Human thrombocytes are able to induce a myocardial dysfunction in the ischemic and reperfused guinea pig heart mediated by free radicals-role of the GPIIb/IIIa-blocker tirofiban

Seligmann, C. G.; Simsek, Yusuf; Schimmer, M; Leitsch, Tobias; Böck, Andreas; Schultheiss, Heinz‐Peter

doi:10.1016/s0024-3205(02)02021-0

Cited by 8 publications

(9 citation statements)

References 19 publications

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“…Yet, another study confirmed the adverse effect of GPIIb/IIIa dependent intracoronary platelet retention during low flow ischemia on cardiac function using the GPIIb/IIIa inhibitor tirofiban. This was partially attributed to tirofiban-induced blockage of platelet adherence to the vessel wall mediated by an interaction of the GPIIb/IIIa-receptor and von Willebrand-factor (56). However, in this study no GPIIb/IIIa effect on cardiac function was observed during the reperfusion phase (56), suggesting that conflicting results between studies might at least partially be based on different time points of inhibitor application during the course of IRI, especially since platelet adhesion to reperfused endothelium and platelet-mediated myocardial damage have been described to occur very early after reperfusion (48).…”

Section: Platelet Membrane Proteins In Irimentioning

confidence: 99%

“…Coapplication of the radical scavenger enzyme superoxide dismutase improved REHW during reperfusion indicating a role of ROS in the provoked IRI. Interestingly, by coapplication of the GPIIb/IIIa-blocker tirofiban the authors could show that the platelet-induced ROS-dependent myocardial dysfunction in their experimental model was independent of intracoronary platelet adhesion (49, 56, 66). In a follow up study, by applying a platelet pretreatment with diphenyliodonium chloride Seligmann et al elegantly proved that the shown cardiodepressive effects were mediated by ROS released from platelets and not the heart itself (49).…”

Section: Mediators Released By Plateletsmentioning

confidence: 99%

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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: Platelet Membrane Proteins In Irimentioning

confidence: 99%

Section: Mediators Released By Plateletsmentioning

confidence: 99%

Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

2019

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“…Platelets are able to exhibit some direct cardiodepressive effects independent of thrombus formation or compromisation of blood-flow in microcirculation [7]. These effects could not completely be prevented by administration of strong antiaggregatory substances like the GPIIb/IIIa-blocker tirofiban [9]. However, coadministration of superoxide dismutase (SOD), an enzyme catalyzing the formation of H 2 O 2 out of superoxide showed a cardioprotective effect, under these condition [8].…”

Section: Discussionmentioning

confidence: 99%

“…These ROS are able to induce an ischemia-and reperfusion injury in isolated working guinea pig hearts. Because strong anti-platelet treatments like tirofiban, as clinically used in acute coronary syndrome, were not effective in this setting [9], there might be a new approach to develop further treatment concepts in acute coronary syndrome.…”

Section: Discussionmentioning

confidence: 99%

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A myocardial ischemia- and reperfusion-induced injury is mediated by reactive oxygen species released from blood platelets

et al. 2012

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In recent experimental studies, blood platelets have been found to exhibit some cardiodepressive effects in ischemic and reperfused guinea pig hearts independent of thrombus formation. These effects seemed to be mediated by reactive oxygen species (ROS). However, the source of these ROS - platelets or heart - remained still unknown. Isolated, buffer-perfused and pressure-volume work performing guinea pig hearts were exposed to a low-flow ischemia (1 ml/min) of 30 min duration and reperfused at a constant flow of 5 ml/min. Human thrombocytes were administered as 1 min bolus (20 000 thrombocytes/µl perfusion buffer) in the 15th min of ischemia or in the 1st or 5th min of reperfusion in the presence of thrombin (0.3 U/ml perfusion buffer). Recovery of external heart work (REHW) was expressed as ratio between postischemic and preischemic EHW in percent. Intracoronary platelet retention (RET) was quantified as percent of platelets applied. In a second set of experiments, thrombocytes were incubated with 10 µM of the irreversible NADPH oxidase blocker diphenyliodonium chloride and washed twice, thereafter, and administered according to the same protocol as described above. Hearts exposed to ischemia and reperfusion in the presence of thrombin but without application of platelets served as controls. Controls without application of platelets did not reveal a severe compromisation of myocardial function (REHW 85.5 ± 1%). However, addition of platelets during ischemia or in the 1st or 5th min of reperfusion led to a significant reduction of REHW as compared with controls (REHW 62.4 ± 6, 53.9 ± 3, 40.5 ± 3, respectively). Application of platelets pretreated with diphenyliodonium chloride did not reveal any cardiodepressive effects being significantly different from controls without platelet application. Moreover, treatment of platelets with diphenyliodonium chloride did not significantly decrease intracoronary platelet retention. In conclusion, these results demonstrate that cardiodepressive effects of human thrombocytes in ischemic and reperfused guinea pig hearts are mediated by ROS released from thrombocytes and not the heart.

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BMS-191095, a cardioselective mitochondrial katp opener, inhibits human platelet aggregation by opening mitochondrial katp channels

et al. 2005

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We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium channel openers (K(ATP) openers) on washed human platelets, and the study's emphasis was on the role of mitochondrial K(ATP) in platelet aggregation. Collagen-induced platelet aggregation was inhibited in a dose dependent manner by lemakalim and SKP-450, which are potent cardio-nonselective K(ATP) openers, and also by cardioselective BMS-180448 and BMS-191095 (IC50: 1,130, >1,500, 305.3 and 63.9 microM, respectively), but a significantly greater potency was noted for the cardioselective K(ATP) openers. The latter two K(ATP) openers also inhibited platelet aggregation induced by thrombin, another important blood-borne platelet activator, with similar rank order of potency (IC50: 498.0 and 104.8 microM for BMS-180448 and BMS-191095, respectively). The inhibitory effects of BMS-191095 on collagen-induced platelet aggregation were significantly blocked by a 30-min pretreatment of platelets with glyburide (1 microM) or sodium 5-hydroxydecanoate (5-HD, 100 microM), a nonselective and selective mitochondrial K(ATP) antagonist, respectively, at similar magnitudes; this indicates the role of mitochondrial K(ATP) in the antiplatelet activity of BMS-191095. However, glyburide and 5-HD had no effect when they were added to the platelet cuvette immediately prior to the addition of BMS-191095. These findings indicate that cardioselective mitochondrial K(ATP) openers like BMS-191095 are able to exert cardioprotective effects in cardiac ischemia/reperfusion injury via dual mechanisms directed at the inhibition of platelet aggregation and the protection of cardiomyocytes, and both these mechanisms are mediated by mitochondrial K(ATP).

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Human thrombocytes are able to induce a myocardial dysfunction in the ischemic and reperfused guinea pig heart mediated by free radicals-role of the GPIIb/IIIa-blocker tirofiban

Cited by 8 publications

References 19 publications

Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

Platelet Contributions to Myocardial Ischemia/Reperfusion Injury

A myocardial ischemia- and reperfusion-induced injury is mediated by reactive oxygen species released from blood platelets

BMS-191095, a cardioselective mitochondrial katp opener, inhibits human platelet aggregation by opening mitochondrial katp channels

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