action of PAF-acether and leukotrienes in shock state.
Anaphylaxis↗
Acute circulatory collapse caused by platelet-activating factor (PAF-acether) in dogs.
Synthetic platelet-activating factor (PAF-acether) was shown to act as a shock inducer when a dose of 9 or 36 nmol . kg-1 was injected i.v. into dogs anesthetized with 30 mg . kg-1 i.v. sodium pentobarbitone. Nine nmol . kg-1 PAF-acether caused portal vein and pulmonary artery hypertension but only transiently; blood TXB2 and 6 keto PGF1 alpha levels rose; there was a lasting fall of 77% in systemic blood pressure, cardiac output fell by 86%, heart rate by 17%, plasma volume by 43%, and femoral artery blood flow by 66%, whereas the hematocrit rose by 33%. A dose of 36 nmol . kg-1 PAF-acether reduced coronary artery blood flow by 56%, diminished myocardial O2 consumption, raised O2 extraction and caused metabolic acidosis leading to death in 2 out of 7 animals. All these changes displayed the typical features of common acute circulatory collapse with distributive and hypovolemic etiologies, suggesting that PAF-acether might be an endogenous mediator in the early and late stages of shock.
6-Ketoprostaglandin F1 alpha↗
Dependency of the Paf-acether induced bronchospasm on the lipoxygenase pathway in the guinea-pig.
The Paf-acether (platelet-activating factor) induced bronchospasm (Paf-BCS) was studied in the anesthetized guinea-pig. The SRS antagonist, FPL-55712, as well as inhibitors of both lipoxygenase and cyclooxygenase, phenidone, nordihydroguaiaretic acid (NDGA), and benoxaprofen, caused a dose-related antagonism of Paf-BCS. By contrast, selective inhibitors of cyclooxygenase, indomethacin and aspirin, exerted moderate antagonism at intermediate doses, but had no effect at high doses. Furthermore, diethylmaleate (DEM), which impairs leukotriene synthesis by interfering with glutathione (GSH), suppressed Paf-BCS. Taken together, these results demonstrate that the lipoxygenase pathway plays a major part in the bronchospasmogenic effect of Paf-acether in the guinea-pig.
Animals↗
Platelet-activating factor acether (PAF-acether) involvement in acute inflammatory and pain processes.
PAF-acether is a potent aggregating agent released by various cells involved in acute inflammatory process. In this paper, exogenous PAF-acether has been investigated for its ability to generate signs of inflammation (edema measured by plethysmometry) and hyperalgesia (Randall-Sellito test) by standard subplantar injection in the rat paw. From 0.005 microgram. PAF-acether induced significant edema of the paw, maximal 1 hour after injection; it was dose-dependent from 0.1 to 5 microgram. Significant dose-dependent hyperalgesia occurred from 1.25 microgram; it reached a plateau from 2 to 4 hours after injection. Both phenomena were long-lasting (greater than 6 h). PAF-acether was 1.5 to 10 times stronger than PGI2 and PGE2 in inducing edema, pain, and in increasing vascular permeability. We investigated the interaction of miscellaneous drugs with the edema and the hyperalgesia caused by 2.5 microgram of PAF-acether. Non-steroidal anti-inflammatory (NSAI) drugs exerted only moderate effects on the edema without affecting hyperalgesia. Edema was highly reduced by various agents: prednisolone, L-cysteine, anti-calcic drugs, theophylline, PGI2, salbutamol, clonidine. All of them, except clonidine, and in contrast to NSAI drugs, were more potent on PAF-acether edema than on kaolin edema; a possible link between these agents is their ability to increase cyclic AMP levels in the cells and consequently to reduce lysosomal enzyme release. PAF-acether itself, injected intra-peritoneally, inhibited PAF-acether edema without preventing pain, at doses inactive on arterial pressure and hematocrit, but inducing marked gastric mucosal damage. Among the drugs tested, including analgesics, only PGI2 and imidazole improved PAF-induced hyperalgesia, showing a dissociation between edema and hyperalgesia not only in their induction (doses of PAF required, time course of the phenomena), but in the drugs able to antagonize their development too.
Analgesics↗
[Tienilic acid and biliary secretion (author's transl)].
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Animals↗
Quantitative structure-activity relationships for N-[N',N'-disubstituted-amino)acetyl]arylamines for local anesthetic activity and acute toxicity.
The synthesis and physicochemical properties of a series of N-[N',N'-disubstituted-amino)acetyl]arylamines are described. A QSAR method is applied to local anesthetic activity and acute toxicity by means of a "nonclassic" substituent variation involving a modification on both aryl and amino moieties. The choice of the different parameters (partition coefficient, pKa, connectivity index, molar refraction, and molar volume) is discussed and their different methods of determination are described. Molar refraction is the parameter which explains best the variance of the local anesthetic activity, and the quadratic regression with MR leads to a "posteriori" synthesis of one compound with optimized activity. However, the partition coefficient is the most explicative parameter for intravenous toxicity.
Amines↗
[Pharmacology of a new cardiotropic drug : (dichloro-2, 3-methoxy 4) phenyl furyl-2-0-(diethylamino-ethyl)-ketone-oxime (ANP 4364)].
The (dichloro-2,3 methoxy 4) phenyl furyl-2 0-(diethylaminoethyl)-cetone-oxime (ANP 4364) is a powerful coronary vasodilator which lowers the resistance of large coronary arteries and decreases the O2 consumption of the myocardium. The activity of ANP 4364 is similar to digitalis: increase of cardiac flow, bradycardia, redistribution of the blood to peripheral area. These properties demonstrated in dogs have been confirmed in patients with cardiac diseases.
Animals↗