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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the role of platelet-activating factor (1-O-hexa-decyl-2-acetyl-sn-glyceryl-phosphoryl-choline, PAF) in myocardial ischemic and reperfusion-induced injury, the effects of a PAF receptor antagonist (WEB 2086) were studied in an anesthetized canine model of ischemia (90 min) and reperfusion (6 h). Thirty minutes after onset of ischemia, WEB 2086 was administered as a bolus (20 mg/kg intravenously, i.v.) followed by a continuous 6-h infusion (10 mg/kg/h i.v.). Controls received vehicle alone (0.9% saline). Platelet aggregation was studied at baseline and at 1, 2, 4, and 6 h of drug administration and at the end of the reperfusion period. WEB 2086 treatment did not significantly affect platelet aggregation stimulated by ADP or arachidonic acid (AA). After 1 h of drug infusion, the ex vivo aggregatory response to exogenous (200 nM) PAF was ablated in WEB 2086-treated animals. WEB 2086 administration did not affect heart rate (HR) or mean arterial blood pressure (MAP) during the occlusion or reperfusion phases. During reperfusion of the ischemic tissue, left circumflex coronary artery (LCX) blood flow of WEB 2086-treated animals increased (p < 0.05) above control value. The area of the left ventricle at risk of infarct was not different between control and WEB 2086-treated groups. Infarct size was not significantly reduced in WEB 2086-treated animals. The results of our investigation using a 90-min ischemic period followed by 6-h reperfusion show that pharmacologic antagonism of PAF by WEB 2086 does not protect the heart against ischemia and reperfusion-induced injury.
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PMID:Inhibition of platelet-activating factor fails to limit ischemia and reperfusion-induced myocardial damage. 128 5

The biologically active lipid platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine; PAF) is a mediator of inflammatory and immune responses, and it accumulates in the brain during convulsions or ischemia. We have examined whether PAF may play a second messenger role in the central nervous system by studying effects on synaptic transmission in cultured hippocampal neurons. Carbamyl-PAF, a nonhydrolyzable PAF analog with a similar pharmacologic profile, augmented glutamate-mediated, evoked excitatory synaptic transmission and increased the frequency of spontaneous miniature excitatory synaptic events without increasing their amplitude or altering their time course. This compound had no significant effect on gamma-aminobutyric acid-mediated inhibitory synaptic responses. Lyso-PAF, the biologically inactive metabolic intermediate, had no effect on synaptic transmission. Moreover, the enhancement of excitatory synaptic transmission by carbamyl-PAF was blocked by a PAF receptor antagonist. These results indicate a specific presynaptic effect of PAF in enhancing excitatory synaptic transmission in cultured rat hippocampal neurons.
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PMID:Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. 133 22

Recent research was shown that oxygen-derived free radicals are involved in the pathogenesis of various diseases, including ischemia-reperfusion injury. We have also reported that oxygen-derived free radicals and lipid peroxidation may play an important role in gastric mucosal injury induced by ischemia-reperfusion. The hypoxanthine-xanthine oxidase system and neutrophils are considered important sources of oxygen-derived free radicals in this process. In recent years, it also has been shown that serum platelet-activating factor (PAF) levels increased during ischemia-reperfusion, and that induction of superoxide generation by neutrophils is one of the important biological effects of PAF. In the present study, we examined the effect of CV-6209, a specific PAF receptor antagonist, on gastric mucosal injury induced by ischemia-reperfusion, to shed some light on the possible involvement of PAF in such lesions. CV-6209 significantly attenuated the gastric mucosal injury induced by ischemia-reperfusion, and inhibited both an increase of thiobarbituric acid reactive substances and a decrease of alpha-tocopherol in gastric mucosa after ischemia-reperfusion. However, CV-6209 had no effect on gastric mucosal blood flow during ischemia-reperfusion. These results suggest that endogenous PAF may play an important role in gastric mucosal injury induced by ischemia-reperfusion, and that CV-6209 exerts its beneficial effect mainly by inhibiting neutrophil superoxide production induced by PAF.
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PMID:Effects of a platelet-activating factor antagonist, CV-6209, on gastric mucosal lesions induced by ischemia-reperfusion. 148 54

