Stereospecific activity of 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine and comparison of analogs in the degranulation of platelets and neutrophils

Wykle, Robert L.; Miller, Claudia; Lewis, Jon C.; Schmitt, Jens; Smith, Jennie A.; Surles, Jefferson R.; Piantadosi, Claude A.; O’Flaherty, Joseph T.

doi:10.1016/0006-291x(81)90708-7

Cited by 99 publications

(22 citation statements)

References 11 publications

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“…C-PAF was 5 times less potent than PAF (O'Flaherty et al, 1987). E-PAF was about 100 times less potent than PAF in releasing 5-hydroxytryptamine from rabbit platelets and required 10 times more in degradation and desensitization of human neutrophils (Wykle et al, 1981). These potency ratios are similar to that observed in the perfused heart.…”

Section: Discussionsupporting

confidence: 68%

Similar coronary vascular effects in the rat perfused heart of platelet‐activating factor structural analogues with agonist and antagonist properties

Man

Kinnaird

1995

British J Pharmacology

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1 Selective blockade of platelet-activating factor (PAF) receptor subtypes by PAF receptor antagonists has been demonstrated. However, selective activation of PAF receptor subtypes by PAF receptor agonists has not been reported. 2 When structural analogues of PAF that have been shown to possess either agonist or antagonist effects were administered by a bolus injection in the rat perfused heart, they all showed agonist effects. Lower amounts produced vasodilatation while higher amounts produced vasodilatation followed by vasoconstriction. These coronary vascular effects were typical of that observed with PAF. Lyso-PAF did not show the same typical pattern of coronary vascular effect, confirming that the detergent effect of PAF structural analogues did not play a role in the coronary vascular effects. Other PAF antagonists, CV-6209 and WEB 2170, also did not produce the PAF-like response in the rat perfused heart. 3 The coronary vascular effects of hexanolamine-PAF (H-PAF, putative antagonist) and ethanolamine-PAF (E-PAF, agonist) were further studied. Pretreatment with FR-900452 (a PAF receptor antagonist) or MK-886 (a leukotriene synthesis inhibitor) significantly reduced the vasodilator and vasoconstrictor effects of H-PAF and E-PAF. 4 Pretreatment of rat perfused hearts with low concentrations of H-PAF and E-PAF blocked the response to PAF administration in a dose-and time-dependent manner. However, the pretreatment with either H-PAF or E-PAF did not result in a coronary vascular effect expected of a PAF receptor agonist. These results were compatible with H-PAF and E-PAF behaving as PAF receptor antagonists. 5 In summary, our results demonstrate that several PAF structural analogues possess agonist action in the rat perfused heart. Like the coronary vascular effects of PAF, the effects of H-PAF and E-PAF were blocked by a PAF antagonist (FR-900452) and a leukotriene synthesis inhibitor (MK-886). This suggests that both H-PAF and E-PAF mediate their effect through activation of PAF receptors with a subsequent release of leukotrienes that produced vasodilatation and vasoconstriction. Furthermore, pretreatment of perfused hearts with these compounds blocked the response to PAF in these hearts. Thus these compounds can also behave like a PAF receptor antagonist. This latter action may be due to a gradual receptor inactivation or desensitization by the pretreatment of H-PAF and E-PAF through a PAF receptor agonist effect rather than being a PAF receptor antagonist.

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Section: Discussionsupporting

confidence: 68%

Similar coronary vascular effects in the rat perfused heart of platelet‐activating factor structural analogues with agonist and antagonist properties

Man

Kinnaird

1995

British J Pharmacology

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“…12-HETE and 15-HETE completely lack potentiating actions (50-5,000 nM). Details of these studies are given elsewhere (O'Flaherty et al, 1983b,c,d;Wykle et al, 1981Wykle et al, , 1982. Thus, PAF, LTB4, and 5-HETE have additive and potentiating interactions that produce prominent responses at relatively low concentrations (e.g., see solid bars of Fig.…”

