Antihypertensive activity of an alkyl ether analog of phosphatidylcholine

Blank, Merle L.; Snyder, Fred; Byers, Lawrence W.; Brooks, B; Muirhead, E. E.

doi:10.1016/0006-291x(79)91163-x

Cited by 558 publications

(139 citation statements)

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“…PAF was initially recognized as a product of IgE-sensitized rabbit basophils (2) and was identified with 1-0-alkyl-2-sn-glyceryl-3-phosphorylcholine (3)(4)(5). It was subsequently shown that PAF is synthesized after appropriate stimulation by monocytes/macrophages (6)(7)(8)(9), polymorphonuclear neutrophils (7,10,11), platelets (12) and endothelial cells (13)(14)(15) .…”

mentioning

confidence: 99%

Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor.

Camussi

Bussolino

Salvidio

et al. 1987

The Journal of Experimental Medicine

339

133

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Platelet-activating factor (PAF)' is a mediator of inflammation with a wide range of biological activities (see reference 1 for review) . PAF was initially recognized as a product of IgE-sensitized rabbit basophils (2) and was identified with 1-0-alkyl-2-sn-glyceryl-3-phosphorylcholine (3-5). It was subsequently shown that PAF is synthesized after appropriate stimulation by monocytes/macrophages (6-9), polymorphonuclear neutrophils (7, 10, 11), platelets (12) and endothelial cells (13-15) . PAF induces aggregation and degranulation of platelets (2, 16), stimulates contraction of smooth muscle (17), promotes chemotaxis and granule secretion of neutrophils (18-19) and monocytes (20), increases vascular permeability, and alters the vascular tone (21).It was recently suggested that PAF is a mediator of endotoxic shock (22-24) on the basis of the following observations : (a) PAF is produced during endotoxic shock and experimental sepsis by Gram-negative bacteria (23-25) ; (b) infusion of experimental animals with PAF results in hypotension, decrease in cardiac output, and hypovolemic shock (26-28) ; (c) three PAF receptor antagonists (CV3988, kadsurenone, and SRI 63072) inhibit or reverse endotoxin-induced hypotension and, in this way, prolong the survival of rats (22,23,29) .Tumor necrosis factor/cachectin (TNF) is a mediator of endotoxic shock (30). Because TNF administration to experimental animals reproduces several aspects of PAF infusion (30), it seems possible that PAF is synthesized in response to

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mentioning

confidence: 99%

Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor.

Camussi

Bussolino

Salvidio

et al. 1987

The Journal of Experimental Medicine

339

133

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“…Paf-acether (Paf, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) (Benveniste et al, 1972;Demopoulos et al, 1979;Blank et al, 1979) exhibits potent inflammatory and hypotensive properties (Vargaftig et al, 1981;Pinckard et al, 1982;Chung & Barnes, 1988). Paf activates platelets independently of the cyclo-oxygenase pathway via a Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Interaction of the Paf antagonist WEB 2086 and its hetrazepine analogues with human platelets and endothelial cells

Korth

Hirafuji

Keraly

et al. 1989

British J Pharmacology

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Intact platelets and confluent human umbilical vein endothelial cells bound [3H]‐Paf‐acether (platelet activating factor, [3H]‐Paf) at 20°C in the presence of 0.25% (w/v) bovine serum albumin (BSA). [3H]‐Paf binding to platelets was inhibited in a concentration‐dependent manner by WEB 2086. An excess of WEB 2086 indicated the presence of specific, saturable Paf binding which reached a maximum of 28.3 ± 3.7 fmol [3H]‐Paf per 5 × 107 platelets. In platelets, different hetrazepines (WEB 2098, 2105, but not 2118) also inhibited [3H]‐Paf binding in a concentration‐dependent manner. WEB 2086 partially displaced platelet‐bound [3H]‐Paf in a concentration‐dependent manner reaching a plateau at 400 nM WEB 2086. No further displacement was observed when WEB 2086 and an excess of unlabelled Paf were added together. The hetrazepines inhibited platelet aggregation. Platelet aggregation IC50 values correlated well with the IC50 values of the hetrazepines against [3H]‐Paf binding (r2 = 0.99). WEB 2086 shifted the Paf dose‐response curve rightwards in a parallel manner. Tested against platelet aggregation the pA2 obtained for WEB 2086 was 7.9. WEB 2086 inhibited [3H]‐Paf binding to endothelial cells in a concentration‐dependent manner. WEB 2086 also inhibited the Paf‐mediated cytosolic calcium increase in endothelial cells with an IC50 value of 23.1 ± 10.4 nM as compared with an IC50 of 21.6 ± 10.4 nM WEB 2086 for platelet aggregation. These results demonstrate an inhibition of [3H]‐Paf binding to platelets and endothelial cells by different hetrazepines, most probably at the Paf receptor level.

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“…Furthermore, it also causes haemoconcentration with extravasation of plasma proteins (McManus et al, 1981b), local leucocyte infiltration (Humphrey etal., 1982), oedema (Bonnet et al, 1981), increased vascular (Humphrey et al, 1984) and glomerular permeability (Camussi et al, 1984), bronchoconstriction (Vergaftig et al, 1980) and hypotension (Blank et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

Effectiveness and tolerability of CV‐3988, a selective PAF antagonist, after intravenous administration to man.

Arnout

Hecken

Lepeleire

et al. 1988

Brit J Clinical Pharma

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1 The efficacy and tolerability of CV-3988, a selective PAF antagonist with structural analogies with PAF, were studied after intravenous infusion in man. 2 The compound, in doses from 750 to 2,000 ,ug kg-l, significantly reduced platelet sensitivity for PAF. The threshold aggregating concentration (TAC) of PAF, expressed in % of the mean predosing value, increased in a dose dependent manner reaching 356 + 162% of the basal TAC at the end and 266 ± 123% of the basal TAC 4 h after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 h after the end of the infusion. 3 CV-3988 did not cause major side effects nor changes in blood pressure, pulse and respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and 4 h after the end of the infusion, indicating a slight haemolysis. 4 Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can safely be adminstered to man and should be useful in elucidating the role of PAF in disease.

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Antihypertensive activity of an alkyl ether analog of phosphatidylcholine

Cited by 558 publications

References 10 publications

Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor.

Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor.

Interaction of the Paf antagonist WEB 2086 and its hetrazepine analogues with human platelets and endothelial cells

Effectiveness and tolerability of CV‐3988, a selective PAF antagonist, after intravenous administration to man.

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