The purpose of this study was to evaluate the role of platelet-activating factor (PAF) in cardiac dysfunctions occurring in ischemic isolated rabbit heart reperfused in the presence of polymorphonuclear neutrophils (PMN) and platelets (PLT). In a first set of experiments two different PAF-receptor antagonists were used to investigate the role of endogenous PAF released in the coronary vessels of post-ischemic heart. Mechanical and electrical dysfunctions occurring during reperfusion of ischemic heart were worsened in the presence of both PMN and PLT. Co-operation between PMN and PLT was suggested by the absence of effect when reperfusion was done with PMN alone, and by the significant enhancement of the effect of PLT after addition of PMN. The activation of PMN and PLT was mediated by PAF, since it was prevented by receptor antagonists SDZ 63-675 (3 x 10(-6)M) and WEB 2170 (3 x 10(-6)M). In a second set of experiments, the infusion of PAF in non-ischemic rabbit heart perfused with PMN and PLT was used to evaluate whether PAF can induce PMN-PLT interaction and reproduce the effects of ischemia. In this condition, the infusion of synthetic PAF (1 x 10(-7)M) induced mechanical and electrical dysfunctions similar to that occurring during reperfusion. The protective effect of both PAF receptor antagonists (SDZ 63-675 and WEB 2170) and of a leukotrienes receptor antagonist (FPL 55712, 1 x 10(-6)M) suggested that PAF is the mediator that triggers the co-operation between PMN and PLT, while leukotrienes produced by these cells are the final effector of cardiac dysfunction. In conclusion, these results suggested that PAF released during reperfusion of ischemic rabbit heart may amplify mechanical and electrical dysfunctions by triggering PMN-PLT co-operation.
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PMID:Platelet-activating factor (PAF) induces platelet/neutrophil co-operation during myocardial reperfusion. 158 99

The effects of platelet-activating factor (PAF) on prostanoid release during mesenteric ischemia-reperfusion-induced shock were investigated in anesthesized dogs 1) by measuring plasma levels of prostaglandin (PG)F2 alpha, 6-keto-PGF1 alpha and thromboxane (TX)B2 in the superior mesenteric vein during reperfusion following 2 hr occlusion of the superior mesenteric artery; 2) by monitoring the effects of BN 52021, a specific PAF receptor antagonist and indomethacin on hemodynamic parameters and prostanoid levels; and 3) by studying circulatory responses to PAF and PGF2 alpha injected into the superior mesenteric vein in the presence of BN 52021 or indomethacin. Restoration of the blood flow following 2 hr ischemia resulted in an immediate dramatic decrease in mean arterial blood pressure, with a concomitant increase in mean portal venous pressure, hematocrit values, and plasma prostanoid levels. Pretreatment of the animals either with BN 52021 (4 mg.kg-1) or indomethacin (2 mg.kg-1 plus 3 mg.kg-1hr-1) prevented the circulatory collapse and the increase in prostanoid levels during reperfusion. Administration of exogenous PAF (0.1 micrograms.kg-1) or PGF2 alpha (10 micrograms.kg-1) into the superior mesenteric vein evoked hypotension similar to that observed during reperfusion. Pretreatment of the animals with BN 52021 completely prevented the effects of PAF but failed to modify the responses to PGF2 alpha. Indomethacin at a dose that inhibited prostanoid formation was highly effective to attenuate the hypotensive response to exogenous PAF. These data suggest that prostanoid formation may be secondary to PAF release in circulatory collapse evoked by intestinal ischemia-reperfusion and give further support to the notion of the importance of PAF prostanoid interaction during ischemia-reperfusion-induced shock.
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PMID:Interactions between platelet-activating factor and prostanoids during mesenteric ischemia-reperfusion-induced shock in the anesthetized dog. 174 56