Section: Lipid-induced Degranulationmentioning

confidence: 98%

Neutrophil degranulation: Evidence pertaining to its mediation by the combined effects of leukotriene B₄, platelet‐activating factor, and 5‐HETE

O’Flaherty

1985

Journal Cellular Physiology

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Stimulus-activated polymorphonuclear neutrophils (PMN) produce leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoate (5-HETE), and platelet-activating factor (PAF). Each of these lipids promotes PMN degranulation; in combination they have additive and potentiating effects that result in prominent degranulation responses at relatively low concentrations. Thus, the combined interactions of LTB4, 5-HETE, and PAF may mediate responses in PMN activated by other stimuli. This possibility was examined by measuring the responses of PMN made insensitive to one or more of these lipids. Cells were pretreated with LTB4, 5-HETE, and/or PAF for 8 min; exposed for 2 min to cytochalasin B (which is required for lipid-induced degranulation); and then challenged. PMN challenged with only buffer released minimal amounts of granule-bound enzymes. Furthermore, the lipid-pretreated cells were hyporesponsive to challenge with 1) various combinations of these same lipids or 2) ionophore A23187. The relative potencies of the lipids in producing hyporesponsiveness to themselves or A23187 were: 5-HETE less than PAF less than or equal to LTB4 less than PAF + LTB4 less than PAF + LTB4 + 5-HETE. For both types of challenge, reduced responsiveness occurred in cells pretreated with greater than 0.1 nM LTB4 and/or greater than 0.2 nM PAF, persisted in cells washed after lipid pretreatment, and did not develop in cells pretreated with various combinations of bioinactive structural analogues of the lipids. Thus, PAF, LTB4, and 5-HETE interacted to desensitize PMN, and the degranulating actions of A23187 required cells that were fully responsive to each of the three lipids. This supports the concept that the lipids act together in mediating certain of the ionophore's effects. However, lipid-desensitized PMN degranulated fully when challenged with C5a, a formylated oligopeptide, or phorbol myristate acetate. Degranulation responses, therefore, may proceed through various pathways, only some of which involve the lipid products studied here.

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“…The mechanism by which PAF activates target cells is ofinterest. Based on the phospholipids striking biological potency, its stereospecificity, and its ability to desensitize target cells, we suggested that cellular receptors were involved in transducing bioactivity (30)(31)(32). Subsequent studies have indeed demonstrated specific binding sites for PAF in or on platelets, PMN, and smooth muscle-containing tissues (33)(34)(35)(36) while other studies have identified compounds that competitively inhibit PAF binding and bioactions (37)(38)(39).…”

Section: Introductionmentioning

confidence: 98%

Binding and metabolism of platelet-activating factor by human neutrophils.

O’Flaherty¹,

Surles²,

Redman³

et al. 1986

J. Clin. Invest.

166

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Stereospecific activity of 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine and comparison of analogs in the degranulation of platelets and neutrophils

Cited by 99 publications

References 11 publications

Similar coronary vascular effects in the rat perfused heart of platelet‐activating factor structural analogues with agonist and antagonist properties

Similar coronary vascular effects in the rat perfused heart of platelet‐activating factor structural analogues with agonist and antagonist properties

Neutrophil degranulation: Evidence pertaining to its mediation by the combined effects of leukotriene B₄, platelet‐activating factor, and 5‐HETE

Binding and metabolism of platelet-activating factor by human neutrophils.

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Stereospecific activity of 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine and comparison of analogs in the degranulation of platelets and neutrophils

Cited by 99 publications

References 11 publications

Similar coronary vascular effects in the rat perfused heart of platelet‐activating factor structural analogues with agonist and antagonist properties

Similar coronary vascular effects in the rat perfused heart of platelet‐activating factor structural analogues with agonist and antagonist properties

Neutrophil degranulation: Evidence pertaining to its mediation by the combined effects of leukotriene B4, platelet‐activating factor, and 5‐HETE

Binding and metabolism of platelet-activating factor by human neutrophils.

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Neutrophil degranulation: Evidence pertaining to its mediation by the combined effects of leukotriene B₄, platelet‐activating factor, and 5‐HETE