Platelet-Activating Factor Antagonism Attenuates Platelet and Neutrophil Activation and Reduces Myocardial Injury during Coronary Reperfusion

Ko, Wilson; Lang, D; Hawes, A S; Zelano, John A.; Isom, O. Wayne; Krieger, Karl H.

doi:10.1006/jsre.1993.1176

Cited by 31 publications

(13 citation statements)

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“…Negative effects of PAF can be mediated either by the generation of secondary mediators, or through the activation of inflammatory cells like platelets and neutrophils (67). For example, it was demonstrated that administration of a specific PAF receptor antagonist immediately before reflow in an intact sheep model reduces myocardial reperfusion injury—an impact which was partially attributed to its anti-platelet effect (44). Furthermore, PAF has been shown to stimulate NHE1 in neutrophils and platelets (63, 71).…”

Section: Mediators Released By Plateletsmentioning

confidence: 99%

Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

2019

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Obstruction of a coronary artery causes ischemia of heart tissue leading to myocardial infarction. Prolonged oxygen deficiency provokes tissue necrosis, which can result in heart failure and death of the patient. Therefore, restoration of coronary blood flow (reperfusion of the ischemic area) by re-canalizing the affected vessel is essential for a better patient outcome. Paradoxically, sudden reperfusion also causes tissue injury, thereby increasing the initial ischemic damage despite restoration of blood flow (=ischemia/reperfusion injury, IRI). Myocardial IRI is a complex event that involves various harmful mechanisms (e.g., production of reactive oxygen species and local increase in calcium ions) as well as inflammatory cells and signals like chemokines and cytokines. An involvement of platelets in the inflammatory reaction associated with IRI was discovered several years ago, but the underlying mechanisms are not yet fully understood. This mini review focusses on platelet contributions to the intricate picture of myocardial IRI. We summarize how upregulation of platelet surface receptors and release of immunomodulatory mediators lead to aggravation of myocardial IRI and subsequent cardiac damage by different mechanisms such as recruitment and activation of immune cells or modification of the cardiac vascular endothelium. In addition, evidence for cardioprotective roles of distinct platelet factors during IRI will be discussed.

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Section: Mediators Released By Plateletsmentioning

confidence: 99%

Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

2019

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“…Much of the evidence implicating the role of PAF in I/R injury has been acquired through the use of PAF antagonists. PAF antagonists used in in vivo models of I/R have proved to be cardioprotective, as indicated in functional measurements such as pressure-volume loops in swine, 11 dP/dt in sheep, 12 and systolic developed pressure in rabbits. 13 Their use has also resulted in reduction of infarct size in the reperfused myocardium and inhibition of reperfusion-induced coronary artery vasoconstriction.…”

Section: Morgan Et Al Paf-ah Reduces Ischemia-reperfusion Injury Ii-367mentioning

confidence: 99%

Platelet-Activating Factor Acetylhydrolase Prevents Myocardial Ischemia-Reperfusion Injury

Morgan

Boyle²,

Wang³

et al. 1999

Circulation

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Background-Platelet-activating factor (PAF) is one of the most potent biological mediators of tissue injury. PAF acetylhydrolase (PAF-AH) is a recently isolated naturally occurring enzyme that hydrolyzes PAF and renders it inactive. We hypothesize that inhibition of PAF with PAF-AH will reduce myocardial ischemia-reperfusion (I/R) injury in vivo. Methods and Results-The coronary ligation model was used in New Zealand white rabbits. The large branch of the marginal coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. Fifteen minutes before reperfusion, animals were given either 2 mg/kg of vehicle or of PAF-AH. At the completion of 120 minutes of reperfusion, percentage of necrosis, degree of neutrophil infiltration, and measurements of regional contractility were assessed. Data are expressed as the meanϮSEM and compared by Student's t test or Mann-Whitney ANOVA. Both groups of animals showed an equivalent area at risk; however, 46.7Ϯ11% was necrotic in the animal treated with vehicle. In contrast, 20.9Ϯ7.0% was necrotic in the animals treated with PAF-AH (PϽ0.05). Systolic shortening and wall thickness were significantly greater in those animals treated with PAF-AH at 15, 30, 60, and 120 minutes of reperfusion (PϽ0.05). Quantification of neutrophil infiltration showed a 62% reduction in the PAF-AH treated animals compared with those treated with vehicle alone. Conclusions-PAF-AH

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“…However, Lp‐PLA 2 is also involved in the degradation of Platelet Activating Factor, a substance that augments IR‐injury in various animal models. This action of dipyridamole could therefore have offset the potential benefit of augmented adenosine signaling to prevent cardiac IR‐injury …”

Section: Discussionmentioning

confidence: 99%

Effect of dipyridamole on myocardial reperfusion injury: A double‐blind randomized controlled trial in patients undergoing elective coronary artery bypass surgery

Messaoudi

Wouters

Swieten

et al. 2015

Clin Pharma and Therapeutics

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Dipyridamole reduces reperfusion-injury in preclinical trials and may be beneficial in patients undergoing coronary angioplasty, but its effect on patients undergoing coronary artery bypass grafting (CABG) is unknown. We hypothesized that dipyridamole limits myocardial reperfusion-injury in patients undergoing CABG. The trial design was a double-blind trial randomizing between pretreatment with dipyridamole or placebo. In all, 94 patients undergoing elective on-pump CABG were recruited between February 2010 and June 2012. The primary endpoint was plasma high-sensitive (hs-) troponin-I at 6, 12, and 24 hours after reperfusion. Secondary endpoints were the occurrence of bleeding, arrhythmias, need for inotropic support, and intensive care unit length of stay. Finally, 79 patients (33 dipyridamole) were included in the per-protocol analysis. Dipyridamole did not significantly affect postoperative hs-troponin-I (change in plasma hs-troponin I 23% [95% confidence interval 223% to 36%]; P > 0.1). Secondary endpoints did not differ between groups. Dipyridamole prior to CABG does not significantly reduce postoperative hs-troponin release. Study Highlights• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? þ During cardiac surgery, myocardial ischemia and reperfusion injury occurs, which is associated with worse patient outcome. The endogenous nucleoside adenosine increases intrinsic myocardial resistance against ischemia and reperfusion. In preclinical studies, ischemia-reperfusion injury can be reduced by drugs that increase the endogenous adenosine concentration, including the adenosine uptake inhibitor dipyridamole. WHAT QUESTION DID THIS STUDY ADDRESS? þ Whether this approach translates into reduced myocardial injury in the clinical setting in patients undergoing coronary artery bypass surgery is currently unknown. We now addressed this question in a double-blinded randomized placebo-controlled study in this patient group. WHAT THIS STUDY ADDS TO OUR KNOWLEDGE þ We showed that pretreatment with dipyridamole did not reduce myocardial injury, as assessed by postoperative plasma troponin levels. Our results, therefore, demonstrate that, in contrast to preclinical studies, dipyridamole cannot be used to limit myocardial injury during cardiac surgery in the clinical setting. HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY AND THERAPEUTICS þ These findings fuel the continuing search for pharmacological strategies aimed at improving patient outcomes in the setting of myocardial ischemia.

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Platelet-Activating Factor Antagonism Attenuates Platelet and Neutrophil Activation and Reduces Myocardial Injury during Coronary Reperfusion

Cited by 31 publications

References 0 publications

Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

Platelet-Activating Factor Acetylhydrolase Prevents Myocardial Ischemia-Reperfusion Injury

Effect of dipyridamole on myocardial reperfusion injury: A double‐blind randomized controlled trial in patients undergoing elective coronary artery bypass surgery

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