Reperfusion of the ischemic mesenterium is frequently followed by acute circulatory collapse. This review focuses on the possible role of platelet-activating factor (PAF) in ischemia-induced damage. It provides evidence that (i) PAF concentrations are elevated in the mesenteric circulation following temporary ischemia; (ii) administration of exogenous PAF into the superior mesenteric vein mimics many events observed during reperfusion; and (iii) pretreatment of the experimental animals with specific PAF receptor antagonists prevent the circulatory collapse. These findings suggest that PAF may play an important role in the development of circulatory collapse caused by mesenteric ischemia-reperfusion.
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PMID:Significance of platelet-activating factor in mesenteric ischemia-reperfusion. 181 28

Platelet-activating factor (PAF) is an unusually potent lipid autacoid with a variety of biological activities. The growing body of evidence suggests that PAF might play an important role in modulation of central nervous system function, particularly during ischemia- and trauma-induced neuronal damage. However, the mechanisms involved in PAF actions on neuronal or other brain cells is virtually unknown. Therefore, this study was designed to characterize PAF receptor-mediated cellular signal transduction in neurohybrid NG108-15 cells with the aid of a new potent PAF antagonist, BN 50739. PAF induced an immediate and concentration-dependent increase in [Ca++]i with an EC50 of 6.8 nM. PAF-induced [Ca++]i mobilization was inhibited by several structurally unrelated PAF antagonists such as BN 50739, WEB 2086, SRI 63-441 and BN 52021, in a dose-dependent manner with IC50 values of 4.8, 6.9, 809 and 98500 nM, respectively. The calcium channel blockers nifedipine (5 microM) and diltiazem (10 microM) had no effect on the PAF-induced increase in [Ca++]i, but omission of CA++ from the incubation buffer caused an 82% reduction of PAF-induced [Ca++]i elevation; the remainder contributed from intracellular sources was completely inhibited by 10 microM TMB-8, an intracellular Ca++ blocker. NG108-15 cells exhibited homologous desensitization to sequential addition of PAF, but no heterologous desensitization between PAF and other agonists such as bradykinin, endothelin, angiotensin II and ATP was observed. PAF stimulated phosphoinositide metabolism in a dose-dependent manner with an EC50 of 5.1 nM for IP3 formation, which was also inhibited by the PAF antagonist BN 50739 in a dose-dependent manner (IC50 = 3.6 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet-activating factor (PAF) receptor-mediated calcium mobilization and phosphoinositide turnover in neurohybrid NG108-15 cells: studies with BN50739, a new PAF antagonist. 185 Apr 73

The objective of this study was to determine whether platelet-activating factor (PAF) mediates the leukocyte-endothelial cell interactions elicited by ischemia/reperfusion. The rates of adherence and extravasation of leukocytes were monitored in cat mesenteric venules subjected to 60 min of ischemia (blood flow reduced to 20% of control) followed by 60 min of reperfusion. Leukocyte rolling velocity, red blood cell velocity, and vessel diameter were also measured. The experiments were performed in control (untreated) animals and in animals pretreated with one of two PAF receptor antagonists, i.e., BN 52021 or WEB 2086. The responses of venular blood flow, wall shear rate, and vessel diameter did not differ between the three groups. In the control group, 1 h of ischemia was associated with significant adherence and extravasation of leukocytes, with reperfusion greatly enhancing these responses. The rates of leukocyte adherence and extravasation during reperfusion were greatly attenuated by both PAF antagonists. Furthermore, the proportion of adherent leukocytes that ultimately extravasate during reperfusion was markedly reduced by WEB 2086. These results suggest that PAF plays an important role in mediating the adhesive interaction between circulating leukocytes and microvascular endothelium induced by ischemia/reperfusion and that the phospholipid promotes the leukocyte extravasation associated with ischemia/reperfusion.
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PMID:Role of platelet-activating factor in ischemia/reperfusion-induced leukocyte adherence. 216 41

Both platelet activating factor and eicosanoids participate in the cerebrovascular response to ischemia. Eicosanoids also modulate cerebrovascular tone under normal physiologic circumstances, but a similar role for platelet activating factor has not been investigated. Therefore, using 16 rats, we studied the effects of the platelet activating factor receptor blockers BN 52021 (10 mg/kg, n = 4 or 30 mg/kg, n = 2) and WEB 2086 (5 mg/kg, n = 6) on global cerebral blood flow and the cerebral metabolic rate for oxygen and compared them with the effect of indomethacin (10 mg/kg, n = 4). Neither antagonist altered cerebral blood flow (112 +/- 16 and 107 +/- 14 ml/100 g/min at baseline versus 108 +/- 16 and 105 +/- 18 ml/100 g/min after BN 52021 and WEB 2086, respectively). In contrast, indomethacin significantly (p less than 0.05) decreased cerebral blood flow from 106 +/- 8 to 69 +/- 4 ml/100 g/min. No treatment altered the cerebral metabolic rate for oxygen compared with baseline. These data suggest that in normal rat brain, concentrations of platelet activating factor, unlike those of eicosanoids, are subthreshold and do not modulate cerebral blood flow or the cerebral metabolic rate for oxygen.
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PMID:Endogenous platelet activating factor does not modulate blood flow and metabolism in normal rat brain. 230 70

PAF is a phospholipid formed from the action of phospholipase A2 upon cellular membranes in response to immunologic or hypoxic stimuli. PAF does not exist in its active form as a storage product within cells, but is synthesized rapidly after phospholipase A2 activation. A potent lipid released by multiple cell types in mammalian systems, the emerging perspective is that PAF is a major endogenous mediator influencing the pathogenesis and outcome of ischemia and conditions of circulatory shock. These effects appear to be especially relevant to the syndrome of MSOF during critical illness. All of the major criteria for validation of a shock factor have been fulfilled for PAF. First, PAF has been measured in biological fluid of animals during shock states, although this is not an easy task since PAF is formed in minute amounts and is rapidly metabolized. Nevertheless, combinations of high pressure liquid chromatography (HPLC) and bioassay methods employing washed rabbit platelets have been successfully utilized in this regard. Second, synthetic PAF has been injected into cell suspensions, isolated tissues, and live animals, where it produces most of the effects attributed to endogenous PAF released by immunologic or hypoxic stimuli. These studies have shown that PAF exerts a variety of pathophysiologic actions, including (1) cardiodepression (that is, a negative inotropic effect), (2) reductions in systemic blood pressure, (3) leakage of fluid from the microvasculature, (4) bronchoconstriction, and (5) platelet aggregation. All of these actions of PAF can initiate or exacerbate shock and ischemic injury in multiple organ systems. Third, specific PAF receptor antagonists have been found to markedly attenuate the severity of endotoxic, anaphylactic, hemorrhagic, and traumatic shock, as well as acute myocardial ischemia. In all these conditions, a variety of PAF receptor antagonists (including PAF analogues and structurally dissimilar substances) have improved survival and have retarded pathophysiologic processes believed to be important in causing tissue injury. These processes include lysosomal membrane damage and proteolysis. Moreover PAF receptor antagonists attenuate the release of secondary toxic factors in shock, such as myocardial depressant factor. Thus, administration of specific PAF receptor antagonists early in the course of circulatory shock and organ ischemia may prove to be useful therapeutic agents in a variety of life-threatening disorders. In addition to having direct actions, PAF appears to function as a pivotal agent in a chain of mediators producing tissue injury. Recent evidence suggests that tumor necrosis factors (i.e., cachectin) stim
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PMID:Induction of tissue injury and altered cardiovascular performance by platelet-activating factor: relevance to multiple systems organ failure. 265 Aug 21


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